Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis

Patterns of cortical interactivity supporting speech production and lexical retrieval: A graph signal processing approach at the individual level

Objective To investigate the small-worldness and the betweenness centrality of the nodes in the brain structural networks and its relationship with the course and the central role of the brain regions in the transmission of information across the whole brain in depression. Methods The diffusion tensor imaging data were obtained from 27 depression patients and 33 healthy controls. The brain structural networks were constructed using the complex network theory. Results The brain structural networks had small-world properties in both groups. When compared with the healthy, the betweenness centrality of the nodes of the networks in depression significantly decreased in right superior frontal gyrus (orbital part) (P=0.00035, region survived critical FDR threshold for multiple comparisons), and left putamen (P=0.00054, region survived critical FDR threshold for multiple comparisons). Significant negative correlation was found between the betweenness centrality of left hippocampus and the course in the depression(r=0.50, P=0.016). Conclusion Both of the brain structural networks in depression patients and normal people have the property of small-worldness. But the central role of orbit frontal cortex and putamen in the transmission of information across the whole brain is declined, and the betweenness centrality of hippocampus is negatively related with the course in the depression. Key words: Depression; Diffusion tensor imaging; Brain structural network; Small-world; Betweenness centrality

Background: Changes in the metabolic and structural brain networks in mild cognitive impairment (MCI) have been widely researched. However, few studies have compared the differences in the topological properties of the metabolic and structural brain networks in patients with MCI.Methods: We analyzedmagnetic resonance imaging (MRI) and fluoro-deoxyglucose positron emission tomography (FDG-PET) data of 137 patients with MCI and 80 healthy controls (HCs). The HC group data comes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The permutation test was used to compare the network parameters (characteristic path length, clustering coefficient, local efficiency, and global efficiency) between the two groups. Partial Pearson’s correlation analysis was used to calculate the correlations of the changes in gray matter volume and glucose intake in the key brain regions in MCI with the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog) sub-item scores.Results: Significant changes in the brain network parameters (longer characteristic path length, larger clustering coefficient, and lower local efficiency and global efficiency) were greater in the structural network than in the metabolic network (longer characteristic path length) in MCI patients than in HCs. We obtained the key brain regions (left globus pallidus, right calcarine fissure and its surrounding cortex, left lingual gyrus) by scanning the hubs. The volume of gray matter atrophy in the left globus pallidus was significantly positively correlated with comprehension of spoken language (p = 0.024) and word-finding difficulty in spontaneous speech item scores (p = 0.007) in the ADAS-cog. Glucose intake in the three key brain regions was significantly negatively correlated with remembering test instructions items in ADAS-cog (p = 0.020, p = 0.014, and p = 0.008, respectively).Conclusion: Structural brain networks showed more changes than metabolic brain networks in patients with MCI. Some brain regions with significant changes in betweenness centrality in both structural and metabolic networks were associated with MCI.

