Examining Neural Connectivity in Schizophrenia Using Task-Based EEG: A Graph Theory Approach.

Schizophrenia (SZ) is a complex disorder characterized by a range of symptoms and behaviors that have significant consequences for individuals, families, and society in general. Electroencephalography (EEG) is a valuable tool for understanding the neural dynamics and functional abnormalities associated with schizophrenia. Research studies utilizing EEG have identified specific patterns of brain activity in individuals diagnosed with schizophrenia that may reflect disturbances in neural synchronization and information processing in cortical circuits. Considering the temporal dynamics of functional connectivity provides a more comprehensive understanding of brain networks' organization and how they change during different cognitive states. This temporal perspective would enhance our understanding of the underlying mechanisms of schizophrenia. In the present study, we will use measures based on graph theory to obtain dynamic and static indicators in order to evaluate differences in the functional connectivity of individuals diagnosed with SZ and healthy controls using an ecologically valid task. At the static level, patients showed alterations in their ability to segregate information, particularly in the default mode network (DMN). As for dynamic measures, patients showed reduced values in most metrics (segregation, integration, centrality, and resilience), reflecting a reduced number of dynamic states of brain networks. Our results show the utility of combining static and dynamic indicators of functional connectivity from EEG sensors.

Lateralization of epilepsy using intra-hemispheric brain networks based on resting-state MEG data.

Focal epilepsy originates within networks in one hemisphere. However, previous studies have investigated network topologies for the entire brain. In this study, magnetoencephalography (MEG) was used to investigate functional intra-hemispheric networks of healthy controls (HCs) and patients with left- or right-hemispheric temporal lobe or temporal plus extra-temporal lobe epilepsy. 22 HCs, 25 left patients (LPs), and 16 right patients (RPs) were enrolled. The debiased weighted phase lag index was used to calculate functional connectivity between 246 brain regions in six frequency bands. Global efficiency, characteristic path length, and transitivity were computed for left and right intra-hemispheric networks. The right global graph measures (GGMs) in the theta band were significantly different (p < .005) between RPs and both LPs and HCs. Right and left GGMs in higher frequency bands were significantly different (p < .05) between HCs and the patients. Right GGMs were used as input features of a Naïve-Bayes classifier to classify LPs and RPs (78.0% accuracy) and all three groups (75.5% accuracy). The complete theta band brain networks were compared between LPs and RPs with network-based statistics (NBS) and with the clustering coefficient (CC), nodal efficiency (NE), betweenness centrality (BC), and eigenvector centrality (EVC). NBS identified a subnetwork primarily composed of right intra-hemispheric connections. Significantly different (p < .05) nodes were primarily in the right hemisphere for the CC and NE and primarily in the left hemisphere for the BC and EVC. These results indicate that intra-hemispheric MEG networks may be incorporated in the diagnosis and lateralization of focal epilepsy.

Graph network measures reveal distinct white matter abnormalities in motor and extra-motor brain regions of two UMN-predominant ALS subtypes.

BACKGROUND: Routine clinical magnetic resonance imaging (MRI) shows bilateral corticospinal tract (CST) hyperintensity in some patients with upper motor neuron (UMN)-predominant ALS (ALS-CST+) but not in others (ALS-CST-). Although, similar in their UMN features, the ALS-CST+ patient group is significantly younger in age, has faster disease progression and shorter survival than the ALS-CST- patient group. Reasons for the differences are unclear. METHOD: In order to evaluate more objective MRI measures of these ALS subgroups, we used diffusion tensor images (DTI) obtained using single shot echo planar imaging sequence from 1.5 T Siemens MRI Scanner. We performed an exploratory whole brain white matter (WM) network analysis using graph theory approach on 45 ALS patients (ALS-CST+) (n = 21), and (ALS-CST-) (n = 24) and neurological controls (n = 14). RESULTS: Significant (p < 0.05) differences in nodal degree measure between ALS patients and controls were observed in motor and extra motor regions, supplementary motor area, subcortical WM regions, cerebellum and vermis. Importantly, WM network abnormalities were significantly (p < 0.05) different between ALS-CST+ and ALS-CST- subgroups. Compared to neurologic controls, both ALS subgroups showed hubs in the right superior occipital gyrus and cuneus as well as significantly (p < 0.05) reduced small worldness supportive of WM network damage. CONCLUSIONS: Significant differences between ALS-CST+ and ALS-CST- subgroups of WM network abnormalities, age of onset, symptom duration prior to MRI, and progression rate suggest these patients represent distinct clinical phenotypes and possibly pathophysiologic mechanisms of ALS.

