Functional Connectivity Network Analysis with Discriminative Hub Detection for Brain Disease Identification

Network science has become an invaluable tool for neuroimaging analysis and has advanced our understanding of the brain's complex structural and functional topology. Network science, an interdisciplinary offshoot of graph theory, conceives of the brain as a system of nodes, representing brain regions or voxels, and edges, representing the structural or functional connection between these regions or voxels. Such a model is considered appealing in neuroscience as it describes a system with various interacting regions that produces complex behaviors. This conception of the brain has revealed that the brain exhibits “small-world” properties, namely that brain networks are systems with regional specialization and efficient global information transfer. More importantly, studies in brain networks have furthered our understanding of diseases and disorders affecting the brain. Assessing group differences in representative samples of brain networks has become increasingly important, yet appropriate methodological developments have remained relatively sparse. Additionally, there is increased interest in understanding dynamic changes, or how a network changes over time. Currently, most network analysis tools are designed to analyze a static representation, thus changes that occur over time are often overlooked or ignored. As the field continues to grow, it is becoming increasingly important to develop methods for understanding the complexity of these data. This research topic features selected contributions that explores group analysis and dynamics in brain network studies including methodological and practical applications employing various imaging modalities. This snapshot of the field represents the growing interest to expand and validate new methods for use in the field of brain network neuroscience. “Defining nodes in complex brain networks” is a review article discussing the methodological choices for defining nodes, particularly how the choice of atlas-based or voxel-based methods affects the computed network (Stanley et al., 2013). “Routing in the brain” is a commentary on network routing focusing on how current methods and models may not be adequate for brain networks. Further exploration of the packet switching network model may be more realistic and appropriate for the brain (Graham, 2014). “A multimodal approach for determining brain networks by jointly modeling functional and structural connectivity” is a methods article introducing a Bayesian model for estimating functional networks, from functional magnetic resonance imaging (fMRI) data, leveraging complementary structural diffusion tensor imaging (DTI) data (Xue et al., 2015). “A permutation testing framework to compare groups of brain networks” is a methods article describing a permutation testing framework to statistically compare groups of functional brain networks while incorporating topological features inherent in each individual network (Simpson et al., 2013). “Assessing dynamics, spatial scale, and uncertainty in task-related brain network analyses” is a methods article describing a statistical approach for computing uncertainty in static and dynamic functional networks and aggregating network measures in task-related electrocorticography (ECoG) data (Stephen et al., 2014). “Hierarchical vector auto-regressive models and their applications to multi-subject effective connectivity” is a methods article introducing a generalization of the vector auto-regressive (VAR) model for comparing effective connectivity between experimental conditions while accounting for between-subject heterogeneity (Gorrostieta et al., 2013). “Statistical network analysis for functional MRI: summary networks and group comparisons” is a review article discussing the construction of summary networks and how to test for topological differences in groups of networks when these groups also exhibit significant differences in density (Ginestet et al., 2014). “Detecting functional connectivity change points for single-subject fMRI data” is a methods article that extends Dynamic Connectivity Regression (DCR), a data-driven technique which detects change points in functional connectivity between brain regions to determine state changes over the course of an experimental task, by introducing a novel algorithm aimed at increasing the estimation of networks for individual subject data (Cribben et al., 2013). “The Laplacian spectrum of neural networks” is an original research article examining the use of the Laplacian spectrum in anatomic networks of the macaque, cat and Caenorhabditis elegans. This method describes network structure at a systems level, assessing systemic infrastructural properties of the entire network as opposed to properties of specific nodes or connections (De Lange et al., 2014). “Quantifying network properties in multi-electrode recordings: spatiotemporal characterization and inter-trial variation of evoked gamma oscillations in mouse somatosensory cortex in vitro” is an original research article on network dynamics in multi-electrode array data focusing on changes in the functional connectivity of evoked gamma oscillations in cortical circuits (Carmeli et al., 2013).