Despite the many neuroimaging studies that suggest gray matter volume reductions in schizophrenia, there is no compelling postmortem evidence to suggest neuronal loss, nor is there a distinctive or specific signature of gray matter abnormalities in schizophrenia. Instead, there appears to be no observed focal lesion that characterizes gray matter pathology in schizophrenia. This state of affairs has led to a movement away from conceptualizing schizophrenia as resulting from a single lesion, to conceptualizing schizophrenia as arising from abnormal communication between brain regions. Abnormal connectivity between brain regions is not a new concept, as Bleuler (1911) postulated such abnormalities. What is new, however, is an appreciation that brain regions that are not spatially proximal may be connected functionally into neural networks and that to understand altered neural connectivity we need to have a better understanding of the connections between brain regions which are made possible by white matter, the main infrastructure in the brain that makes possible long distance communication among neurons. Accordingly, a focus on white matter connections in the brain has become increasingly of interest in schizophrenia, particularly in the areas of imaging studies, postmortem studies, and new animal models of schizophrenia. This special issue focuses on schizophrenia and oligodendrocytes, the latter a class of neuroglia that give rise to myelin. The primary aim of this special issue is to understand and to clarify further white matter pathology in schizophrenia and how it may contribute to disconnectivity among brain regions, which results in the observed cognitive, behavioral, and clinical symptoms in this disorder. The first paper begins with a description of the theory that schizophrenia reflects a disorder of connectivity. The proposition put forth is that schizophrenia is, at least in part, the result of abnormal communication between brain regions that may be spatially distant but nonetheless functionally connected. As white matter is the main infrastructure for brain connectivity, this paper focuses on the use of a magnetic resonance imaging (MRI) technique called diffusion tensor imaging (DTI) to gain insight into the role of white matter abnormalities in schizophrenia. This paper also focuses on the functional implications of white matter abnormalities, particularly with regard to the possible role of myelin in modulating the transmission velocity of neural discharges. The paper ends with a speculative hypothesis about the relationship between gray matter and white matter abnormalities in schizophrenia. The second paper also focuses on altered neuronal connectivity. Here, however, the focus is on altered connectivity and impaired myelination in a postmortem study of schizophrenia and normal controls, where electron microscopy is used to study myelinated fibers and oligodendrocytes. This morphometric study examines myelinated fibers in the prefrontal cortex in both gray and white matter. Six types of abnormal fibers and ultrastructural alterations are described in the schizophrenia sample. The study reveals increased pathological fibers in gray matter in both young and elderly patients that are associated with positive symptoms, while in elderly patients, the frequency of pathological fibers in white matter is increased and these changes are associated with more negative symptoms. The key implication here is that altered myelinated fibers in white matter in schizophrenia likely follow alterations of myelinated fibers in gray matter that occur earlier in the course of illness. The third paper is a postmortem study on age-related changes in the number of oligodendrocytes in prefrontal cortex in schizophrenia, bipolar disorder and major depression. The study reveals an age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA9 and 10 that is seen only in normal controls and not in schizophrenia or in mood disorders. The absence of the normal age-related increase in oligodendrocytes in patients suggests that this aspect of normal brain development is dysregulated in schizophrenia and in mood disorders, and confirms postmortem and imaging data, further highlighting the fact that the absence of a normal age-related increase in oligodendrocytes is a key shared feature in these psychiatric populations. The fourth paper reviews white matter abnormalities in schizophrenia, including imaging and postmortem findings on the disconnectivity theory of schizophrenia, a major theme that underlies the three previous papers in this special issue. This paper then reviews some of the white matter diseases that commonly lead to psychotic symptoms and then reviews transgenic and mutant mouse models of schizophrenia. More specifically, genetic mouse models such as Plp1 transgenic mice and mutant mice heterogeneous for either NRG1 or its receptor erbB4, as well as Nogo-A- deficient mice are reviewed. This is followed by a focus on the myelin toxicity model of mice fed cuprizone. In the early stage (the second and third week) of the cuprizone feeding, mice show higher dopamine levels and lower norepinephrine levels in their prefrontal cortex, along with behavioral changes indicative of increased CNS activity. In the late stage (weeks 4–6), when demyelination and oligodendrocyte loss are obvious, mice display cognitive deficits as well as deficits in social interactions that are reminiscent of social withdrawal seen in patients with schizophrenia. Importantly, this cuprizone-feeding mouse may be used as an in vivo platform for psychopharmacological studies testing the effects of antipsychotic drugs on white matter alterations and associated behavioral changes, in addition to providing a new animal model of schizophrenia. The fifth and final paper of this special issue focuses on abnormal behavior and microstructural changes in juvenile mice that are repeatedly exposed to nonneurotoxic levels of amphetamine. These mice are compared with nonamphetamine treated mice. Oligodendrocyte numbers and three proteins expressed in mature oligodendrocytes are investigated in these young male mice at sacrifice. Treated mice showed higher locomotion and impaired spatial working memory, along with lowered Noga-A and GST-pi proteins, and lower MBP proteins, in frontal cortex and hippocampus and fewer mature oligodendrocytes in frontal cortex and corpus callosum, as well as lower MBP staining in frontal cortex, corpus callosum, and hippocampus, than untreated mice. These differences suggest that in wild-type mice late developing white matter is vulnerable to amphetamine and may lead to compromised white matter with increased dopamine in specific brain regions. Not only do these findings explain well the increased locomotion and impaired spatial working memory observed in amphetamine-treated mice, but also may serve as a principle for the amphetamine-treated mouse being used as a novel animal model of schizophrenia. To summarize, compared to the focus on gray matter and neurons, research on white matter and myelin/glial has been sparse in schizophrenia. In this special issue, neuroimaging findings are presented that suggest that myelin abnormalities in schizophrenia may underlie the white matter abnormalities observed using diffusion tensor imaging techniques. Data from postmortem studies also confirm the presence of oligodendrocyte and myelin abnormalities in schizophrenia as well as mood disorders. Oligodendrocytes provide protection and improve communication between brain regions and the oligodendroglia-producing myelin is approaching maturity in the same time frame as the onset of symptoms. Further, normal age-related white matter increases and related gray matter changes that likely predate the white matter changes are dysregulated in schizophrenia and may contribute to the clinical symptomatology of the disease. Finally, the recently developed animal models are not only of help in understanding connectivity abnormalities in schizophrenia but also provide novel platforms to test novel therapeutic approaches for schizophrenic patients. Treatments specifically targeting white matter, for example, may improve on the efficacy of those treatments currently in use. Martha E. Shenton Haiyun Xu Vahram Haroutunian George Bartzokis

