Identifying functional network changing patterns in individuals at clinical high-risk for psychosis and patients with early illness schizophrenia: A group ICA study.

Although individuals at clinical high risk (CHR) for psychosis exhibit a psychosis-risk syndrome involving attenuated forms of the positive symptoms typical of schizophrenia (SZ), it remains unclear whether their resting-state brain intrinsic functional networks (INs) show attenuated or qualitatively distinct patterns of functional dysconnectivity relative to SZ patients. Based on resting-state functional magnetic imaging data from 70 healthy controls (HCs), 53 CHR individuals (among which 41 subjects were antipsychotic medication-naive), and 58 early illness SZ (ESZ) patients (among which 53 patients took antipsychotic medication) within five years of illness onset, we estimated subject-specific INs using a novel group information guided independent component analysis (GIG-ICA) and investigated group differences in INs. We found that when compared to HCs, both CHR and ESZ groups showed significant differences, primarily in default mode, salience, auditory-related, visuospatial, sensory-motor, and parietal INs. Our findings suggest that widespread INs were diversely impacted. More than 25% of voxels in the identified significant discriminative regions (obtained using all 19 possible changing patterns excepting the no-difference pattern) from six of the 15 interrogated INs exhibited monotonically decreasing Z-scores (in INs) from the HC to CHR to ESZ, and the related regions included the left lingual gyrus of two vision-related networks, the right postcentral cortex of the visuospatial network, the left thalamus region of the salience network, the left calcarine region of the fronto-occipital network and fronto-parieto-occipital network. Compared to HCs and CHR individuals, ESZ patients showed both increasing and decreasing connectivity, mainly hypo-connectivity involving 15% of the altered voxels from four INs. The left supplementary motor area from the sensory-motor network and the right inferior occipital gyrus in the vision-related network showed a common abnormality in CHR and ESZ groups. Some brain regions also showed a CHR-unique alteration (primarily the CHR-increasing connectivity). In summary, CHR individuals generally showed intermediate connectivity between HCs and ESZ patients across multiple INs, suggesting that some dysconnectivity patterns evident in ESZ predate psychosis in attenuated form during the psychosis risk stage. Hence, these connectivity measures may serve as possible biomarkers to predict schizophrenia progression

A Selective Review of Multimodal Fusion Methods in Schizophrenia

Schizophrenia (SZ) is one of the most cryptic and costly mental disorders in terms of human suffering and societal expenditure (van Os and Kapur, 2009). Though strong evidence for functional, structural, and genetic abnormalities associated with this disease exists, there is yet no replicable finding which has proven accurate enough to be useful in clinical decision making (Fornito et al., 2009), and its diagnosis relies primarily upon symptom assessment (Williams et al., 2010a). It is likely in part that the lack of consistent neuroimaging findings is because most models favor only one data type or do not combine data from different imaging modalities effectively, thus missing potentially important differences which are only partially detected by each modality (Calhoun et al., 2006a). It is becoming increasingly clear that multimodal fusion, a technique which takes advantage of the fact that each modality provides a limited view of the brain/gene and may uncover hidden relationships, is an important tool to help unravel the black box of schizophrenia. In this review paper, we survey a number of multimodal fusion applications which enable us to study the schizophrenia macro-connectome, including brain functional, structural, and genetic aspects and may help us understand the disorder in a more comprehensive and integrated manner. We also provide a table that characterizes these applications by the methods used and compare these methods in detail, especially for multivariate models, which may serve as a valuable reference that helps readers select an appropriate method based on a given research question

Altered Topological Properties of Functional Network Connectivity in Schizophrenia during Resting State: A Small-World Brain Network Study

