RASSF1A promotes radiosensitivity in nasopharyngeal carcinoma by promoting FoxO3a and inhibiting the Nrf2/TXNRD1 signaling pathway.

Radiotherapy is widely used as the first-line treatment for nasopharyngeal carcinoma (NPC). However, the resistance of some patients to treatment lowers its clinical effectiveness. Compared to typical epithelial cells, NPC markedly lowers the Ras-association domain family 1A (RASSF1A) protein expression. RASSF1A overexpression sensitizes NPC cells to radiotherapy. Mechanistically, RASSF1A promotes the expression of Forkhead box O3a (FoxO3a) in the nucleus and inhibits the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway via binding to the Kelch-like ECH-associated protein 1 (Keap1) promoter. Through elevating intracellular ROS levels, RASSF1A overexpression inhibits the expression of thioredoxin reductase 1 (TXNRD1), a crucial Nrf2 target gene, and increases NPC sensitivity to radiation. Immunohistochemical staining of NPC tissue sections revealed that the expression of RASSF1A is negatively correlated with that of TXNRD1. The traditional Chinese medicine component andrographolide (AGP), which induces RASSF1A expression, increased the sensitivity of NPC cells to radiotherapy in vitro and in vivo. Our findings implied that RASSF1A increases the sensitivity of NPC to radiation by increasing FoxO3a expression in the nucleus, inhibiting the Nrf2/TXNRD1 signaling pathway, and elevating intracellular ROS levels. AGP targets RASSF1A and may be a promising adjuvant sensitizer for enhancing radiosensitivity in NPC.

Antimalarial activity and sensitization of chrysosplenetin against artemisinin-resistant genotype Plasmodium berghei K173 potentially via dual-mechanism of maintaining host P-glycoprotein homeostasis mediated by NF-κB p52 or PXR/CAR signaling pathways and regulating heme/haemozoin metabolism.

This study investigated antimalarial efficacy and sensitization of chrysosplenetin against artemisinin-resistant Plasmodium berghei K173 and potential molecular mechanism. Our data indicated a risk of artemisinin resistance because a higher parasitaemia% and lower inhibition% under artemisinin treatment against resistant parasites than those in the sensitive groups were observed. Two non-antimalarial components, verapamil and chrysosplentin, being P-gp inhibitors, possessed a strong efficacy against resistant parasites but it was not the case for Bcrp inhibitor novobiocin. Artemisinin-chrysosplenetin combination improved artemisinin susceptibility of resistant P. berghei. Artemisinin activated intestinal P-gp and Abcb1/Abcg2 expressions and suppressed Bcrp whereas chrysosplenetin reversed them. Resistant parasite infection led to a decreased haemozoin in organs or an increased heme in peripheral bloods compared with the sensitives; however, that in Abcb1-deficient knockout (KO)-resistant mice reversely got increased or decreased versus wild type (WT)-resistant animals. Chrysosplenetin as well as rifampin (nuclear receptor agonist) increased the transcription levels of PXR/CAR while showed a versatile regulation on hepatic and enternal PXR/CAR in WT- or KO-sensitive or -resistant parasites. Oppositely, hepatic and enteric NF-κB p52 mRNA decreased conformably in WT but increased in KO-resistant mice. NF-κB pathway potentially involved in the mechanism of chrysosplenetin on inhibiting P-gp expressions while PXR/CAR play a more complicated role in this mechanism.

Aberrant cerebral blood flow in tinnitus patients with migraine: a perfusion functional MRI study.