Repeated episodes of hypoxia, hypercapnia and transient blood pressure elevation in obstructive sleep apnea syndrome (OSAS) may damage neutral structures and induce cerebral metabolic impairment. This study aimed to determine the impact of OSAS on cerebral metabolites measured by (1)H magnetic resonance spectroscopy ((1)H -MRS). Twenty OSAS patients underwent standard overnight polysomnography and (1)H-MRS separately. Proton volumes of interest (VOIs) were placed in frontal and midtemporal regions bilaterally. Significantly lower values of the N-acetylaspartate (NAA)/creatine (Cr) ratio were found in frontal regions (P < 0.004) compared with 20 age-matched control subjects. A significant increase in the myo-inositol (Ins)/Cr ratio was evident bilaterally in temporal and frontal regions (P < 0.00002 and P < 0.04). Choline (Cho)/Cr ratio values were also significantly greater in temporal regions (P < 0.00001). A significant negative correlation (r = -0.51, P < 0.03) was found between the apnea-hypopnea index (AHI) and NAA/Cr ratio in the frontal regions of OSAS patients. Reduction in the NAA/Cr ratio in frontal regions of OSAS patients could be related to neural loss. Increase in the Cho/Cr ratio in temporal regions and Ins/Cr ratio in both frontal and temporal regions could be interpreted as evidence of membrane breakdown and reactive gliosis, respectively, consequent to repeated episodes of hypoxia in OSAS.

The Lateral Asymmetry of the Human Brain Studied by Volumetric Magnetic Resonance Imaging

The Lateral Asymmetry of the Human Brain Studied by Volumetric Magnetic Resonance Imaging

Neuroimaging studies suggested that drug addiction is linked to abnormal brain functional connectivity. However, little is known about the alteration of brain white matter (WM) connectivity in addictive drug users and nearly no study has been performed to examine the alterations of brain WM connectivity in heroin-dependent individuals (HDIs). Diffusion tensor imaging (DTI) offers a comprehensive technique to map the whole brain WM connectivity in vivo. In this study, we acquired DTI datasets from 20 HDIs and 18 healthy controls and constructed their brain WM structural networks using a deterministic fibre tracking approach. Using graph theoretical analysis, we explored the global and nodal topological parameters of brain network for both groups and adopted a network-based statistic (NBS) approach to assess between-group differences in inter-regional WM connections. Statistical analysis indicated the global efficiency and network strength were significantly increased, but the characteristic path length was significantly decreased in the HDIs compared with the controls. We also found that in the HDIs, the nodal efficiency was significantly increased in the left prefrontal cortex, bilateral orbital frontal cortices and left anterior cingulate gyrus. Moreover, the NBS analysis revealed that in the HDIs, the significant increased connections were located in the paralimbic, orbitofrontal, prefrontal and temporal regions. Our results may reflect the disruption of whole brain WM structural networks in the HDIs. Our findings suggest that mapping brain WM structural network may be helpful for better understanding the neuromechanism of heroin addiction.

