A Novel Directed Seed-Based Connectivity Analysis Toolbox Applied to Human and Marmoset Resting-State fMRI.

Estimating the direction of functional connectivity (FC) can help to further elucidate complex brain function. However, the estimation of directed FC at the voxel level in fMRI data, and evaluating its performance, has yet to be done. We therefore developed a novel directed seed-based connectivity analysis (SCA) method based on normalized pairwise Granger causality that provides greater detail and accuracy over ROI-based methods. We evaluated its performance against 145 cortical retrograde tracer injections in male and female marmosets that were used as ground truth cellular connectivity on a voxel-by-voxel basis. The ROC curve was calculated for each injection, and we achieved AUC (Area Under the ROC Curve) of 0.95 for undirected and 0.942 for directed SCA in the case of high cell count threshold. This indicates that SCA can reliably estimate the strong cellular connections between voxels in fMRI data. We then used our directed SCA method to analyze the human default mode network (DMN) and found that dlPFC (dorsolateral prefrontal cortex) and temporal lobe were separated from other DMN regions, forming part of the language-network that works together with the core DMN regions. We also found that the cerebellum (Crus I & II) was strongly targeted by the posterior parietal cortices and dlPFC, but reciprocal connections were not observed. Thus, the cerebellum may not be a part of, but instead a target of, the DMN and language-network. Summarily, our novel directed SCA method, visualized with a new functional flat mapping technique, opens a new paradigm for whole-brain functional analysis.Significant Statement We developed a novel directed seed-based connectivity analysis (SCA) method. To evaluate its performance, we used 145 retrograde tracer injections into the common marmoset left cortex as ground truth cellular connectivity. These were compared with directed and undirected SCA on a voxel-by-voxel basis. We achieved AUC=0.95 for undirected and AUC=0.942 for directed SCA, thus SCA can estimate strong cellular connections with high accuracy. Then, we analysed the human default mode network (DMN) with directed SCA and found that the dorsolateral prefrontal cortex and temporal lobe were not part of the DMN, but part of the language network. Secondly, our analysis showed that the cerebellum may not be part of, but instead a target of, the DMN and language network.

Group Surrogate Data Generating Models and similarity quantification of multivariate time-series: A resting-state fMRI study.

Advancements in non-invasive brain analysis through novel approaches such as big data analytics and in silico simulation are essential for explaining brain function and associated pathologies. In this study, we extend the vector auto-regressive surrogate technique from a single multivariate time-series to group data using a novel Group Surrogate Data Generating Model (GSDGM). This methodology allowed us to generate biologically plausible human brain dynamics representative of a large human resting-state (rs-fMRI) dataset obtained from the Human Connectome Project. Simultaneously, we defined a novel similarity measure, termed the Multivariate Time-series Ensemble Similarity Score (MTESS). MTESS showed high accuracy and f-measure in subject identification, and it can directly compare the similarity between two multivariate time-series. We used MTESS to analyze both human and marmoset rs-fMRI data. Our results showed similarity differences between cortical and subcortical regions. We also conducted MTESS and state transition analysis between single and group surrogate techniques, and confirmed that a group surrogate approach can generate plausible group centroid multivariate time-series. Finally, we used GSDGM and MTESS for the fingerprint analysis of human rs-fMRI data, successfully distinguishing normal and outlier sessions. These new techniques will be useful for clinical applications and in silico simulation.

A reappraisal of the default mode and frontoparietal networks in the common marmoset brain.

In recent years the common marmoset homolog of the human default mode network (DMN) has been a hot topic of discussion in the marmoset research field. Previously, the posterior cingulate cortex regions (PGM, A19M) and posterior parietal cortex regions (LIP, MIP) were defined as the DMN, but some studies claim that these form the frontoparietal network (FPN). We restarted from a neuroanatomical point of view and identified two DMN candidates: Comp-A (which has been called both the DMN and FPN) and Comp-B. We performed GLM analysis on auditory task-fMRI and found Comp-B to be more appropriate as the DMN, and Comp-A as the FPN. Additionally, through fingerprint analysis, a DMN and FPN in the tasking human was closer to the resting common marmoset. The human DMN appears to have an advanced function that may be underdeveloped in the common marmoset brain.

Vector Auto-Regressive Deep Neural Network: A Data-Driven Deep Learning-Based Directed Functional Connectivity Estimation Toolbox.

An important goal in neuroscience is to elucidate the causal relationships between the brain's different regions. This can help reveal the brain's functional circuitry and diagnose lesions. Currently there are a lack of approaches to functional connectome estimation that leverage the state-of-the-art in deep learning architectures and training methodologies. Therefore, we propose a new framework based on a vector auto-regressive deep neural network (VARDNN) architecture. Our approach consists of a set of nodes, each with a deep neural network structure. These nodes can be mapped to any spatial sub-division based on the data to be analyzed, such as anatomical brain regions from which representative neural signals can be obtained. VARDNN learns to reproduce experimental time series data using modern deep learning training techniques. Based on this, we developed two novel directed functional connectivity (dFC) measures, namely VARDNN-DI and VARDNN-GC. We evaluated our measures against a number of existing functional connectome estimation measures, such as partial correlation and multivariate Granger causality combined with large dimensionality counter-measure techniques. Our measures outperformed them across various types of ground truth data, especially as the number of nodes increased. We applied VARDNN to fMRI data to compare the dFC between 41 healthy control vs. 32 Alzheimer's disease subjects. Our VARDNN-DI measure detected lesioned regions consistent with previous studies and separated the two groups well in a subject-wise evaluation framework. Summarily, the VARDNN framework has powerful capabilities for whole brain dFC estimation. We have implemented VARDNN as an open-source toolbox that can be freely downloaded for researchers who wish to carry out functional connectome analysis on their own data.