PURPOSE: Migraine is often accompanied with chronic tinnitus that will affect the cerebral blood flow (CBF) and exacerbate the tinnitus distress. However, the potential relationship between migraine and tinnitus remains unclear. This study will investigate whether aberrant CBF patterns exist in migraine patients with tinnitus and examine the influence of migraine on CBF alterations in chronic tinnitus. MATERIALS AND METHODS: Participants included chronic tinnitus patients (n = 45) and non-tinnitus controls (n = 50), matched for age, sex, education, and hearing thresholds. CBF images were collected and analyzed using arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI). Regions with major CBF differences between tinnitus patients and non-tinnitus controls were first detected. The effects of migraine on tinnitus for CBF alterations were further examined. Correlation analyses illustrated the association between CBF values and tinnitus severity as well as between CBF and severity of migraine. RESULTS: Compared with non-tinnitus controls, chronic tinnitus patients without migraine exhibited decreased CBF, primarily in right superior temporal gyrus (STG), bilateral middle frontal gyrus (MFG), and left superior frontal gyrus (SFG); decreased CBF in these regions was correlated with tinnitus distress. There was a significant effect of migraine on tinnitus for CBF in right STG and MFG. Moreover, the severity of migraine correlated negatively with CBF in tinnitus patients. CONCLUSIONS: Chronic tinnitus patients exhibited reduced CBF in the auditory and prefrontal cortex. Migraine may facilitate a CBF decrease in the setting of tinnitus, which may underlie the neuropathological mechanisms of chronic tinnitus comorbid with migraine.

CircRNA inhibits DNA damage repair by interacting with host gene.

BACKGROUND: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. METHOD: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. RESULTS: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. CONCLUSION: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

Tinnitus distress is linked to enhanced resting-state functional connectivity from the limbic system to the auditory cortex.

The phantom sound of tinnitus is believed to be triggered by aberrant neural activity in the central auditory pathway, but since this debilitating condition is often associated with emotional distress and anxiety, these comorbidities likely arise from maladaptive functional connections to limbic structures such as the amygdala and hippocampus. To test this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to identify aberrant effective connectivity of the amygdala and hippocampus in tinnitus patients and to determine the relationship with tinnitus characteristics. Chronic tinnitus patients (n = 26) and age-, sex-, and education-matched healthy controls (n = 23) were included. Both groups were comparable for hearing level. Granger causality analysis utilizing the amygdala and hippocampus as seed regions were used to investigate the directional connectivity and the relationship with tinnitus duration or distress. Relative to healthy controls, tinnitus patients demonstrated abnormal directional connectivity of the amygdala and hippocampus, including primary and association auditory cortex, and other non-auditory areas. Importantly, scores on the Tinnitus Handicap Questionnaires were positively correlated with increased connectivity from the left amygdala to left superior temporal gyrus (r = 0.570, P = 0.005), and from the right amygdala to right superior temporal gyrus (r = 0.487, P = 0.018). Moreover, enhanced effective connectivity from the right hippocampus to left transverse temporal gyrus was correlated with tinnitus duration (r = 0.452, P = 0.030). The results showed that tinnitus distress strongly correlates with enhanced effective connectivity that is directed from the amygdala to the auditory cortex. The longer the phantom sensation, the more likely acute tinnitus becomes permanently encoded by memory traces in the hippocampus. Hum Brain Mapp 38:2384-2397, 2017. © 2017 Wiley Periodicals, Inc.

Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/C(Cdh1) regulation.

DNA damage triggers cell cycle arrest to provide a time window for DNA repair. Failure of arrest could lead to genomic instability and tumorigenesis. DNA damage-induced G1 arrest is generally achieved by the accumulation of Cyclin-dependent kinase inhibitor 1 (p21). However, p21 is degraded and does not play a role in UV-induced G1 arrest. The mechanism of UV-induced G1 arrest thus remains elusive. Here, we have identified a critical role for CUE domain-containing protein 2 (CUEDC2) in this process. CUEDC2 binds to and inhibits anaphase-promoting complex/cyclosome-Cdh1 (APC/C(Cdh1)), a critical ubiquitin ligase in G1 phase, thereby stabilizing Cyclin A and promoting G1-S transition. In response to UV irradiation, CUEDC2 undergoes ERK1/2-dependent phosphorylation and ubiquitin-dependent degradation, leading to APC/C(Cdh1)-mediated Cyclin A destruction, Cyclin-dependent kinase 2 inactivation, and G1 arrest. A nonphosphorylatable CUEDC2 mutant is resistant to UV-induced degradation. Expression of this stable mutant effectively overrides UV-induced G1-S block. These results establish CUEDC2 as an APC/C(Cdh1) inhibitor and indicate that regulated CUEDC2 degradation is critical for UV-induced G1 arrest.