To compare white matter (WM) injuries associated with vision loss in multiple sclerosis (MS) and optic neuritis (ON). Twenty-three patients with clinically definite relapsing-remitting MS and chronic unilateral ON and 14 neurologically healthy volunteers were monocularly tested with Sloan 100%, 2.5%, and 1.25% contrast visual acuity charts. Primary visual pathway and whole-brain WM injury were assessed with optical coherence tomography (OCT) and diffusion tensor imaging (DTI). OCT and DTI correlates of high- and low-contrast visual impairment were identified using correlation analyses. The MS patients displayed significantly reduced retinal nerve fiber layer (RNFL) thickness and altered optic nerve and radiation DTI measures compared with the controls. In the patients, 2.5% and 1.25% contrast letter acuity in the unaffected eye correlated significantly and independently with optic nerve and optic radiation DTI measures. Visual acuity in affected eyes did not correlate with optic nerve or optic radiation DTI measures, but did correlate with DTI measures in prefrontal and temporal brain regions that were shown to connect structurally to visual cortices. In unaffected eyes, visual impairment was associated with WM injury in the visual pathway. In contrast, irrecoverable visual impairment after ON was associated with injury to frontal WM, which potentially impairs the capacity for remapping visual processing.

Background and PurposeIncreasing evidence suggests that cirrhosis may affect the connectivity among different brain regions in patients before overt hepatic encephalopathy (OHE) occurs. However, there has been no study investigating the structural reorganization of these altered connections at the network level. The primary focus of this study was to investigate the abnormal topological organization of the structural network in patients with hepatitis B virus-related cirrhosis (HBV-RC) without OHE using structural MRI.MethodsUsing graph theoretical analysis, we compared the global and regional topological properties of gray matter structural networks between 28 patients with HBV-RC without OHE and 30 age-, sex- and education-matched healthy controls. The structural correlation networks were constructed for the two groups based on measures of gray matter volume.ResultsThe brain network of the HBV-RC group exhibited a significant decrease in the clustering coefficient and reduced small-worldness at the global level across a range of network densities. Regionally, brain areas with altered nodal degree/betweenness centrality were observed predominantly in association cortices (frontal and temporal regions) (p < 0.05, uncorrected), including a significantly decreased nodal degree in the inferior temporal gyrus (p < 0.001, uncorrected). Furthermore, the HBV-RC group exhibited a loss of association hubs and the emergence of an increased number of non-association hubs compared with the healthy controls.ConclusionThe results of this large-scale gray matter structural network study suggest reduced topological organization efficiency in patients with HBV-RC without OHE. Our findings provide new insight concerning the mechanisms of neurobiological reorganization in the HBV-RC brain from a network perspective.

Information about brain structure, especially information about how neurons or brain regions are wired is essential for the study of brain function and brain disease [1,2]. Recently, brain networks have drawn increasing attention due to the success of graph-theoretic or statistical physics-based network analysis of complex systems such as WWW, social networks, and metabolic networks [3] and the development of techniques for obtaining brain connectivity information. Graph theory enables us to describe a neural system simply as a graph which is a collection of nodes corresponding to neurons, neuronal population, or brain regions and links corresponding to the structural links or statistical or causal relationships between the nodes [1,2]. Since elements of the brain group together to perform functions, it is important to find out how closely two elements are related and which elements form a module which can be defined as a subsystem of a system that is functionally or structurally distinct from other parts of the system. Here, we introduce a similarity measure between nodes based on random walks in which the diffusion flux decays with the path length in the network [4]. The similarity is measured as how similarly two diffusion processes starting from two different nodes affect other nodes of the network. The decaying diffusion process reveals the landscape of the networks and using this similarity measure, we propose a multi-scale clustering method to uncover hierarchically modular structures in brain networks. In hierarchically modular networks (HMN), modules consist of sub-modules and those sub-modules may be composed of smaller sub-modules and so on. HMNs reflect the functional segregation of local areas and global integration in complex systems such as the brain and society. We incorporate multi-scale multiple grouping which gives the information about the frequency of nodes being grouped together in various sizes of groups. Then, we sequentially remove weak ties, which are defined by low co-membership frequency, and find out connected components which correspond to the modules of the system. We apply our method to analyze hierarchical modular structure of macaque monkey brain network and discuss the results. This method can be used to analyze both structural and functional brain networks.

