The causal relationship between COVID-19 and ten esophageal diseases: a study utilizing Mendelian randomization.

Background: Clinical signs of dysphagia, pancreatic achalasia, and esophagitis have been reported in patients with COVID-19. However, the causal relationship between COVID-19 and esophageal diseases is not clear. Therefore, we utilized Mendelian randomization to explore the potential association between COVID-19 and esophageal diseases. Methods: The summary statistics for a Genome-wide association study (GWAS) were obtained from The COVID-19 Host Genetics Initiative, encompassing four types of COVID-19 as exposure: severe COVID-19, hospitalized COVID-19 versus ambulatory COVID-19, hospitalized COVID-19 versus uninfected, and confirmed COVID-19. Additionally, summary statistics for ten esophageal diseases as outcomes were sourced from the GWAS Catalog and FinnGen databases. Univariate Mendelian randomization (MR) analysis was utilized to thoroughly investigate and validate the potential causal association between COVID-19 and various esophageal conditions, including esophageal varices, Barrett's esophagus, esophagitis, esophageal obstruction, esophageal ulcer, esophageal perforation, gastroesophageal reflux, congenital esophageal malformations, benign esophageal tumors, and esophageal adenocarcinoma. Results: An inverse variance-weighted (IVW) model was utilized for univariate Mendelian randomization (MR) analysis, which revealed that genetic liability in patients with confirmed COVID-19 was associated with esophageal obstruction (OR [95% CI]: 0.5275458 [0.2822400-0.9860563]; p-value = 0.0450699). Furthermore, a suggestive causal association was found between genetic liability and a reduced risk of benign esophageal tumors (OR [95% CI]: 0.2715453 [0.09368493-0.7870724]; p-value = 0.0163510), but with a suggestively increased risk of congenital esophageal malformations (OR [95% CI]: 6.959561 [1.1955828-40.51204]; p-value = 0.03086835). Additionally, genetic liability in hospitalized COVID-19 patients, compared to non-hospitalized COVID-19 patients, was suggestively associated with an increased risk of esophagitis (OR [95% CI]: 1.443859 [1.0890568-1.914252]; p-value = 0.01068201). The reliability of these causal findings is supported by Cochran's Q statistic and the MR-Egger intercept test. Conclusion: The results of this study suggest the existence of a causal relationship between COVID-19 and esophageal diseases, highlighting differing risk effects of COVID-19 on distinct esophageal conditions.

Angiogenesis coupled with osteogenesis in a bone tissue engineering scaffold enhances bone repair in osteoporotic bone defects.

Increased life expectancy has resulted in an increase in osteoporosis incidence worldwide. The coupling of angiogenesis and osteogenesis is indispensable for bone repair. Although traditional Chinese medicine (TCM) exerts therapeutic effects on osteoporosis, TCM-related scaffolds, which focus on the coupling of angiogenesis and osteogenesis, have not yet been used for the treatment of osteoporotic bone defects.Panax notoginsengsaponin (PNS), the active ingredient ofPanax notoginseng, was added to a poly (L-lactic acid) (PLLA) matrix. Osteopractic total flavone (OTF), the active ingredient ofRhizoma Drynariae, was encapsulated in nano-hydroxyapatite/collagen (nHAC) and added to the PLLA matrix. Magnesium (Mg) particles were added to the PLLA matrix to overcome the bioinert character of PLLA and neutralize the acidic byproducts generated by PLLA. In this OTF-PNS/nHAC/Mg/PLLA scaffold, PNS was released faster than OTF. The control group had an empty bone tunnel; scaffolds containing OTF:PNS = 100:0, 50:50, and 0:100 were used as the treatment groups. Scaffold groups promoted new vessel and bone formation, increased the osteoid tissue, and suppressed the osteoclast activity around osteoporotic bone defects. Scaffold groups upregulated the expression levels of angiogenic and osteogenic proteins. Among these scaffolds, the OTF-PNS (50:50) scaffold exhibited a better capacity for osteogenesis than the OTF-PNS (100:0 and 0:100) scaffolds. Activation of the bone morphogenic protein (BMP)-2/BMP receptor (BMPR)-1A/runt-related transcription factor (RUNX)-2signaling pathway may be a possible mechanism for the promotion of osteogenesis. Our study demonstrated that the OTF-PNS/nHAC/Mg/PLLA scaffold could promote osteogenesis via the coupling of angiogenesis and osteogenesis in osteoporotic rats with bone defects, and activating theBMP-2/BMPR1A/RUNX2signaling pathway may be an osteogenesis-related mechanism. However, further experiments are necessary to facilitate its practical application in the treatment of osteoporotic bone defects.