Aberrant topological properties of small-world human brain networks in patients with schizophrenia (SZ) have been documented in previous neuroimaging studies. Aberrant functional network connectivity (FNC, temporal relationships among independent component time courses) has also been found in SZ by a previous resting state functional magnetic resonance imaging (fMRI) study. However, no study has yet determined if topological properties of FNC are also altered in SZ. In this study, small-world network metrics of FNC during the resting state were examined in both healthy controls (HCs) and SZ subjects. FMRI data were obtained from 19 HCs and 19 SZ. Brain images were decomposed into independent components (ICs) by group independent component analysis (ICA). FNC maps were constructed via a partial correlation analysis of ICA time courses. A set of undirected graphs were built by thresholding the FNC maps and the small-world network metrics of these maps were evaluated. Our results demonstrated significantly altered topological properties of FNC in SZ relative to controls. In addition, topological measures of many ICs involving frontal, parietal, occipital and cerebellar areas were altered in SZ relative to controls. Specifically, topological measures of whole network and specific components in SZ were correlated with scores on the negative symptom scale of the Positive and Negative Symptom Scale (PANSS). These findings suggest that aberrant architecture of small-world brain topology in SZ consists of ICA temporally coherent brain networks

Altered Small-World Brain Networks in Temporal Lobe in Patients with Schizophrenia Performing an Auditory Oddball Task

The functional architecture of the human brain has been extensively described in terms of complex networks characterized by efficient small-world features. Recent functional magnetic resonance imaging (fMRI) studies have found altered small-world topological properties of brain functional networks in patients with schizophrenia (SZ) during the resting state. However, little is known about the small-world properties of brain networks in the context of a task. In this study, we investigated the topological properties of human brain functional networks derived from fMRI during an auditory oddball (AOD) task. Data were obtained from 20 healthy controls and 20 SZ; A left and a right task-related network which consisted of the top activated voxels in temporal lobe of each hemisphere were analyzed separately. All voxels were detected by group independent component analysis. Connectivity of the left and right task-related networks were estimated by partial correlation analysis and thresholded to construct a set of undirected graphs. The small-worldness values were decreased in both hemispheres in SZ. In addition, SZ showed longer shortest path length and lower global efficiency only in the left task-related networks. These results suggested small-world attributes are altered during the AOD task-related networks in SZ which provided further evidences for brain dysfunction of connectivity in SZ

Differential association of the Na+/H+ exchanger regulatory factor (NHERF) family of adaptor proteins with the raft- and the non-raft brush border membrane fractions of NHE3

Background/Aims: Trafficking, brush border membrane (BBM) retention, and signal-specific regulation of the Na+/H+ exchanger NHE3 is regulated by the Na+/H+ Exchanger Regulatory Factor (NHERF) family of PDZ-adaptor proteins, which enable the formation of multiprotein complexes. It is unclear, however, what determines signal specificity of these NHERFs. Thus, we studied the association of NHE3, NHERF1 (EBP50), NHERF2 (E3KARP), and NHERF3 (PDZK1) with lipid rafts in murine small intestinal BBM. Methods: Detergent resistant membranes ('lipid rafts') were isolated by floatation of Triton X-incubated small intestinal BBM from a variety of knockout mouse strains in an Optiprep step gradient. Acid-activated NHE3 activity was measured fluorometrically in BCECF-loaded microdissected villi, or by assessment of CO2/HCO3 - mediated increase in fluid absorption in perfused jejunal loops of anethetized mice. Results: NHE3 was found to partially associate with lipid rafts in the native BBM, and NHE3 raft association had an impact on NHE3 transport activity and regulation in vivo. NHERF1, 2 and 3 were differentially distributed to rafts and non-rafts, with NHERF2 being most raft-associated and NHERF3 entirely non-raft associated. NHERF2 expression enhanced the localization of NHE3 to membrane rafts. The use of acid sphingomyelinase-deficient mice, which have altered membrane lipid as well as lipid raft composition, allowed us to test the validity of the lipid raft concept in vivo. Conclusions: The differential association of the NHERFs with the raft-associated and the non-raft fraction of NHE3 in the brush border membrane is one component of the differential and signal-specific NHE3 regulation by the different NHERFs

Multimodal Fusion With Reference: Searching for Joint Neuromarkers of Working Memory Deficits in Schizophrenia