Investigating directional interactions between brain regions plays a critical role in fully understanding brain function. Consequently, multiple methods have been developed for noninvasively inferring directional connectivity in human brain networks using functional MRI (fMRI). Recent simulations by Smith et al. showed that Patel's τ, a method based on higher-order statistics, was the best approach for inferring directional interactions from fMRI. Because simulations make restrictive assumptions about reality, we set out to verify this finding using experimental fMRI data obtained from a three-region network in a rat model with electrophysiological validation. Previous studies have shown that dynamic causal modeling can correctly estimate the directionality of this three-region network; Granger causality can also work after the deconvolution of the hemodynamic response. Therefore, we set out to test the hypothesis that Patel's τ obtained from either raw or deconvolved fMRI data should correctly estimate the directionality of neuronal influences obtained from intracerebral electroencephalogram in this network. Our results indicate that the accuracy of network directionality estimated using Patel's τ was not better than chance. First, our results highlight the necessity of experimental validation of simulation results. Second, it is unclear which brain mechanism is modeled by a directionality inferred from Patel's τ. Third, this study shows that a directional connection ascertained by different methods may mean different things and more experimental studies are needed for investigating the neuronal mechanisms underlying the direction of a connection in the brain ascertained by fMRI using different methods. M Magn Reson Med 78:2003-2010, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

ObjectiveUsing the phase synchronization of EEG signals, two different phases, PLI and PLV, were used to construct brain network analysis and graph convolutional neural network, respectively, to achieve automatic identification of Alzheimer’s disease (AD) and to assist in the early diagnosis of Alzheimer’s disease.MethodsIn this paper, we selected outpatients (16 AD subjects, 20 mild cognitive impairment (MCI) subjects and 21 healthy control (HC) subjects) from the outpatient clinic of Yangpu Mental Health Center in Shanghai, China, from January 2023 to December 2023, and collected resting-state EEG data. To collect resting-state EEG data, each patient was asked to sit down with eyes closed for 5 min. Firstly, the acquired EEG data were preprocessed to extract the data in the α-band at 8–13 Hz; secondly, the phase lag index (PLI) and phase-locked value (PLV) were used to construct the brain functional network, and the brain functional connectivity map was visualized by brain functional connectivity analysis. Finally, the constructed PLI and PLV were input into the graph convolutional neural network (GCN) model as node features for training and classification, respectively.ResultsHealthy controls had relatively strong mean brain functional connectivity in the PLV brain network compared to AD and MCI patients. MCI patients showed lower mean brain functional connectivity in the brain network of PLI, while all three groups showed significant differences in brain functional connectivity between parietal and occipital lobes. The GCN model improved classification accuracy by more than 10% compared to using a machine learning classifier. When PLV was used as the nodal feature in the GCN model, the model achieved an average classification accuracy of 77.80% for the three groups of AD, MCI and HC, which was an improvement over the accuracy of choosing raw EEG data and PLI as the nodal feature. The performance of the model was further validated.ConclusionsThe experimental results show that the GCN model can effectively identify the graph structure compared with the traditional machine learning model, the GCN-PLV model can better classify AD patients, and the alpha band is proved to be more suitable for AD resting-state EEG by tenfold cross-validation. The brain network map constructed based on PLI and PLV can further capture the local features of EEG signals and the intrinsic functional relationships between brain regions, and the combination of these two models has certain reference value for the diagnosis of AD patients.

BackgroundRecently, many academic research groups focused their attention on changes in human brain networks related to several kinds of pathologies and diseases. Generally speaking, Network Medicine promises to identify the principles to understand, at the molecular level, the human life complex system. We applied the theoretical approach of the Network Medicine mainly to brain diseases, testing the potentiality of the method to produce an early and more in-depth diagnostic process. However, the range of our topics and application of the Network Medicine spans from common neurological and neuropsychological spectrum disorders to other physiological systems or district, only apparently out of the action range of the neurological one. In the areas of Neurology and Neuropsychology we are studying brain networks in Tourette Syndrome [TS] and Multiple Sclerosis [MS]. Moreover, we are studying brain networking related to genotype alteration responsible for different gustatory stimuli processing in the brain. Further, we recently started to study infective diseases and immunological system.Main body of the abstractThe analysis of brain networks is made feasible by the development and application of imaging acquisition methods based on the Magnetic Resonance Imaging and functional MRI, as well as the availability of innovative calculation tools from graph theory and complex dynamical systems. This paper highlights the Network Medicine concepts and the application of the functional connectivity for the brain networks description. We will describe all these methods with a reduced use of formulas, along with some technical tools available in the WEB to perform the calculations of the related parameters. We will briefly describe the freely available software CONN used for calculating different connectivity parameters. In all these studies, the networks characterisation is performed using indexes from metric and topology of the brain networks. The possibility of early recognition of the diseases by the identification of the alteration in the network’s parameters may significantly improve patient outcome, with also significant social community benefits. We intend to illustrate a possible pipeline for the Networks Brain application to neuroradiologists involved in the diagnosis of complex diseases.Short conclusionThe multidisciplinary approach is one of the essential characteristics of journals in the imaging sciences field; the issues and the methodologies examined in this paper could be of great interest to the reader’s community. Furthermore, until today very few studies focused on the network medicine and connectivity explored in functional MRI. Hence this might have an additional value for the journal.

