Tangent functional connectomes uncover more unique phenotypic traits.

Functional connectomes (FCs) containing pairwise estimations of functional couplings between pairs of brain regions are commonly represented by correlation matrices. As symmetric positive definite matrices, FCs can be transformed via tangent space projections, resulting into tangent-FCs. Tangent-FCs have led to more accurate models predicting brain conditions or aging. Motivated by the fact that tangent-FCs seem to be better biomarkers than FCs, we hypothesized that tangent-FCs have also a higher fingerprint. We explored the effects of six factors: fMRI condition, scan length, parcellation granularity, reference matrix, main-diagonal regularization, and distance metric. Our results showed that identification rates are systematically higher when using tangent-FCs across the "fingerprint gradient" (here including test-retest, monozygotic and dizygotic twins). Highest identification rates were achieved when minimally (0.01) regularizing FCs while performing tangent space projection using Riemann reference matrix and using correlation distance to compare the resulting tangent-FCs. Such configuration was validated in a second dataset (resting-state).

Incorporation of spatial- and connectivity-based cortical brain region information in regularized regression: Application to Human Connectome Project data.

Studying the association of the brain's structure and function with neurocognitive outcomes requires a comprehensive analysis that combines different sources of information from a number of brain-imaging modalities. Recently developed regularization methods provide a novel approach using information about brain structure to improve the estimation of coefficients in the linear regression models. Our proposed method, which is a special case of the Tikhonov regularization, incorporates structural connectivity derived with Diffusion Weighted Imaging and cortical distance information in the penalty term. Corresponding to previously developed methods that inform the estimation of the regression coefficients, we incorporate additional information via a Laplacian matrix based on the proximity measure on the cortical surface. Our contribution consists of constructing a principled formulation of the penalty term and testing the performance of the proposed approach via extensive simulation studies and a brain-imaging application. The penalty term is constructed as a weighted combination of structural connectivity and proximity between cortical areas. Simulation studies mimic the real brain-imaging settings. We apply our approach to the study of data collected in the Human Connectome Project, where the cortical properties of the left hemisphere are found to be associated with vocabulary comprehension.

Improving Functional Connectome Fingerprinting with Degree-Normalization.

Background: Functional connectivity quantifies the statistical dependencies between the activity of brain regions, measured using neuroimaging data such as functional magnetic resonance imaging (fMRI) blood-oxygenation-level dependent time series. The network representation of functional connectivity, called a functional connectome (FC), has been shown to contain an individual fingerprint allowing participants identification across consecutive testing sessions. Recently, researchers have focused on the extraction of these fingerprints, with potential applications in personalized medicine. Materials and Methods: In this study, we show that a mathematical operation denominated degree-normalization can improve the extraction of FC fingerprints. Degree-normalization has the effect of reducing the excessive influence of strongly connected brain areas in the whole-brain network. We adopt the differential identifiability framework and apply it to both original and degree-normalized FCs of 409 individuals from the Human Connectome Project, in resting-state and 7 fMRI tasks. Results: Our results indicate that degree-normalization systematically improves three fingerprinting metrics, namely differential identifiability, identification rate, and matching rate. Moreover, the results related to the matching rate metric suggest that individual fingerprints are embedded in a low-dimensional space. Discussion: The results suggest that low-dimensional functional fingerprints lie in part in weakly connected subnetworks of the brain and that degree-normalization helps uncovering them. This work introduces a simple mathematical operation that could lead to significant improvements in future FC fingerprinting studies.

A morphospace of functional configuration to assess configural breadth based on brain functional networks.