Chinese herbal formula, modified Xianfang Huoming Yin, alleviates the inflammatory proliferation of rat synoviocytes induced by IL-1ß through regulating the migration and differentiation of T lymphocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Xianfang Huoming Yin (XFH) is a traditional Chinese herbal formula, which has the effect of clearing heat and detoxifying toxins, dispersing swellings, activating blood circulation, and relieving pain. It is usually applied to treat various autoimmune diseases, including Rheumatoid arthritis (RA). AIM OF THE STUDY: The migration of T lymphocytes plays an indispensable role in the pathogenesis of RA. Our previous studies demonstrated that modified Xianfang Huoming Yin (XFHM) could modulate the differentiation of T, B, and NK cells, and contribute to the restoration of immunologic balance. It also could downregulate the production of pro-inflammatory cytokines by regulating the activation of NF-κ B and JAK/STAT signaling pathways in the collagen-induced arthritis mouse model. In this study, we want to investigate whether XFHM has therapeutic effects on the inflammatory proliferation of rat fibroblast-like synovial cells (FLSs) by interfering with the migration of T lymphocytes in vitro experiments. MATERIALS AND METHODS: High performance liquid chromatography-electrospray ionization/mass spectrometer system was used to identify the constituents of the XFHM formula. A co-culture system of rat fibroblast-like synovial cells (RSC-364 cells) and peripheral blood lymphocytes stimulated by interleukin-1 beta (IL-1ß) was used as the cell model. IL-1ß inhibitor (IL-1ßRA) was used as a positive control medicine, and two concentrations (100 µg/mL and 250 µg/mL) of freeze-dried XFHM powder were used as intervention measure. The lymphocyte migration levels were analyzed by the Real-time xCELLigence analysis system after 24 h and 48 h of treatment. The percentage of CD3+CD4+ T cells and CD3+CD8+ T cells, and the apoptosis rate of FLSs were detected by flow cytometry. The morphology of RSC-364 cells was observed by hematoxylin-eosin staining. The protein expression of key factors for T cell differentiation and NF-κ B signaling pathway-related proteins in RSC-364 cells were examined by western-blot analysis. The migration-related cytokines levels of P-selectin, VCAM-1, and ICAM-1 in the supernatant were measured by enzyme-linked immunosorbent assay. RESULTS: Twenty-one different components in XFHM were identified. The migration CI index of T cells was significantly decreased in treatment with XFHM. XFHM also could significantly downregulate the levels r of CD3+CD4+T cells and CD3+CD8+T cells that migrated to the FLSs layer. Further study found that XFHM suppresses the production of P-selectin, VCAM-1, and ICAM-1. Meanwhile, it downregulated the protein levels of T-bet, ROR γ t, IKKα/ß, TRAF2, and NF-κ B p50, upregulated the expression of GATA-3 and alleviated synovial cells inflammation proliferation, contributing to the FLSs apoptosis. CONCLUSION: XFHM could attenuate the inflammation of synovium by inhibiting T lymphocyte cell migration, regulating differentiation of T cells through modulating the activation of the NF-κ B signaling pathway.

Sequential Release of Panax Notoginseng Saponins and Osteopractic Total Flavone from Poly (L-Lactic Acid) Scaffold for Treating Glucocorticoid-Associated Osteonecrosis of Femoral Head.

Glucocorticoids inhibit angiogenesis in the femoral head, which fails to nourish the bone tissue and leads to osteonecrosis. Restoring angiogenesis is not only essential for vessel formation, but also crucial for osteogenesis. Poly (L-lactic acid) (PLLA) is commonly used in the bone tissue engineering field. Panax notoginseng saponins (PNS) and osteopractic total flavone (OTF) promote angiogenesis and osteogenesis, respectively. We designed a sequentially releasing PLLA scaffold including PLLA loaded with OTF (inner layer) and PLLA loaded with PNS (outer layer). We assessed the osteogenic effect of angiogenesis in this scaffold by comparing it with the one-layered scaffold (PLLA embedded with OTF and PNS) in vivo. Results from the micro-CT showed that the data of bone mineral density (BMD), bone volume (BV), and percent bone volume (BV/TV) in the PO-PP group were significantly higher than those in the POP group (p < 0.01). Histological analyses show that the PO-PP scaffold exhibits better angiogenic and osteogenic effects compared with the one-layered scaffold. These might result from the different structures between them, where the sequential release of a bi-layer scaffold achieves the osteogenic effect of vascularization by initially releasing PNS in the outer layer. We further explored the possible mechanism by an immunohistochemistry analysis and an immunofluorescence assay. The results showed that the protein expressions of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1(CD31) in the PO-PP scaffold were significantly higher than those in the POP scaffold (p < 0.01); the protein expressions of osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP) in the PO-PP scaffold were significantly higher than those in the POP scaffold (p < 0.05). Upregulating the expressions of angiogenic and osteogenic proteins might be the possible mechanism.