A Comparative Study of Correlation Methods in Functional Connectivity Analysis Using fMRI Data of Alzheimer's Patients.

Background: Functional Magnetic Resonance Imaging (fMRI) is a non-invasive neuroimaging tool, used in brain function research and is also a low-frequency signal, showing brain activation by means of Oxygen consumption. Objective: One of the reliable methods in brain functional connectivity analysis is the correlation method. In correlation analysis, the relationship between two time-series has been investigated. In fMRI analysis, the Pearson correlation is used while there are other methods. This study aims to investigate the different correlation methods in functional connectivity analysis. Material and Methods: In this analytical research, based on fMRI signals of Alzheimer's Disease (AD) and healthy individuals from the ADNI database, brain functional networks were generated using correlation techniques, including Pearson, Kendall, and Spearman. Then, the global and nodal measures were calculated in the whole brain and in the most important resting-state network called Default Mode Network (DMN). The statistical analysis was performed using non-parametric permutation test. Results: Results show that although in nodal analysis, the performance of correlation methods was almost similar, in global features, the Spearman and Kendall were better in distinguishing AD subjects. Note that, nodal analysis reveals that the functional connectivity of the posterior areas in the brain was more damaged because of AD in comparison to frontal areas. Moreover, the functional connectivity of the dominant hemisphere was disrupted more. Conclusion: Although the Pearson method has limitations in capturing non-linear relationships, it is the most prevalent method. To have a comprehensive analysis, investigating non-linear methods such as distance correlation is recommended.

Achieving Net Zero-An Illustration of Carbon Emissions Reduction with A New Meta-Inverse DEA Approach.

To achieve the goal of limiting global warming to 1.5 °C above preindustrial levels, net-zero emissions targets were proposed to assist countries in planning their long-term reduction. Inverse Data Envelopment Analysis (DEA) can be used to determine optimal input and output levels without sacrificing the set environmental efficiency target. However, treating countries as having the same capability to mitigate carbon emissions without considering their different developmental stages is not only unrealistic but also inappropriate. Therefore, this study incorporates a meta-concept into inverse DEA. This study adopts a three-stage approach. In the first stage, a meta-frontier DEA method is adopted to assess and compare the eco-efficiency of developed and developing countries. In the second stage, the specific super-efficiency method is adopted to rank the efficient countries specifically focused on carbon performance. In the third stage, carbon dioxide emissions reduction targets are proposed for the developed and developing countries separately. Then, a new meta-inverse DEA method is used to allocate the emissions reduction target to the inefficient countries in each of the specific groups. In this way, we can find the optimal CO2 reduction amount for the inefficient countries with unchanged eco-efficiency levels. The implications of the new meta-inverse DEA method proposed in this study are twofold. The method can identify how a DMU can reduce undesirable outputs without sacrificing the set eco-efficiency target, which is especially useful in achieving net-zero emissions since this method provides a roadmap for decision-makers to understand how to allocate the emissions reduction targets to different units. In addition, this method can be applied to heterogeneous groups where they are assigned to different emissions reduction targets.

Classification of Rajayoga Meditators Based on the Duration of Practice Using Graph Theoretical Measures of Functional Connectivity from Task-Based Functional Magnetic Resonance Imaging.