The quantification of human brain functional (re)configurations across varying cognitive demands remains an unresolved topic. We propose that such functional configurations may be categorized into three different types: (a) network configural breadth, (b) task-to task transitional reconfiguration, and (c) within-task reconfiguration. Such functional reconfigurations are rather subtle at the whole-brain level. Hence, we propose a mesoscopic framework focused on functional networks (FNs) or communities to quantify functional (re)configurations. To do so, we introduce a 2D network morphospace that relies on two novel mesoscopic metrics, trapping efficiency (TE) and exit entropy (EE), which capture topology and integration of information within and between a reference set of FNs. We use this framework to quantify the network configural breadth across different tasks. We show that the metrics defining this morphospace can differentiate FNs, cognitive tasks, and subjects. We also show that network configural breadth significantly predicts behavioral measures, such as episodic memory, verbal episodic memory, fluid intelligence, and general intelligence. In essence, we put forth a framework to explore the cognitive space in a comprehensive manner, for each individual separately, and at different levels of granularity. This tool that can also quantify the FN reconfigurations that result from the brain switching between mental states.

Toward an information theoretical description of communication in brain networks.

Modeling communication dynamics in the brain is a key challenge in network neuroscience. We present here a framework that combines two measurements for any system where different communication processes are taking place on top of a fixed structural topology: path processing score (PPS) estimates how much the brain signal has changed or has been transformed between any two brain regions (source and target); path broadcasting strength (PBS) estimates the propagation of the signal through edges adjacent to the path being assessed. We use PPS and PBS to explore communication dynamics in large-scale brain networks. We show that brain communication dynamics can be divided into three main "communication regimes" of information transfer: absent communication (no communication happening); relay communication (information is being transferred almost intact); and transducted communication (the information is being transformed). We use PBS to categorize brain regions based on the way they broadcast information. Subcortical regions are mainly direct broadcasters to multiple receivers; Temporal and frontal nodes mainly operate as broadcast relay brain stations; visual and somatomotor cortices act as multichannel transducted broadcasters. This work paves the way toward the field of brain network information theory by providing a principled methodology to explore communication dynamics in large-scale brain networks.

A Structural Connectivity Disruption One Decade before the Typical Age for Dementia: A Study in Healthy Subjects with Family History of Alzheimer's Disease.

The concept of the brain has shifted to a complex system where different subnetworks support the human cognitive functions. Neurodegenerative diseases would affect the interactions among these subnetworks and, the evolution of impairment and the subnetworks involved would be unique for each neurodegenerative disease. In this study, we seek for structural connectivity traits associated with the family history of Alzheimer's disease, that is, early signs of subnetworks impairment due to Alzheimer's disease. The sample in this study consisted of 123 first-degree Alzheimer's disease relatives and 61 nonrelatives. For each subject, structural connectomes were obtained using classical diffusion tensor imaging measures and different resolutions of cortical parcellation. For the whole sample, independent structural-connectome-traits were obtained under the framework of connICA. Finally, we tested the association of the structural-connectome-traits with different factors of relevance for Alzheimer's disease by means of a multiple linear regression. The analysis revealed a structural-connectome-trait obtained from fractional anisotropy associated with the family history of Alzheimer's disease. The structural-connectome-trait presents a reduced fractional anisotropy pattern in first-degree relatives in the tracts connecting posterior areas and temporal areas. The family history of Alzheimer's disease structural-connectome-trait presents a posterior-posterior and posterior-temporal pattern, supplying new evidences to the cascading network failure model.

Optimizing differential identifiability improves connectome predictive modeling of cognitive deficits from functional connectivity in Alzheimer's disease.

Functional connectivity, as estimated using resting state functional MRI, has shown potential in bridging the gap between pathophysiology and cognition. However, clinical use of functional connectivity biomarkers is impeded by unreliable estimates of individual functional connectomes and lack of generalizability of models predicting cognitive outcomes from connectivity. To address these issues, we combine the frameworks of connectome predictive modeling and differential identifiability. Using the combined framework, we show that enhancing the individual fingerprint of resting state functional connectomes leads to robust identification of functional networks associated to cognitive outcomes and also improves prediction of cognitive outcomes from functional connectomes. Using a comprehensive spectrum of cognitive outcomes associated to Alzheimer's disease (AD), we identify and characterize functional networks associated to specific cognitive deficits exhibited in AD. This combined framework is an important step in making individual level predictions of cognition from resting state functional connectomes and in understanding the relationship between cognition and connectivity.