SeeSaw: Learning Soft Tissue Deformation from Laparoscopy Videos with GNNs.

A major challenge in image-guided laparoscopic surgery is that structures of interest often deform and go, even if only momentarily, out of view. Methods which rely on having an up-to-date impression of those structures, such as registration or localisation, are undermined in these circumstances. This is particularly true for soft-tissue structures that continually change shape - in registration, they must often be re-mapped. Furthermore, methods which require 'revisiting' of previously seen areas cannot in principle function reliably in dynamic contexts, drastically weakening their uptake in the operating room. We present a novel approach for learning to estimate the deformed states of previously seen soft tissue surfaces from currently observable regions, using a combined approach that includes a Graph Neural Network (GNN). The training data is based on stereo laparoscopic surgery videos, generated semi-automatically with minimal labelling effort. Trackable segments are first identified using a feature detection algorithm, from which surface meshes are produced using depth estimation and delaunay triangulation. We show the method can predict the displacements of previously visible soft tissue structures connected to currently visible regions with observed displacements, both on our own data and porcine data. Our innovative approach learns to compensate non-rigidity in abdominal endoscopic scenes directly from stereo laparoscopic videos through targeting a new problem formulation, and stands to benefit a variety of target applications in dynamic environments. Project page for this work: https://gitlab.com/nct_tso_public/seesaw-soft-tissue-deformation.

Aberrant Intra- and Inter-Network Connectivity in Idiopathic Sudden Sensorineural Hearing Loss with Tinnitus.

BACKGROUND: Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL) is related to alterations in brain cortical and subcortical structures, and changes in brain functional activities involving multiple networks, which is often accompanied by tinnitus. There have been many in-depth research studies conducted concerning ISSNHL. Despite this, the neurophysiological mechanisms of ISSNHL with tinnitus are still under exploration. OBJECTIVE: The study aimed to investigate the neural mechanism in ISSNHL patients with tinnitus based on the alterations in intra- and inter-network Functional Connectivity (FC) of multiple networks. METHODS: Thirty ISSNHL subjects and 37 healthy subjects underwent resting-state functional Magnetic Resonance Imaging (rs-fMRI). Independent Component Analysis (ICA) was used to identify 8 Resting-state Networks (RSNs). Furthermore, the study used a two-sample t-test to calculate the intra-network FC differences, while calculating Functional Network Connectivity (FNC) to detect the inter-network FC differences. RESULTS: By using the ICA approach, tinnitus patients with ISSNHL were found to have FC changes in the following RSNs: CN, VN, DMN, ECN, SMN, and AUN. In addition, the interconnections of VN-SMN, VN-ECN, and ECN-DAN were weakened. CONCLUSION: The present study has demonstrated changes in FC within and between networks in ISSNHL with tinnitus, providing ideas for further study on the neuropathological mechanism of the disease.

The dual role and mutual dependence of heme/HO-1/Bach1 axis in the carcinogenic and anti-carcinogenic intersection.