Context: Functional magnetic resonance imaging (fMRI) studies on mental training techniques such as meditation have reported benefits like increased attention and concentration, better emotional regulation, as well as reduced stress and anxiety. Although several studies have examined functional activation and connectivity in long-term as well as short-term meditators from different meditation traditions, it is unclear if long-term meditation practice brings about distinct changes in network properties of brain functional connectivity that persist during task performance. Indeed, task-based functional connectivity studies of meditators are rare. Aims: This study aimed to differentiate between long-term and short-term Rajayoga meditators based on functional connectivity between regions of interest in the brain. Task-based fMRI was captured as the meditators performed an engaging task. The graph theoretical-based functional connectivity measures of task-based fMRI were calculated using CONN toolbox and were used as features to classify the two groups using Machine Learning models. Subjects and Methods: In this study, we recruited two age and sex-matched groups of Rajayoga meditators from the Brahma Kumaris tradition that differed in the duration of their meditation experience: Long-term practitioners (n = 12, mean 13,596 h) and short-term practitioners (n = 10, mean 1095 h). fMRI data were acquired as they performed an engaging task and functional connectivity metrics were calculated from this data. These metrics were used as features in training machine learning algorithms. Specifically, we used adjacency matrices generated from graph measures, global efficiency, and local efficiency, as features. We computed functional connectivity with 132 ROIs as well as 32 network ROIs. Statistical Analysis Used: Five machine learning models, such as logistic regression, SVM, decision tree, random forest, and gradient boosted tree, were trained to classify the two groups. Accuracy, precision, sensitivity, selectivity, area under the curve receiver operating characteristics curve were used as performance measures. Results: The graph measures were effective features, and tree-based algorithms such as decision tree, random forest, and gradient boosted tree yielded the best performance (test accuracy >84% with 132 ROIs) in classifying the two groups of meditators. Conclusions: Our results support the hypothesis that long-term meditative practices alter brain functional connectivity networks even in nonmeditative contexts. Further, the use of adjacency matrices from graph theoretical measures of high-dimensional fMRI data yields a promising feature set for machine learning classifiers.

A novel index of functional connectivity: phase lag based on Wilcoxon signed rank test.

Phase synchronization has been an effective measurement of functional connectivity, detecting similar dynamics over time among distinct brain regions. However, traditional phase synchronization-based functional connectivity indices have been proved to have some drawbacks. For example, the phase locking value (PLV) index is sensitive to volume conduction, while the phase lag index (PLI) and the weighted phase lag index (wPLI) are easily affected by noise perturbations. In addition, thresholds need to be applied to these indices to obtain the binary adjacency matrix that determines the connections. However, the selection of the thresholds is generally arbitrary. To address these issues, in this paper we propose a novel index of functional connectivity, named the phase lag based on the Wilcoxon signed-rank test (PLWT). Specifically, it characterizes the functional connectivity based on the phase lag with a weighting procedure to reduce the influence of volume conduction and noise. Besides, it automatically identifies the important connections without relying on thresholds, by taking advantage of the framework of the Wilcoxon signed-rank test. The performance of the proposed PLWT index is evaluated on simulated electroencephalograph (EEG) datasets, as well as on two resting-state EEG datasets. The experimental results on the simulated EEG data show that the PLWT index is robust to volume conduction and noise. Furthermore, the brain functional networks derived by PLWT on the real EEG data exhibit a reasonable scale-free characteristic and high test-retest (TRT) reliability of graph measures. We believe that the proposed PLWT index provides a useful and reliable tool to identify the underlying neural interactions, while effectively diminishing the influence of volume conduction and noise.

Reproducibility of graph measures at the subject level using resting-state fMRI.