The Herbal Combination of Radix astragali, Radix angelicae sinensis, and Caulis lonicerae Regulates the Functions of Type 2 Innate Lymphocytes and Macrophages Contributing to the Resolution of Collagen-Induced Arthritis.

Type 2 innate lymphocytes (ILC2s), promoting inflammation resolution, was a potential target for rheumatoid arthritis (RA) treatment. Our previous studies confirmed that R. astragali and R. angelicae sinensis could intervene in immunologic balance of T lymphocytes. C. lonicerae also have anti-inflammatory therapeutic effects. In this study, the possible molecular mechanisms of the combination of these three herbs for the functions of ILC2s and macrophages contributing to the resolution of collagen-induced arthritis (CIA) were studied. Therefore, we used R. astragali, R. angelicae sinensis, and C. lonicerae as treatment. The synovial inflammation and articular cartilage destruction were alleviated after herbal treatment. The percentages of ILC2s and Tregs increased significantly. The differentiation of Th17 cells and the secretion of IL-17 and IFN-γ significantly decreased. In addition, treatment by the combination of these three herbs could increase the level of anti-inflammatory cytokine IL-4 secreted, active the STAT6 signaling pathway, and then contribute to the transformation of M1 macrophages to M2 phenotype. The combination of the three herbs could promote inflammation resolution of synovial tissue by regulating ILC2s immune response network. The synergistic effects of three drugs were superior to the combination of R. astragali and R. angelicae sinensis or C. lonicerae alone.

Development of software enabling Chinese medicine-based precision treatment for osteoporosis at the gene and pathway levels.

BACKGROUND: Precision medicine aims to address the demand for precise therapy at the gene and pathway levels. We aimed to design software to allow precise treatment of osteoporosis (OP) with Chinese medicines (CMs) at the gene and pathway levels. METHODS: PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP database), and the Wanfang database were searched to identify studies treating osteoporosis with CMs. The TCMSP was used to identify bioactive ingredients and related genes for each CM. Gene expression omnibus (GEO) database and the limma package were used to identify differentially expressed genes in osteoporosis. Perl software was used to identify the shared genes between the bioactive components in CM and osteoporosis. R packages and bioconductor packages were used to define the target relationship between shared genes and their related pathways. Third-party Python libraries were used to write program codes. Pyinstaller library was used to create an executable program file. RESULTS: Data mining: a total of 164 CMs were included, but Drynariae Rhizoma (gusuibu) was used to present this process. We obtained 44 precise relationships among the bioactive ingredients of Drynariae Rhizoma, shared genes, and pathways. Python programming: we developed the software to show the precise relationship among bioactive ingredients, shared genes, and pathways for each CM, including Drynariae Rhizoma. CONCLUSIONS: This study could increase the precision of CM, and could provide a valuable and convenient software for searching precise relationships among bioactive ingredients, shared genes, and pathways.

Glycosides of Caulis Lonicerae inhibits the inflammatory proliferation of IL-1ß-mediated fibroblast-like synovial cells cocultured with lymphocytes.

Caulis Lonicerae, the dried stem of Lonicera japonica, has been confirmed to have antiinflammatory and antioxidant therapeutic effects. In the present study, we aimed to evaluate the functional mechanism of glycosides extracted from Caulis Lonicerae on the inflammatory proliferation of interleukin-1 beta (IL-1ß)-mediated fibroblast-like synoviocytes (FLSs) from rats. Rat FLSs (RSC-364) co-cultured with lymphocytes induced by IL-1ß were used as a cell model. Glycosides in a freeze-dried powder of aqueous extract from Caulis Lonicerae were identified using high-performance liquid chromatography-electrospray ionization/mass spectrometry. After treatment with glycosides, the inflammatory proliferation of FLS, induced by IL-1ß, decreased significantly. Flow cytometry analysis showed that treatment with glycosides restored the abnormal balance of T cells by intervening in the proliferation and differentiation of helper T (Th) cells. Glycosides also inhibited the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and nuclear factor (NF)-κB signaling pathways by suppressing the protein expression of key molecules in these pathways. Therefore, we concluded that the glycosides of Caulis Lonicerae can intervene in the differentiation of Th cells, suppressing the activation of JAK-STAT and NF-κB signaling pathways, contributing to the inhibitory effect on inflammatory proliferation of FLS co-cultured with lymphocytes induced by pro-inflammatory cytokines.