INTRODUCTION: In physiological concentrations, heme is nontoxic to the cell and is essential for cell survival and proliferation. Increasing intracellular heme concentrations beyond normal levels, however, will lead to carcinogenesis and facilitate the survival of tumor cells. Simultaneously, heme in an abnormally high quantity is also a potent inducer of tumor cell death, contributing to its ability to generate oxidative stress on the cells by boosting oxidative phosphorylation and suppressing tumors through ferroptosis. During tumorigenesis and progression, therefore, heme works as a double-edged sword. Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme catabolism, which converts heme into physiologically active catabolites of carbon monoxide (CO), biliverdin, and ferrous iron (Fe2+). HO-1 maintains redox equilibrium in healthy cells and functions as a carcinogenesis inhibitor. It is widely recognized that HO-1 is involved in the adaptive response to cellular stress and the anti-inflammation effect. Notably, its expression level in cancer cells corresponds with tumor growth, aggressiveness, metastasis, and angiogenesis. Besides, heme-binding transcription factor BTB and CNC homology 1 (Bach1) play a critical regulatory role in heme homeostasis, oxidative stress and senescence, cell cycle, angiogenesis, immune cell differentiation, and autoimmune disorders. Moreover, it was found that Bach1 influences cancer cells' metabolism and metastatic capacity. Bach1 controls heme level by adjusting HO-1 expression, establishing a negative feedback loop. MATERIALS AND METHODS: Herein, the authors review recent studies on heme, HO-1, and Bach1 in cancer. Specifically, they cover the following areas: (1) the carcinogenic and anticarcinogenic aspects of heme; (2) the carcinogenic and anticarcinogenic aspects of HO-1; (3) the carcinogenic and anticarcinogenic aspects of Bach1; (4) the interactions of the heme/HO-1/Bach1 axis involved in tumor progression. CONCLUSION: This review summarized the literature about the dual role of the heme/HO-1/Bach1 axis and their mutual dependence in the carcinogenesis and anti-carcinogenesis intersection.

Multicomponent Dearomative Difluoroalkylation of Isoquinolines with Difluorinated Silyl Enol Ethers: Divergent Synthesis of gem-Difluorinated Heterocycles.

A multicomponent dearomative difluoroalkylation of isoquinolines has been developed with difluorinated silyl enol ethers serving as poor nucleophiles without an additional transition-metal or organic catalyst. The sequential oxidative rearomatization under different alkaline conditions provides a controllable formal C-H difluoroalkylation and difluoromethylation method for isoquinolines without peroxide or metal oxidant. A series of isoquinolines including a pharmaceutical, phenanthridine, quinolines, and difluorinated silyl enol ethers were suitable substrates to construct gem-difluorinated heterocycles. The inexpensive starting materials, mild reaction conditions, and simple operation also show practical and environmentally benign advantages.

Synthesis of Fluoro 3(2H)-Furanones via a TFA-Catalyzed Dehydrofluorinative Cyclization of 2,2-Difluoro-3-hydroxy-1,4-diketones.

A TFA-catalyzed dehydrofluorinative cyclization of 2,2-difluoro-3-hydroxy-1,4-diketones has been developed in the presence of amines under mild conditions in which the difluorinated substrates are readily prepared according to our reported literature. This protocol provides a rapid construction of fluoro 3(2H)-furanones in good to excellent yields with good functional group tolerance. Easy scale-up synthesis also shows a practical advantage.

Role of STAT3 in the pathogenesis of nasopharyngeal carcinoma and its significance in anticancer therapy.

Nasopharyngeal carcinoma (NPC) is a type of head and neck tumor with noticeable regional and ethnic differences. It is associated with Epstein-Barr virus infection and has a tendency for local and distant metastasis. NPC is also highly sensitive to radiotherapy and chemotherapy. Over 70% of patients present with locoregionally advanced disease, and distant metastasis is the primary reason for treatment failure. A signal transducer and activator of transcription 3 (STAT3) promotes NPC oncogenesis through mechanisms within cancerous cells and their interactions with the tumor microenvironment, which is critical in the initiation, progression, and metastasis of NPC. Further, p-STAT3 is strongly associated with advanced NPC. Recent research on STAT3 has focused on its expression at the center of various oncogenic pathways. Here, we discuss the role of STAT3 in NPC and its potential therapeutic inhibitors and analogs for the treatment and control of NPC.

Abnormal cerebellar network and effective connectivity in sudden and long-term sensorineural hearing loss.