INTRODUCTION: Graph metrics have been proposed as potential biomarkers for diagnosis in clinical work. However, before it can be applied in a clinical setting, their reproducibility should be evaluated. METHODS: This study systematically investigated the effect of two denoising pipelines and different whole-brain network constructions on reproducibility of subject-specific graph measures. We used the multi-session fMRI dataset from the Brain Genomics Superstruct Project consisting of 69 healthy young adults. RESULTS: In binary networks, the test-retest variability for global measures was large at low density irrespective of the denoising strategy or the type of correlation. Weighted networks showed very low test-retest values (and thus a good reproducibility) for global graph measures irrespective of the strategy used. Comparing the test-retest values for different strategies, there were significant main effects of the type of correlation (Pearson correlation vs. partial correlation), the (partial) correlation value (absolute vs. positive vs. negative), and weight calculation (based on the raw (partial) correlation values vs. based on transformed Z-values). There was also a significant interaction effect between type of correlation and weight calculation. Similarly as for the binary networks, there was no main effect of the denoising pipeline. CONCLUSION: Our results demonstrated that normalized global graph measures based on a weighted network using the absolute (partial) correlation as weight were reproducible. The denoising pipeline and the granularity of the whole-brain parcellation used to define the nodes were not critical for the reproducibility of normalized graph measures.

Dynamic changes of brain networks during feedback-related processing of reinforcement learning in schizophrenia.

Previous studies have reported that schizophrenia (SZ) patients showed selective reinforcement learning deficits and abnormal feedback-related event-related potential (ERP) components. However, how the brain networks and their topological properties evolve over time during transient feedback-related cognition processing in SZ patients has not been investigated so far. In this paper, using publicly available feedback-related ERP data which were recorded from SZ patients and healthy controls (HC) when they performed a reinforcement learning task, we carried out an event-related network analysis where topology of brain functional networks was characterized with some graph measures including clustering coefficient (C), global efficiency (Eglobal) and local efficiency (Elocal) on a millisecond timescale. Our results showed that the brain functional networks displayed rapid rearrangements of topological properties during transient feedback-related cognition process for both two groups. More importantly, we found that SZ patients exhibited significantly reduced theta-band (time window of 170-350 ms after stimuli onset) brain functional connectivity strength, Eglobal, Elocal and C in response to negative feedback stimuli compared to HC group. The network based statistic (NBS) analysis detected one significantly decreased theta-band subnetwork in SZ patients mainly involving in frontal-occipital and temporal-occipital connections compared to HC group. In addition, clozapine treatment seemed to greatly reduce theta-band power and topological measures of brain networks in SZ patients. Finally, the theta-band power, graph measures and functional connectivity were extracted to train a support vector machine classifier for classification of HC from SZ, or Cloz + SZ or Cloz- SZ, and a relatively good classification accuracy of 84.48%, 89.47% and 78.26% was obtained, respectively. The above results suggested a less optimal organization of theta-band brain network in SZ patients, and studying the topological parameters of brain networks evolve over time during transient feedback-related processing could be useful for understanding the pathophysiologic mechanisms underlying reinforcement learning deficits in SZ patients.

Schizophrenia Identification Using Multi-View Graph Measures of Functional Brain Networks.

Schizophrenia (SZ) is a functional mental disorder that seriously affects the social life of patients. Therefore, accurate diagnosis of SZ has raised extensive attention of researchers. At present, study of brain network based on resting-state functional magnetic resonance imaging (rs-fMRI) has provided promising results for SZ identification by studying functional network alteration. However, previous studies based on brain network analysis are not very effective for SZ identification. Therefore, we propose an improved SZ identification method using multi-view graph measures of functional brain networks. Firstly, we construct an individual functional connectivity network based on Brainnetome atlas for each subject. Then, multi-view graph measures are calculated by the brain network analysis method as feature representations. Next, in order to consider the relationships between measures within the same brain region in feature selection, multi-view measures are grouped according to the corresponding regions and Sparse Group Lasso is applied to identify discriminative features based on this feature grouping structure. Finally, a support vector machine (SVM) classifier is employed to perform SZ identification task. To evaluate our proposed method, computational experiments are conducted on 145 subjects (71 schizophrenic patients and 74 healthy controls) using a leave-one-out cross-validation (LOOCV) scheme. The results show that our proposed method can obtain an accuracy of 93.10% for SZ identification. By comparison, our method is more effective for SZ identification than some existing methods.