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To identify subgroups of people with internet gaming disorder (IGD) based on addiction-related resting-state functional connectivity and how these subgroups show different clinical correlates and responses to treatment. Secondary analysis of two functional magnetic resonance imaging (fMRI) data sets. Zhejiang province and Beijing, China. One hundred and sixty-nine IGD and 147 control subjects. k-Means algorithmic and support-vector machine-learning approaches were used to identify subgroups of IGD subjects. These groups were examined with respect to assessments of craving, behavioral activation and inhibition, emotional regulation, cue-reactivity and guessing-related measures. Two groups of subjects with IGD were identified and defined by distinct patterns of connectivity in brain networks previously implicated in addictions: subgroup 1 ('craving-related subgroup') and subgroup 2 ('mixed psychological subgroup'). Clustering IGD on this basis enabled the development of diagnostic classifiers with high sensitivity and specificity for IGD subgroups in 10-fold validation (n = 218) and out-of-sample replication (n = 98) data sets. Subgroup 1 is characterized by high craving scores, cue-reactivity during fMRI and responsiveness to a craving behavioral intervention therapy. Subgroup 2 is characterized by high craving, behavioral inhibition and activations scores, non-adaptive emotion-regulation strategies and guessing-task fMRI measures. Subgroups 1 and 2 showed largely opposite functional-connectivity patterns in overlapping networks. There appear to be two subgroups of people with internet gaming disorder, each associated with differing patterns of brain functional connectivity and distinct clinical symptom profiles and gender compositions.

In the last decade, network science has shed new light both on the structural (anatomical) and on the functional (correlations in the activity) connectivity among the different areas of the human brain. The analysis of brain networks has made possible to detect the central areas of a neural system and to identify its building blocks by looking at overabundant small subgraphs, known as motifs. However, network analysis of the brain has so far mainly focused on anatomical and functional networks as separate entities. The recently developed mathematical framework of multi-layer networks allows us to perform an analysis of the human brain where the structural and functional layers are considered together. In this work, we describe how to classify the subgraphs of a multiplex network, and we extend the motif analysis to networks with an arbitrary number of layers. We then extract multi-layer motifs in brain networks of healthy subjects by considering networks with two layers, anatomical and functional, respectively, obtained from diffusion and functional magnetic resonance imaging. Results indicate that subgraphs in which the presence of a physical connection between brain areas (links at the structural layer) coexists with a non-trivial positive correlation in their activities are statistically overabundant. Finally, we investigate the existence of a reinforcement mechanism between the two layers by looking at how the probability to find a link in one layer depends on the intensity of the connection in the other one. Showing that functional connectivity is non-trivially constrained by the underlying anatomical network, our work contributes to a better understanding of the interplay between the structure and function in the human brain.

Human Brain can be studied and analysed using neuroimages viz. MRI(Magnetic Resonance Imaging) / fMRI(Functional Magnetic Resonance Imaging) / PET(Positron Emission Tomography) / EEG(Electroencephalography) / MEG(Magnetoencephalography), which brings out the hidden information from it. Connectomes are graph like structure which represents complex brain network connectivity which are of two type's mainly structural connectivity and functional connectivity. Connectivity can be anatomical and functional properties of the brain. Nodes are voxels or Regions of Interest whereas edges are fibre bundles, temporal correlation between regions, in structural connectome and functional connectome respectively. This work focuses on functional connectivity analysis of brain network obtained through RS- fMRI images for identification of important regions in the human brain using image processing and graph theoretical approaches. The RS-fMRI images are obtained from 1000 Functional connectomes project and preprocessed using image processing techniques. Then the image is parcellated using AAL(Automated Anatomical Labeling) atlas and binary matrix is obtained. The graph is constructed from the derived matrix that exhibits functional connectivity between ROIs(Region of Interest). The various centrality measures (degree centrality, eigenvector centrality, betweenness centrality and closeness centrality) are used to identify the ROIs that act as provincial and/or connector hubs. The prominent provincial hubs are Rolandic Operculum, Thalamus, Insula, Hippocampus, Olfactory and connector hubs are Insula, Putamen, Occipital superior gyrus, Parietal Superior gyrus and Supramarginal gyrus. This work highlights the key regions in human brain which is involved in massive communication and information flow within the network.