Objective To explore the topological properties of the brain structural network in patients with neuromyelitis optica spectrum disorder (NMOSD). Methods Diffusion tensor imaging was performed in 41 NMOSD patients (patient group) and 40 age- and sex-matched healthy volunteers (control group) who were admitted to the Department of Neurology, The Third Affiliated Hospital to Sun Yat-sen University from September 2014 to October 2017. The deterministic fiber tracking techniques were used to construct the white matter structural weighted network. Topological properties of the brain structural network were then calculated based on complex graph theory analysis. The 2 groups were compared in terms of global and local parameters of the brain structural network using statistical methods. Results The brain structural networks in both groups exhibited small world properties. Compared with the control group, the global efficiency of the brain structural network in the patient group was significantly decreased and the shortest path length significantly increased (P=0.002, P= 0.002, FDR correction). There were no statistically significant differences between the brain structural networks of the 2 groups in terms of clustering coefficient, the shortest path length on average, value of small world property, average clustering coefficient or local efficiency (P=0.780, P=0.496, P=0.279, P=0.269, P= 0.050, FDR correction). Compared with the control group, the nodal efficiency of the brain structural network of the patient group was significantly decreased in the frontal lobe (bilateral precentral gyrus, middle frontal gyrus of the right orbital part, inferior frontal gyrus of the right opercular part, right rolandic operculum, bilateral median cingulate and paracingulate gyri), parietal lobe (right posterior cingulate gyrus, right superior parietal gyrus, left inferior parietal of angular gyri, right angle gyrus, and right precuneus), temporal lobe (bilateral hippocampus and right parahippocampal gyrus), occipital lobe (left cuneus, left superior occipital gyrus, bilateral middle occipital gyrus, and left inferior occipital gyrus) and subcortical region (right caudate nucleus and right thalamus) (P<0.05, FDR correction). Conclusion There is abnormal connection in brain structural network in NMOSD patients. Key words: Neuromyelitis optica spectrum disorder; Diffusion tensor imaging; Brain structural network; Topological property

Alzheimer's disease (AD) is the most common type of dementia, comprising an estimated 60-80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging (structural magnetic resonance imaging (MRI), diffusion MRI, and functional MRI) and neurophysiological techniques (electroencephalography and magnetoencephalography) with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment (MCI), the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks (i.e., connectomics) and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.

BackgroundThe earliest brain changes in Huntington’s disease (HD) are characterised by loss of caudate volume and surrounding white matter occurring early in the premanifest stage, with more extensive loss seen...

BackgroundAlzheimer’s disease (AD) is one of the most complex diseases and is characterized by neuropathological features, including accumulation of beta‐amyloid plaques and tau neurofibrillary tangles. These neuropathological features exhibit heterogeneity across brain regions in different patients, leading to different symptoms. Dysregulation of alternative splicing (AS) has been observed to contribute to neuropathological features in AD; however, their molecular mechanisms via AS remain unclear. Therefore, we aimed to systemically investigate the impact of AS (i.e., exon skipping) on AD‐related neuropathological features (i.e., Braak stage and plaque density) and the functional connections of alternately spliced genes across multiple brain regions in AD patients.MethodWe analyzed RNA‐seq data generated by the MSBB project representing two brain regions: the frontal region (frontal pole; FP, n = 175, inferior frontal gyrus; IF, n = 87) and the temporal (parahippocampal gyrus; PH, n = 93 and superior temporal gyrus; ST, n = 101). The data were mapped to the hg19 reference genome with the STAR aligner and exon skipping rates were estimated as percent spliced in (PSI) by rMATs. Then, we performed a linear regression to evaluate clinical or pathogenic associations between exon PSI levels and the Braak stage and plaque density mean for each brain region, considering sex as a covariate.ResultWe identified 192 and 158 exon skipping (ES) associated with Braak stages in the frontal and temporal regions, respectively. In addition, 863 and 845 events were associated with plaque density. Notably, while the two regions shared only 20% (60 events) of Braak‐associated ES, they coincided in 90% (808 events) of plaque‐associated ES. Enrichment analysis of functional annotations found that frontal‐specific ES associated with Braak stage was enriched in interleukin signaling and the neurodegenerative‐related CDK5 pathway, while temporal‐specific ES was enriched in lipoprotein clearance functional pathways. For plaque density‐associated ES shared between regions, the most significantly enriched pathway was Notch4 signaling, represented for example by SOD2, in which skipping of the functional domain‐encoding exon 4 was associated with plaque mean in both regions.ConclusionThis study provides a landscape of brain region‐dependent AS events and of AD risk genes that contribute to neuropathological features in AD patients.