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Alzheimer's disease (AD) is a neurodegenerative disorder that is beginning with amyloidosis, followed by neuronal loss and deterioration in structure, function, and cognition. The accumulation of amyloid-beta in the brain, measured through 18F-florbetapir (AV45) positron emission tomography (PET) imaging, has been widely used for early diagnosis of AD. However, the relationship between amyloid-beta accumulation and AD pathophysiology remains unclear, and causal inference approaches are needed to uncover how amyloid-beta levels can impact AD development. In this paper, we propose a graph varying coefficient neural network (GVCNet) for estimating the individual treatment effect with continuous treatment levels using a graph convolutional neural network. We highlight the potential of causal inference approaches, including GVCNet, for measuring the regional causal connections between amyloid-beta accumulation and AD pathophysiology, which may serve as a robust tool for early diagnosis and tailored care.

Brain networks can be defined and explored through their connectivity. Here, we analyzed the relationship between structural connectivity (SC) across 2,514 regions that cover the entire brain and brainstem, and their dynamic functional connectivity (DFC). To do so, we focused on a combination of two metrics: the first assesses the degree of SC-DFC similarity and the second is the intrinsic variability of the DFC networks over time. Overall, we found that cerebellar networks have a smaller DFC variability than other networks in the brain. Moreover, the internal structure of the cerebellum could be clearly divided in two distinct posterior and anterior parts, the latter also connected to the brainstem. The mechanism to maintain small variability of the DFC in the posterior part of the cerebellum is consistent with another of our findings, namely, that this structure exhibits the highest SC-DFC similarity relative to the other networks studied. By contrast, the anterior part of the cerebellum also exhibits small DFC variability but it has the lowest SC-DFC similarity, suggesting a different mechanism is at play. Because this structure connects to the brainstem, which regulates sleep cycles, cardiac and respiratory functioning, we suggest that such critical functionality drives the low variability in the DFC. Overall, the low variability detected in DFC expands our current knowledge of cerebellar networks, which are extremely rich and complex, participating in a wide range of cognitive functions, from movement control and coordination to executive function or emotional regulation. Moreover, the association between such low variability and structure suggests that differentiated computational principles can be applied in the cerebellum as opposed to other structures, such as the cerebral cortex., Comment: 19 pages, 6 figures

Functional networks provide a topological description of activity patterns in the brain, as they stem from the propagation of neural activity on the underlying anatomical or structural network of synaptic connections. This latter is well known to be organized in hierarchical and modular way. While it is assumed that structural networks shape their functional counterparts, it is also hypothesized that alterations of brain dynamics come with transformations of functional connectivity. In this computational study, we introduce a novel methodology to monitor the persistence and breakdown of hierarchical order in functional networks, generated from computational models of activity spreading on both synthetic and real structural connectomes. We show that hierarchical connectivity appears in functional networks in a persistent way if the dynamics is set to be in the quasi-critical regime associated with optimal processing capabilities and normal brain function, while it breaks down in other (supercritical) dynamical regimes, often associated with pathological conditions. Our results offer important clues for the study of optimal neurocomputing architectures and processes, which are capable of controlling patterns of activity and information flow. We conclude that functional connectivity patterns achieve optimal balance between local specialized processing (i.e. segregation) and global integration by inheriting the hierarchical organization of the underlying structural architecture., Comment: 5 figures. Accepted for publication in Neurocomputing

The resting brain dynamics self-organizes into a finite number of correlated patterns known as resting state networks (RSNs). It is well known that techniques like independent component analysis can separate the brain activity at rest to provide such RSNs, but the specific pattern of interaction between RSNs is not yet fully understood. To this aim, we propose here a novel method to compute the information flow (IF) between different RSNs from resting state magnetic resonance imaging. After haemodynamic response function blind deconvolution of all voxel signals, and under the hypothesis that RSNs define regions of interest, our method first uses principal component analysis to reduce dimensionality in each RSN to next compute IF (estimated here in terms of Transfer Entropy) between the different RSNs by systematically increasing k (the number of principal components used in the calculation). When k = 1, this method is equivalent to computing IF using the average of all voxel activities in each RSN. For k greater than one our method calculates the k-multivariate IF between the different RSNs. We find that the average IF among RSNs is dimension-dependent, increasing from k =1 (i.e., the average voxels activity) up to a maximum occurring at k =5 to finally decay to zero for k greater than 10. This suggests that a small number of components (close to 5) is sufficient to describe the IF pattern between RSNs. Our method - addressing differences in IF between RSNs for any generic data - can be used for group comparison in health or disease. To illustrate this, we have calculated the interRSNs IF in a dataset of Alzheimer's Disease (AD) to find that the most significant differences between AD and controls occurred for k =2, in addition to AD showing increased IF w.r.t. controls., Comment: 47 pages, 5 figures, 4 tables, 3 supplementary figures. Accepted for publication in Brain Connectivity in its current form

Elucidating the intricate relationship between brain structure and function, both in healthy and pathological conditions, is a key challenge for modern neuroscience. Recent technical and methodological progress in neuroimaging has helped advance our understanding of this important issue, with diffusion weighted images providing information about structural connectivity (SC) and functional magnetic resonance imaging shedding light on resting state functional connectivity (rsFC). However, comparing these two distinct datasets, each of which can be encoded into a different complex network, is by no means trivial as pairwise link-to-link comparisons represent a relatively restricted perspective and provide only limited information. Thus, we have adopted a more integrative systems approach, exploiting theoretical graph analyses to study both SC and rsFC datasets gathered independently from healthy human subjects. The aim is to find the main architectural traits shared by the structural and functional networks by paying special attention to their common hierarchical modular organization. This approach allows us to identify a common skeleton from which a new, optimal, brain partition can be extracted, with modules sharing both structure and function. We describe these emerging common structure-function modules (SFMs) in detail. In addition, we compare SFMs with the classical Resting State Networks derived from independent component analysis of rs-fMRI functional activity, as well as with anatomical parcellations in the Automated Anatomical Labeling atlas and with the Broadmann partition, highlighting their similitude and differences. The unveiling of SFMs brings to light the strong correspondence between brain structure and resting-state dynamics., Comment: Accepted in Nature Scientific Reports. 56 pages, 15 figures

Severe traumatic brain injury can lead to disorders of consciousness (DOC) characterized by deficit in conscious awareness and cognitive impairment including coma, vegetative state, minimally consciousness, and lock-in syndrome. Of crucial importance is to find objective markers that can account for the large-scale disturbances of brain function to help the diagnosis and prognosis of DOC patients and eventually the prediction of the coma outcome. Following recent studies suggesting that the functional organization of brain networks can be altered in comatose patients, this work analyzes brain functional connectivity (FC) networks obtained from resting-state functional magnetic resonance imaging (rs-fMRI). Two approaches are used to estimate the FC: the Partial Correlation (PC) and the Transfer Entropy (TE). Both the PC and the TE show significant statistical differences between the group of patients and control subjects; in brief, the inter-hemispheric PC and the intra-hemispheric TE account for such differences. Overall, these results suggest two possible rs-fMRI markers useful to design new strategies for the management and neuropsychological rehabilitation of DOC patients., Comment: 25 pages; 4 figures; 3 tables; 1 supplementary figure; 4 supplementary tables; accepted for publication in Frontiers in Neuroinformatics