Geodesic Distance on Optimally Regularized Functional Connectomes Uncovers Individual Fingerprints.

Background: Functional connectomes (FCs) have been shown to provide a reproducible individual fingerprint, which has opened the possibility of personalized medicine for neuro/psychiatric disorders. Thus, developing accurate ways to compare FCs is essential to establish associations with behavior and/or cognition at the individual level. Methods: Canonically, FCs are compared using Pearson's correlation coefficient of the entire functional connectivity profiles. Recently, it has been proposed that the use of geodesic distance is a more accurate way of comparing FCs, one which reflects the underlying non-Euclidean geometry of the data. Computing geodesic distance requires FCs to be positive-definite and hence invertible matrices. As this requirement depends on the functional magnetic resonance imaging scanning length and the parcellation used, it is not always attainable and sometimes a regularization procedure is required. Results: In the present work, we show that regularization is not only an algebraic operation for making FCs invertible, but also that an optimal magnitude of regularization leads to systematically higher fingerprints. We also show evidence that optimal regularization is data set-dependent and varies as a function of condition, parcellation, scanning length, and the number of frames used to compute the FCs. Discussion: We demonstrate that a universally fixed regularization does not fully uncover the potential of geodesic distance on individual fingerprinting and indeed could severely diminish it. Thus, an optimal regularization must be estimated on each data set to uncover the most differentiable across-subject and reproducible within-subject geodesic distances between FCs. The resulting pairwise geodesic distances at the optimal regularization level constitute a very reliable quantification of differences between subjects.

Uncovering differential identifiability in network properties of human brain functional connectomes.

The identifiability framework (𝕀f) has been shown to improve differential identifiability (reliability across-sessions and -sites, and differentiability across-subjects) of functional connectomes for a variety of fMRI tasks. But having a robust single session/subject functional connectome is just the starting point to subsequently assess network properties for characterizing properties of integration, segregation, and communicability, among others. Naturally, one wonders whether uncovering identifiability at the connectome level also uncovers identifiability on the derived network properties. This also raises the question of where to apply the 𝕀f framework: on the connectivity data or directly on each network measurement? Our work answers these questions by exploring the differential identifiability profiles of network measures when 𝕀f is applied (a) on the functional connectomes, and (b) directly on derived network measurements. Results show that improving across-session reliability of functional connectomes (FCs) also improves reliability of derived network measures. We also find that, for specific network properties, application of 𝕀f directly on network properties is more effective. Finally, we discover that applying the framework, either way, increases task sensitivity of network properties. At a time when the neuroscientific community is focused on subject-level inferences, this framework is able to uncover FC fingerprints, which propagate to derived network properties.

GEFF: Graph embedding for functional fingerprinting.

It has been well established that Functional Connectomes (FCs), as estimated from functional MRI (fMRI) data, have an individual fingerprint that can be used to identify an individual from a population (subject-identification). Although identification rate is high when using resting-state FCs, other tasks show moderate to low values. Furthermore, identification rate is task-dependent, and is low when distinct cognitive states, as captured by different fMRI tasks, are compared. Here we propose an embedding framework, GEFF (Graph Embedding for Functional Fingerprinting), based on group-level decomposition of FCs into eigenvectors. GEFF creates an eigenspace representation of a group of subjects using one or more task FCs (Learning Stage). In the Identification Stage, we compare new instances of FCs from the Learning subjects within this eigenspace (validation dataset). The validation dataset contains FCs either from the same tasks as the Learning dataset or from the remaining tasks that were not included in Learning. Assessment of validation FCs within the eigenspace results in significantly increased subject-identification rates for all fMRI tasks tested and potentially task-independent fingerprinting process. It is noteworthy that combining resting-state with one fMRI task for GEFF Learning Stage covers most of the cognitive space for subject identification. Thus, while designing an experiment, one could choose a task fMRI to ask a specific question and combine it with resting-state fMRI to extract maximum subject differentiability using GEFF. In addition to subject-identification, GEFF was also used for identification of cognitive states, i.e. to identify the task associated to a given FC, regardless of the subject being already in the Learning dataset or not (subject-independent task-identification). In addition, we also show that eigenvectors from the Learning Stage can be characterized as task- and subject-dominant, subject-dominant or neither, using two-way ANOVA of their corresponding loadings, providing a deeper insight into the extent of variance in functional connectivity across individuals and cognitive states.