Connectivity Between Brain Networks Dynamically Reflects Cognitive Status of Parkinson's Disease: A Longitudinal Study.

BACKGROUND: Cognitive impairment in Parkinson's disease (PD) is associated with altered connectivity of the resting state networks (RSNs). Longitudinal studies in well cognitively characterized PD subgroups are missing. OBJECTIVES: To assess changes of the whole-brain connectivity and between-network connectivity (BNC) of large-scale functional networks related to cognition in well characterized PD patients using a longitudinal study design and various analytical methods. METHODS: We explored the whole-brain connectivity and BNC of the frontoparietal control network (FPCN) and the default mode, dorsal attention, and visual networks in PD with normal cognition (PD-NC, n = 17) and mild cognitive impairment (PD-MCI, n = 22) as compared to 51 healthy controls (HC). We applied regions of interest-based, partial least squares, and graph theory based network analyses. The differences among groups were analyzed at baseline and at the one-year follow-up visit (37 HC, 23 PD all). RESULTS: The BNC of the FPCN and other RSNs was reduced, and the whole-brain analysis revealed increased characteristic path length and decreased average node strength, clustering coefficient, and global efficiency in PD-NC compared to HC. Values of all measures in PD-MCI were between that of HC and PD-NC. After one year, the BNC was further increased in the PD-all group; no changes were detected in HC. No cognitive domain z-scores deteriorated in either group. CONCLUSION: As compared to HC, PD-NC patients display a less efficient transfer of information globally and reduced BNC of the visual and frontoparietal control network. The BNC increases with time and MCI status, reflecting compensatory efforts.

Predicting seizure outcome of vagus nerve stimulation using MEG-based network topology.

Vagus nerve stimulation (VNS) is a low-risk surgical option for patients with drug resistant epilepsy, although it is impossible to predict which patients may respond to VNS treatment. Resting-state magnetoencephalography (rs-MEG) connectivity analysis has been increasingly utilized to investigate the impact of epilepsy on brain networks and identify alteration of these networks after different treatments; however, there is no study to date utilizing this modality to predict the efficacy of VNS treatment. We investigated whether the rs-MEG network topology before VNS implantation can be used to predict efficacy of VNS treatment. Twenty-three patients with epilepsy who had MEG before VNS implantation were included in this study. We also included 89 healthy control subjects from the Human Connectome Project. Using the phase-locking value in the theta, alpha, and beta frequency bands as a measure of rs-MEG functional connectivity, we calculated three global graph measures: modularity, transitivity, and characteristic path length (CPL). Our results revealed that the rs-MEG graph measures were significantly heritable and had an overall good test-retest reliability, and thus these measures may be used as potential biomarkers of the network topology. We found that the modularity and transitivity in VNS responders were significantly larger and smaller, respectively, than those observed in VNS non-responders. We also observed that the modularity and transitivity in three frequency bands and CPL in delta and beta bands were significantly different in controls than those found in responders or non-responders, although the values of the graph measures in controls were closer to those of responders than non-responders. We used the modularity and transitivity as input features of a naïve Bayes classifier, and achieved an accuracy of 87% in classification of non-responders, responders, and controls. The results of this study revealed that MEG-based graph measures are reliable biomarkers, and that these measures may be used to predict seizure outcome of VNS treatment.

Ensemble Classification of Alzheimer's Disease and Mild Cognitive Impairment Based on Complex Graph Measures from Diffusion Tensor Images.