Herbal Formula Longteng Decoction Promotes the Regression of Synovial Inflammation in Collagen-Induced Arthritis Mice by Regulating Type 2 Innate Lymphocytes.

The etiology and pathogenesis of rheumatoid arthritis (RA) have not yet been fully elucidated, with greater adverse drug effects in traditional treatment of RA. It is particularly necessary to develop and study Chinese herbal formula as a supplement and alternative drug for the treatment of RA. The traditional Chinese medicine compound Longteng Decoction (LTD), as an empirical prescription in the treatment of RA in Dongzhimen Hospital of Beijing University of Chinese Medicine, has been widely used in clinic. Type 2 innate lymphocytes (ILC2s) have specific transcription factors and signature cytokines that are very similar to Th cells, which have been proved to be necessary in addressing RA inflammation, and are potential targets for RA prevention and treatment. Our previous studies have confirmed that LTD can intervene in the differentiation of peripheral blood Th17 and Treg cells, reduce joint pain index and swelling degree, shorten the time of morning stiffness, reduce ESR, and inhibit joint inflammation. However, it is unclear whether LTD can promote the regression of RA synovial inflammation by regulating the immune response mechanism of ILC2s.Therefore, our team established a collagen-induced arthritis mouse model and conducted an experimental study with LTD as the intervention object. The results showed that joint swelling, synovial inflammatory infiltration, and articular cartilage destruction were alleviated in CIA mice after intervention with LTD. The proliferation and differentiation of Th17 inflammatory cells and the secretion of proinflammatory cytokines (IL-17 and IFN-γ) were inhibited. In addition, LTD can also activate ILC2s to secrete the anti-inflammatory cytokine IL-4, activate the STAT6 signaling pathway, and act synergistic with Treg cells to inhibit the infiltration of type M1 macrophages in synovial tissue and promote its transformation to M2 phenotype. Taken together, these results confirm that LTD can be used as an adjunct or alternative to RA therapy by modulating the ILC2s immune response network and slowing down the inflammatory process of synovial tissue.

An evaluation of the effects and safety of Zuogui pill for treating osteoporosis: Current evidence for an ancient Chinese herbal formula.

The aim of this study is to systematically evaluate existing evidence of the Chinese herbal formula, Zuogui pill (ZGP), for the treatment of osteoporosis. A systematic literature search was performed in six electronic databases. The authors independently extracted data in pairs and evaluated the risk of bias. A total of 221 articles were identified initially, of which 12 relevant studies were enrolled. The primary outcome was fracture incidence and bone mineral density (BMD) at different sites. Bone metabolism markers, clinical symptoms, quality of life, and adverse events or adverse drug reactions (ADRs) were secondary outcomes. The results showed that ZGP, combined with anti-osteoporosis drugs, significantly increased BMD at the lumbar spine, Ward's area, and total hip. In terms of markers for improved bone metabolism, ZGP plus conventional drugs dramatically improved the levels of alkaline phosphatase, bone Gla protein, bone alkaline phosphatase, and tartrate-resistant acid phosphatase. Gastrointestinal discomfort, dizziness, and fatigue were found in the combined therapy group. Although the results indicate that ZGP is a potential candidate for osteoporosis, evidence remains insufficient. Further rigorously designed and high-quality trials with a larger sample size are warranted to verify the current conclusions.

Efficacy and Safety of Duhuo Jisheng Decoction for Postmenopausal Osteoporosis: A Systematic Review and Meta-Analysis.