Multimodal fusion is an effective approach to take advantage of cross-information among multiple imaging data to better understand brain diseases. However, most current fusion approaches are blind, without adopting any prior information. To date, there is increasing interest to uncover the neurocognitive mapping of specific behavioral measurement on enriched brain imaging data; hence, a supervised, goal-directed model that enables a priori information as a reference to guide multimodal data fusion is in need and a natural option. Here we proposed a fusion with reference model, called “multi-site canonical correlation analysis with reference plus joint independent component analysis” (MCCAR+jICA), which can precisely identify co-varying multimodal imaging patterns closely related to reference information, such as cognitive scores. In a 3-way fusion simulation, the proposed method was compared with its alternatives on estimation accuracy of both target component decomposition and modality linkage detection. MCCAR+jICA outperforms others with higher precision. In human imaging data, working memory performance was utilized as a reference to investigate the covarying functional and structural brain patterns among 3 modalities and how they are impaired in schizophrenia. Two independent cohorts (294 and 83 subjects respectively) were used. Interestingly, similar brain maps were identified between the two cohorts, with substantial overlap in the executive control networks in fMRI, salience network in sMRI, and major white matter tracts in dMRI. These regions have been linked with working memory deficits in schizophrenia in multiple reports, while MCCAR+jICA further verified them in a repeatable, joint manner, demonstrating the potential of such results to identify potential neuromarkers for mental disorders

Aberrant Dynamic Functional Network Connectivity and Graph Properties in Major Depressive Disorder

Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified abnormalities in large scale functional brain networks in MDD, yet most of them were based on static functional connectivity. In contrast, here we explored disrupted topological organization of dynamic functional network connectivity (dFNC) in MDD based on graph theory. One hundred and eighty-two MDD patients and 218 healthy controls were included in this study, all Chinese Han people. By applying group information guided independent component analysis (GIG-ICA) to resting-state functional magnetic resonance imaging (fMRI) data, the dFNCs of each subject were estimated using a sliding window method and k-means clustering. Network properties including global efficiency, local efficiency, node strength and harmonic centrality, were calculated for each subject. Five dynamic functional states were identified, three of which demonstrated significant group differences in their percentage of state occurrence. Interestingly, MDD patients spent much more time in a weakly-connected State 2, which includes regions previously associated with self-focused thinking, a representative feature of depression. In addition, the FNCs in MDD were connected differently in different states, especially among prefrontal, sensorimotor, and cerebellum networks. MDD patients exhibited significantly reduced harmonic centrality primarily involving parietal lobule, lingual gyrus and thalamus. Moreover, three dFNCs with disrupted node properties were commonly identified in different states, and also correlated with depressive symptom severity and cognitive performance. This study is the first attempt to investigate the dynamic functional abnormalities in MDD in a Chinese population using a relatively large sample size, which provides new evidence on aberrant time-varying brain activity and its network disruptions in MDD, which might underscore the impaired cognitive functions in this mental disorder

Altered Small-World Brain Networks in Schizophrenia Patients during Working Memory Performance

Impairment of working memory (WM) performance in schizophrenia patients (SZ) is well-established. Compared to healthy controls (HC), SZ patients show aberrant blood oxygen level dependent (BOLD) activations and disrupted functional connectivity during WM performance. In this study, we examined the small-world network metrics computed from functional magnetic resonance imaging (fMRI) data collected as 35 HC and 35 SZ performed a Sternberg Item Recognition Paradigm (SIRP) at three WM load levels. Functional connectivity networks were built by calculating the partial correlation on preprocessed time courses of BOLD signal between task-related brain regions of interest (ROIs) defined by group independent component analysis (ICA). The networks were then thresholded within the small-world regime, resulting in undirected binarized small-world networks at different working memory loads. Our results showed: 1) at the medium WM load level, the networks in SZ showed a lower clustering coefficient and less local efficiency compared with HC; 2) in SZ, most network measures altered significantly as the WM load level increased from low to medium and from medium to high, while the network metrics were relatively stable in HC at different WM loads; and 3) the altered structure at medium WM load in SZ was related to their performance during the task, with longer reaction time related to lower clustering coefficient and lower local efficiency. These findings suggest brain connectivity in patients with SZ was more diffuse and less strongly linked locally in functional network at intermediate level of WM when compared to HC. SZ show distinctly inefficient and variable network structures in response to WM load increase, comparing to stable highly clustered network topologies in HC