The human brain is a complex network of interacting regions. The gray matter regions of brain are interconnected by white matter tracts, together forming one integrative complex network. In this article, we report our investigation about the potential of applying brain connectivity patterns as an aid in diagnosing Alzheimer's disease and Mild Cognitive Impairment (MCI). We performed pattern analysis of graph theoretical measures derived from Diffusion Tensor Imaging (DTI) data representing structural brain networks of 45 subjects, consisting of 15 patients of Alzheimer's disease (AD), 15 patients of MCI, and 15 healthy subjects (CT). We considered pair-wise class combinations of subjects, defining three separate classification tasks, i.e., AD-CT, AD-MCI, and CT-MCI, and used an ensemble classification module to perform the classification tasks. Our ensemble framework with feature selection shows a promising performance with classification accuracy of 83.3% for AD vs. MCI, 80% for AD vs. CT, and 70% for MCI vs. CT. Moreover, our findings suggest that AD can be related to graph measures abnormalities at Brodmann areas in the sensorimotor cortex and piriform cortex. In this way, node redundancy coefficient and load centrality in the primary motor cortex were recognized as good indicators of AD in contrast to MCI. In general, load centrality, betweenness centrality, and closeness centrality were found to be the most relevant network measures, as they were the top identified features at different nodes. The present study can be regarded as a "proof of concept" about a procedure for the classification of MRI markers between AD dementia, MCI, and normal old individuals, due to the small and not well-defined groups of AD and MCI patients. Future studies with larger samples of subjects and more sophisticated patient exclusion criteria are necessary toward the development of a more precise technique for clinical diagnosis.

Using Large-Scale Granger Causality to Study Changes in Brain Network Properties in the Clinically Isolated Syndrome (CIS) Stage of Multiple Sclerosis.

Clinically Isolated Syndrome (CIS) is often considered to be the first neurological episode associated with Multiple sclerosis (MS). At an early stage the inflammatory demyelination occurring in the CNS can manifest as a change in neuronal metabolism, with multiple asymptomatic white matter lesions detected in clinical MRI. Such damage may induce topological changes of brain networks, which can be captured by advanced functional MRI (fMRI) analysis techniques. We test this hypothesis by capturing the effective relationships of 90 brain regions, defined in the Automated Anatomic Labeling (AAL) atlas, using a large-scale Granger Causality (lsGC) framework. The resulting networks are then characterized using graph-theoretic measures that quantify various network topology properties at a global as well as at a local level. We study for differences in these properties in network graphs obtained for 18 subjects (10 male and 8 female, 9 with CIS and 9 healthy controls). Global network properties captured trending differences with modularity and clustering coefficient (p<0.1). Additionally, local network properties, such as local efficiency and the strength of connections, captured statistically significant (p<0.01) differences in some regions of the inferior frontal and parietal lobe. We conclude that multivariate analysis of fMRI time-series can reveal interesting information about changes occurring in the brain in early stages of MS.

Investigating Changes in Brain Network Properties in HIV-Associated Neurocognitive Disease (HAND) using Mutual Connectivity Analysis (MCA).

About 50% of subjects infected with HIV present deficits in cognitive domains, which are known collectively as HIV associated neurocognitive disorder (HAND). The underlying synaptodendritic damage can be captured using resting state functional MRI, as has been demonstrated by a few earlier studies. Such damage may induce topological changes of brain connectivity networks. We test this hypothesis by capturing the functional interdependence of 90 brain network nodes using a Mutual Connectivity Analysis (MCA) framework with non-linear time series modeling based on Generalized Radial Basis function (GRBF) neural networks. The network nodes are selected based on the regions defined in the Automated Anatomic Labeling (AAL) atlas. Each node is represented by the average time series of the voxels of that region. The resulting networks are then characterized using graph-theoretic measures that quantify various network topology properties at a global as well as at a local level. We tested for differences in these properties in network graphs obtained for 10 subjects (6 male and 4 female, 5 HIV+ and 5 HIV-). Global network properties captured some differences between these subject cohorts, though significant differences were seen only with the clustering coefficient measure. Local network properties, such as local efficiency and the degree of connections, captured significant differences in regions of the frontal lobe, precentral and cingulate cortex amongst a few others. These results suggest that our method can be used to effectively capture differences occurring in brain network connectivity properties revealed by resting-state functional MRI in neurological disease states, such as HAND.