AIM: To evaluate the effects and medication safety of Duhuo Jisheng Decoction (DHJSD) alone or as a combination therapy with other interventions on the related clinical index in postmenopausal osteoporosis condition. METHODS: Search in CNKI, WanFang, CBM, VIP, PubMed, EMBASE, and Cochrane Library databases and randomized controlled trials where at least one group received any form of DHJSD for postmenopausal osteoporosis condition. Risk of bias was based on the Cochrane handbook, the quality of evidence was assessed by the GRADEpro online, and analyses were performed by RevMan 5.3 software. RESULTS: Eight studies were enrolled with 650 participants. DHJSD alone or with other interventions had a significant effect on BMD of the lumbar spine (MD = 0.46, 95%CI (0.24, 0.68), P < 0.0001), E2 (SMD = 0.49, 95%CI (0.30, 0.68), P < 0.0001), and clinical effectiveness (OR = 5.07, 95%CI (3.07, 8.35), P < 0.0001). However, no effect at BGP (MD = -0.84, 95%CI (-1.69, 0.00), P=0.05) was seen. CONCLUSION: The pooled estimate suggested that DHJSD combined with conventional medical therapies has a certain clinical curative effect on postmenopausal osteoporosis. However, considering the unsatisfactory quality of included trials, more high-quality trials are needed to elucidate this issue.

The Clinical Effectiveness of Cognitive Behavioral Therapy for Patients with Insomnia and Depression: A Systematic Review and Meta-Analysis.

BACKGROUND: Insomnia and depression often co-occurr. However, there is lack of effective treatment for such comorbidity. CBT-I has been recommended as the first-line treatment for insomnia; whether it is also effective for comorbidity of insomnia and depression is still unknown. Therefore, we conducted this meta-analysis of randomized controlled trials to assess the clinical effectiveness and safety of CBT-I for insomnia comorbid with depression. Data Sources. Seven electronic databases, including China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science Technology Journal Database, SinoMed Database, PubMed, the Cochrane Library, and EMBASE, as well as grey literature, were searched from the beginning of each database to July 1, 2019. Study Eligibility Criteria. Randomized controlled trials that compared CBT-I to no treatment or hypnotics (zopiclone, estazolam, and benzodiazepine agonist) for insomnia comorbid with depression and reported both insomnia scales and depression scales. Study Assessment and Synthesis Methods. Cochrane Reviewer's Handbook was used for evaluating the risk of bias of included studies. Review Manager 5.3 software was used for meta-analysis. Online GRADEpro was used to assess the quality of evidence. RESULTS: The pooled data showed that CBT-I was superior to no treatment for insomnia, while it was unsure whether CBT-I was better than no treatment for depression. And the effectiveness of CBT-I was comparable to hypnotics for both insomnia and depression. CBT-I was likely to be safe due to its noninvasive nature. The methodological quality varied across these trials. The evidence quality varied from moderate to very low, and the recommendation level was low. CONCLUSIONS: Currently, findings support that CBT-I seems to be effective and safe for insomnia comorbid with depression to improve the insomnia condition, while it is unsure whether CBT-I could improve depression condition. More rigorous trials are needed to confirm our findings.

Clinical effectiveness of Tui Na for insomnia compared with estazolam: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The purpose of this systematic review (SR) is to evaluate the effectiveness and safety of Tui Na therapy for insomnia. METHODS: Two authors separately searched PubMed, the Cochrane Library, EMBASE, SinoMed Database, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science Technology Journal Database, related SR and published protocols at the same time to find randomized controlled trials (RCTs), which compared Tui Na therapy with estazolam therapy for insomnia, from their inception to January1st 2019. Screening documents, data extraction, quality assessment of methodology and quality assessment of evidence were also conducted by two authors separately at the same time. We used Cochrane Risk of Bias tool to assess the methodological quality of included RCTs. The results of meta-analysis were made via RevMan software (5.3). The quality of evidence was assessed by on-line GRADEpro. The primary outcome: Pittsburgh Sleep Quality Index (PSQI) score, the secondary outcome: clinical effectiveness rate and the safety index: adverse events. The clinical effectiveness of these included RCTs all focused on the improvement of patients' satisfaction with sleep time and sleep quality. RESULTS: We included 22 RCTs(1,999 participants), meeting the inclusion and exclusion criteria. The assessment of methodological quality was not satisfied, in which "high risk", "unclear risk" and "low risk" all existed. The results of meta-analysis demonstrated that (1)for primary outcome, the PSQI score of Tui Na therapy was lower than that of estazolam therapy after treatment in subgroup1(Head)(MD-2.39,95%CI[-3.79,-0.98],I2 = 82%,n = 291,3 trials) and subgroup4(Abdomen)(MD-1.7,95%CI[-2.53,-0.87],I2 = 0%,n = 120,2 trials);while there was no significant difference between Tui Na therapy and estazolam therapy in subgroup2(Head and trunk)(MD-1.39,95%CI[-3.03,0.24],I2 = 90%,n = 200, 2 trials) and subgroup3(Head, trunk and extremities)(MD-0.51,95%CI[-1.53,0.5],I2 = 30%,n = 126,2 trials).(2) for secondary outcomes(the clinical effectiveness rate and safety index),the clinical effectiveness rate of Tui Na therapy was higher than that of estazolam therapy after treatment in subgroup1(Head)(RR1.21,95%CI[1.05,1.39],I2 = 26%,n = 239,3 trials), subgroup2(Head and trunk)(RR1.15,95%CI[1.08,1.23],I2 = 33%,n = 1024,10 trials) and subgroup4(Abdomen)(RR1.12,95%CI[1.01,1.23],I2 = 0%,n = 180,3 trials); while there was no significant difference between Tui Na therapy and estazolam therapy in subgroup3(Head, trunk and extremities)(RR1.03,95%CI[0.94,1.13],I2 = 28%,n = 346,4 trials).Safety index, 5 RCTs reported adverse events. Among them, only 1 RCT reported adverse event in Tui Na therapy, which was daytime drowsiness; all 5 RCTs reported adverse events in estazolam therapy, which were dry mouth, dizziness, daytime drowsiness etc. The evidence quality was generally low to very low. CONCLUSION: Tui Na therapy appeared to be superior to estazolam therapy in treating areas(head; abdomen), while there was no significant difference between Tui Na therapy and estazolam therapy in treating areas(head and trunk; head, trunk and extremities). No serious adverse event was reported in Tui Na therapy. However the methodological quality and evidence quality were not satisfied. Therefore we could not make a convincing conclusion on the effectiveness and safety of Tui Na therapy for insomnia. Practitioners should combine their experience, evidence of our review and patients' preferences to make a proper treatment. And more high quality RCTs and well-designed protocols of Tui Na therapy for insomnia are needed in the future.