FMRI of visual working memory in high school football players.

Visual working memory deficits have been observed in at-risk athletes. This study uses a visual N-back working memory functional magnetic resonance imaging task to longitudinally assess asymptomatic football athletes for abnormal activity. Athletes were increasingly "flagged" as the season progressed. Flagging may provide early detection of injury.

Cerebrovascular reactivity alterations in asymptomatic high school football players.

Cerebrovascular reactivity (CVR) is impaired following brain injury, increasing susceptibility to subsequent injury. CVR was tracked in football and non-collision athletes throughout one season. CVR transiently decreased in football athletes during the first half of the season. Results indicate the brain adapts slowly to increases in loading, increasing risk for injury.

Sub-concussive hit characteristics predict deviant brain metabolism in football athletes.

Magnetic resonance spectroscopy and helmet telemetry were used to monitor the neural metabolic response to repetitive head collisions in 25 high school American football athletes. Specific hit characteristics were determined highly predictive of metabolic alterations, suggesting that sub-concussive blows can produce biochemical changes and potentially lead to neurological problems.

Effects of repetitive sub-concussive brain injury on the functional connectivity of Default Mode Network in high school football athletes.

Sub-concussive head impacts are identified as a source of accrued damage. Football athletes experience hundreds of such blows each season. Resting state functional magnetic resonance imaging was used to prospectively study changes in Default Mode Network connectivity for clinically asymptomatic high school football athletes. Athletes exhibited short-term changes relative to baseline and across sessions.

Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study.

Long-term neurological damage as a result of head trauma while playing sports is a major concern for football athletes today. Repetitive concussions have been linked to many neurological disorders. Recently, it has been reported that repetitive subconcussive events can be a significant source of accrued damage. Since football athletes can experience hundreds of subconcussive hits during a single season, it is of utmost importance to understand their effect on brain health in the short and long term. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was used to study changes in the default mode network (DMN) after repetitive subconcussive mild traumatic brain injury. Twenty-two high school American football athletes, clinically asymptomatic, were scanned using the rs-fMRI for a single season. Baseline scans were acquired before the start of the season, and follow-up scans were obtained during and after the season to track the potential changes in the DMN as a result of experienced trauma. Ten noncollision-sport athletes were scanned over two sessions as controls. Overall, football athletes had significantly different functional connectivity measures than controls for most of the year. The presence of this deviation of football athletes from their healthy peers even before the start of the season suggests a neurological change that has accumulated over the years of playing the sport. Football athletes also demonstrate short-term changes relative to their own baseline at the start of the season. Football athletes exhibited hyperconnectivity in the DMN compared to controls for most of the sessions, which indicates that, despite the absence of symptoms typically associated with concussion, the repetitive trauma accrued produced long-term brain changes compared to their healthy peers.

MR spectroscopic evidence of brain injury in the non-diagnosed collision sport athlete.

With growing evidence of long-term neurological damage in individuals enduring repetitive head trauma, it is critical to detect lower-level damage accumulation for the early diagnosis of injury in at-risk populations. Proton magnetic resonance spectroscopic scans of the dorsolateral prefrontal cortex and primary motor cortex were collected from high school American (gridiron) football athletes, prior to and during their competition seasons. Although no concussions were diagnosed, significant metabolic deviations from baseline and non-collision sport controls were revealed. Overall the findings indicate underlying biochemical changes, consequential to repetitive hits, which have previously gone unnoticed due to a lack of traditional neurological symptoms.