Mental disorders often emerge during adolescence and have been associated with age-related differences in connection strengths of brain networks (static functional connectivity), manifesting in non-typical trajectories of brain development. However, little is known about the direction of information flow (directed functional connectivity) in this period of functional brain progression. We employed dynamic graphical models (DGM) to estimate directed functional connectivity from resting state functional magnetic resonance imaging data on 1143 participants, aged 6 to 17 years from the healthy brain network (HBN) sample. We tested for effects of age, sex, cognitive abilities and psychopathology on estimates of direction flow. Across participants, we show a pattern of reciprocal information flow between visual-medial and visual-lateral connections, in line with findings in adults. Investigating directed connectivity patterns between networks, we observed a positive association for age and direction flow from the cerebellar to the auditory network, and for the auditory to the sensorimotor network. Further, higher cognitive abilities were linked to lower information flow from the visual occipital to the default mode network. Additionally, examining the degree networks overall send and receive information to each other, we identified age-related effects implicating the right frontoparietal and sensorimotor network. However, we did not find any associations with psychopathology. Our results suggest that the directed functional connectivity of large-scale resting-state brain networks is sensitive to age and cognition during adolescence, warranting further studies that may explore directed relationships at rest and trajectories in more fine-grained network parcellations and in different populations.

<p>My dissertation focused on understanding how different areas of the brain coordinate in networks to drive higher cognitive functions, and how damage, changes the brain’s synchronized activity (or functional connectivity) in the short and long term. In this dissertation, I studied the functional connectivity of brain networks that are thought to underlie emotion and decision-making, and how these networks change in the face of neurological injury.</p><p>In my first set of experiments, I studied participants with chronic focal brain damage to determine how damage to brain areas which have been identified as important in emotion and decision-making behaviors (amygdala, ventromedial prefrontal cortex, & insula), affected connectivity of brain networks, and how changes in connectivity following damage to these areas related to emotion and decision-making behavior. Supporting my predictions, I found evidence that damage to the amygdala, ventromedial prefrontal cortex, and insula all result in significantly weaker connections between a network of areas important for assigning value to stimuli. Additionally, I found that stronger connectivity in this valuation network was significantly positively associated with performance on ratings of disgusted faces, while stronger connectivity in a network important for processing emotional salience was significantly positively correlated with decision-making performance.</p><p>In the second set of studies in this dissertation, I utilized a population of epilepsy patients who were undergoing brain surgery to treat their seizures to investigate how a brain network related to emotional salience changed from before to after surgery. This approach allowed me to study how the connectivity and associated behavior of this network changed from preoperative baseline, to the weeks and months after part of this network was removed. While I expected a decline in this network in the weeks following surgery, instead I found a significant positive correlation between preoperative and acute postoperative connectivity in a subset of this network. However, my hypothesis that there would be a significant increase in the connectivity of this network between acute and chronic postoperative epochs was supported. I only have partial evidence for a significant correlation between the change in salience network connectivity between preoperative and acute postoperative assessments and the associated change in decision-making behavior. This correlation was in the opposite direction of my hypothesis, with increased change in connectivity being positively associated with change in risk-taking behavior. I did not observe a significant correlation between the change in network connectivity and change in behavior across acute and chronic measurements.</p><p>These findings provide important insight on how measures of network connectivity can inform theories of neuroplasticity and reorganization following brain damage. Understanding how these networks change over time, and how changes in these networks relate to behavioral outcomes, are critical for the development and effective deployment of therapeutic interventions. Together, these studies provide a foundation for further study, demonstrating that these networks change over time with damage, and the residual network strength is associated with performance on measures of emotion and decision-making.</p>

With the rapid economic development, the rapid increase in motor vehicle holdings, a sharp increase in urban road traffic, road traffic noise exposure is becoming increasingly serious. This paper focuses on the impact of traffic noise exposure on the human brain. We collected road traffic noise sounds of different sound pressure levels (SPLs), and recorded the electroencephalograph (EEG) when subjects exposed under different SPLs’ road noise. Using the graphic theoretical-based EEG method, the effects of road traffic noise with different SPLs on the functional connectivity of human brain networks were studied. Using time-frequency analysis, the beta2 bands was found to be most sensitive frequency band to different SPLs road noise. The brain network characteristic parameters of different SPLs noises were calculated. It is found that in these two frequency bands, the higher the noise SPL, the lower the clustering coefficient and the higher the characteristic path length. In summary, the paper points out the specific effects of road noise with different SPLs on the human brains. It is found that the higher the SPL of noise, the greater the damage to the functional connectivity of the human brain. That means, noise exposure can affect the rate at which the brain processes, analyses, and transmits information. The research results can provide a basis for road noise evaluation and prevention.