Discriminative analysis of non-linear brain connectivity in schizophrenia: an fMRI Study.

BACKGROUND: Dysfunctional integration of distributed brain networks is believed to be the cause of schizophrenia, and resting-state functional connectivity analyses of schizophrenia have attracted considerable attention in recent years. Unfortunately, existing functional connectivity analyses of schizophrenia have been mostly limited to linear associations. OBJECTIVE: The objective of the present study is to evaluate the discriminative power of non-linear functional connectivity and identify its changes in schizophrenia. METHOD: A novel measure utilizing the extended maximal information coefficient was introduced to construct non-linear functional connectivity. In conjunction with multivariate pattern analysis, the new functional connectivity successfully discriminated schizophrenic patients from healthy controls with relative higher accuracy rate than the linear measure. RESULT: We found that the strength of the identified non-linear functional connections involved in the classification increased in patients with schizophrenia, which was opposed to its linear counterpart. Further functional network analysis revealed that the changes of the non-linear and linear connectivity have similar but not completely the same spatial distribution in human brain. CONCLUSION: The classification results suggest that the non-linear functional connectivity provided useful discriminative power in diagnosis of schizophrenia, and the inverse but similar spatial distributed changes between the non-linear and linear measure may indicate the underlying compensatory mechanism and the complex neuronal synchronization underlying the symptom of schizophrenia.

OI and fMRI signal separation using both temporal and spatial autocorrelations.

Separating brain imaging signals by maximizing their autocorrelations is an important component of blind source separation (BSS). Canonical correlation analysis (CCA), one of leading BSS techniques, has been widely used for analyzing optical imaging (OI) and functional magnetic resonance imaging (fMRI) data. However, because of the need to reduce dimensionality and ignore spatial autocorrelation, CCA is problematic for separating temporal signal sources. To solve the problems of CCA, "straightforward image projection" (SIP) has been incorporated into temporal BSS. This novel method, termed low-dimensional canonical correlation analysis (LD-CCA), relies on the spatial and temporal autocorrelations of all genuine signals of interest. Incorporating both spatial and temporal information, here we introduce a "generalized timecourse" technique in which data are artificially reorganized prior to separation. The quantity of spatial plus temporal autocorrelations can then be defined. By maximizing temporal and spatial autocorrelations in combination, LD-CCA is able to obtain expected "real" signal sources. Generalized timecourses are low-dimensional, eliminating the need for dimension reduction. This removes the risk of discarding useful information. The new method is compared with temporal CCA and temporal independent component analysis (tICA). Comparison of simulated data showed that LD-CCA was more effective for recovering signal sources. Comparisons using real intrinsic OI and fMRI data also supported the validity of LD-CCA.