Burning mouth syndrome (BMS) is a chronic intraoral pain syndrome featuring idiopathic oral pain and burning discomfort despite clinically normal oral mucosa. The etiology of chronic pain syndrome is unclear, but preliminary neuroimaging research has suggested the alteration of volume, metabolism, blood flow, and diffusion at multiple brain regions. According to the neuromatrix theory of Melzack, pain sense is generated in the brain by the network of multiple pain-related brain regions. Therefore, the alteration of pain-related network is also assumed as an etiology of chronic pain. In this study, we investigated the brain network of BMS brain by using probabilistic tractography and graph analysis. Fourteen BMS patients and 14 age-matched healthy controls underwent 1.5T MRI. Structural connectivity was calculated in 83 anatomically defined regions with probabilistic tractography of 60-axis diffusion tensor imaging and 3D T1-weighted imaging. Graph theory network analysis was used to evaluate the brain network at local and global connectivity. In BMS brain, a significant difference of local brain connectivity was recognized at the bilateral rostral anterior cingulate cortex, right medial orbitofrontal cortex, and left pars orbitalis which belong to the medial pain system; however, no significant difference was recognized at the lateral system including the somatic sensory cortex. A strengthened connection of the anterior cingulate cortex and medial prefrontal cortex with the basal ganglia, thalamus, and brain stem was revealed. Structural brain network analysis revealed the alteration of the medial system of the pain-related brain network in chronic pain syndrome.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.

Patients with traumatic brain injury show clear impairments in behavioural flexibility and inhibition that often persist beyond the time of injury, affecting independent living and psychosocial functioning. Functional magnetic resonance imaging studies have shown that patients with traumatic brain injury typically show increased and more broadly dispersed frontal and parietal activity during performance of cognitive control tasks. We constructed binary and weighted functional networks and calculated their topological properties using a graph theoretical approach. Twenty-three adults with traumatic brain injury and 26 age-matched controls were instructed to switch between coordination modes while making spatially and temporally coupled circular motions with joysticks during event-related functional magnetic resonance imaging. Results demonstrated that switching performance was significantly lower in patients with traumatic brain injury compared with control subjects. Furthermore, although brain networks of both groups exhibited economical small-world topology, altered functional connectivity was demonstrated in patients with traumatic brain injury. In particular, compared with controls, patients with traumatic brain injury showed increased connectivity degree and strength, and higher values of local efficiency, suggesting adaptive mechanisms in this group. Finally, the degree of increased connectivity was significantly correlated with poorer switching task performance and more severe brain injury. We conclude that analysing the functional brain network connectivity provides new insights into understanding cognitive control changes following brain injury.

The human brain is a complex system able to continuously adapt. How and where brain activity is modulated by behavior can be studied with functional magnetic resonance imaging (fMRI), a non-invasive neuroimaging technique with excellent spatial resolution and whole-brain coverage. FMRI scans of healthy adults completing a variety of behavioral tasks have greatly contributed to our understanding of the functional role of individual brain regions. However, by statistically analyzing each region independently, these studies ignore that brain regions act in concert rather than in unison. Thus, many studies since have instead examined how brain regions interact. Surprisingly, structured interactions between distinct brain regions not only occur during behavioral tasks but also while a subject rests quietly in the MRI scanner. Multiple groups of regions interact very strongly with each other and not only do these groups bear a striking resemblance to the sets of regions co-activated in tasks, but many of these interactions are also progressively disrupted in neurological diseases. This suggests that spontaneous fluctuations in activity can provide novel insights into fundamental organizing principles of the human brain in health and disease. Many techniques to date have segregated regions into spatially distinct networks, which ignores that any brain region can take part in multiple networks across time. A more natural view is to estimate dynamic brain networks that allow flexible functional interactions (or connectivity) over time. The estimation and analysis of such dynamic functional interactions is the subject of this dissertation. We take the perspective that dynamic brain networks evolve in a low-dimensional space and can be described by a small number of characteristic spatiotemporal patterns. Our proposed approaches are based on well-established statistical methods, such as principal component analysis (PCA), sparse matrix decompositions, temporal clustering, as well as a multiscale analysis by novel graph wavelet designs. We adapt and extend these methods to the analysis of dynamic brain networks. We show that PCA and its higher-order equivalent can identify co-varying functional interactions, which reveal disturbed dynamic properties in multiple sclerosis and which are related to the timing of stimuli for task studies, respectively. Further we show that sparse matrix decompositions provide a valid alternative approach to PCA and improve interpretability of the identified patterns. Finally, assuming an even simpler low-dimensional space and the exclusive temporal expression of individual patterns, we show that specific transient interactions of the medial prefrontal cortex are disturbed in aging and relate to impaired memory.