Sudden sensorineural hearing loss (SSNHL) is a common otology emergency and some SSNHL will develop into a long-term hearing loss (LSNHL). However, whether SSNHL and LSNHL have similar psychiatric patterns remains unknown, as well as the neural substrates. Increasing evidence has proved that the cerebellar network plays a vital role in hearing, cognition processing, and emotion control. Thus, we recruited 20 right SSNHL (RSSNHL), 20 right LSNHL (RLSNHL), and 24 well-matched healthy controls to explore the cerebellar patterns among the three groups. Every participant underwent pure tone audiometry tests, neuropsychological evaluations, and MRI scanning. Independent component analysis (ICA) was carried out on the MRI data and the cerebellar network was extracted. Granger causality analysis (GCA) was conducted using the significant cerebellar region as a seed. Pearson's correlation analysis was computed between imaging characteristics and clinical features. ICA found the effect of group on right cerebellum lobule V for the cerebellar network. Then, we found decreased outflow from right cerebellum lobule V to right middle orbitofrontal cortex, inferior frontal gyrus, anterior cingulate cortex, superior temporal gyrus, and dorsal lateral prefrontal cortex in RSSNHL group in GCA analysis. No significance was found in RLSNHL subjects. Additionally, the RSSNHL group showed increased effective connectivity from the right middle frontal gyrus (MFG) and the RLSNHL group showed increased effective connectivity from the right insula and temporal pole to the right cerebellum lobule V. Moreover, connections between right cerebellum lobule V and mean time series of the cerebellar network was negatively correlated with anxiety score in RSSNHL and negatively correlated with depression scores in RLSNHL. Effective connectivity from right MFG to right cerebellum lobule V could predict anxiety status in RSSNHL subjects. Our results may prove potential imaging biomarkers and treatment targets for hearing loss in future work.

Degree centrality and functional connections in presbycusis with and without cognitive impairments.

Presbycusis is a major public issue that affecting elderly adults. However, the neural substrates between normal cognition and cognitive deficits in these patients need to be illustrated. 47 patients with presbycusis and 33 well-matched healthy controls were recruited in present study. Each subject underwent pure-tone audiometry (PTA), MRI scanning and cognition evaluations, then we found 22 patients with cognitive deficits and 25 patients with common cognition. We analyzed the Degree centrality (DC) characteristics among three groups, and try to recognize key nodes which contribute significantly. Subsequent functional connectivity analysis was applied using the key nodes as seeds. Compared with controls, presbycusis without cognitive impairments showed deceased DC in superior temporal gyrus (STG), inferior frontal gyrus (IFG) and supramarginal gyrus (SMG). Additionally, presbycusis with cognitive impairments showed enhanced DC in fusiform gurus (FFG), cerebellum and para-hippocampal gyrus (PHG), while weakened DC in SMG, middle frontal gyrus (IFG) and inferior Parietal lobule (IPL). Compared with normal cognition, increased DC value of cerebellum and STG, as well as decreased DC value of IPL in presbycusis with cognitive impairments were observed. We noticed that SMG may play an important role. Then the left and right SMG were used as seeds in functional connections analysis. With the seed set at left SMG, presbycusis without cognitive impairments showed decreases connections with cerebellum, temporal pole (TP), superior temporal gyrus (STG) and median cingulate cortex (MCC). Presbycusis with cognitive impairments showed weakened connectivity with cerebellum, IFG, IPL and superior frontal gyrus (SFG). The right SMG showed decrease connections with cerebellum, middle temporal gyrus (MTG), STG and increase connection with middle frontal gyrus (MFG) in presbycusis without cognitive impairments. While the right SMG showed enhanced connections with left TP, caudate, anterior cingulate cortex (ACC), angular, SFG and weakened connectivity with right SFG presbycusis with cognitive impairments. In comparison with normal cognition and impaired cognition, MFG, IFG, PHG, rolandic operculum and cerebellum were involved. These findings enriched our understanding of the neural mechanisms underlying cognitive impairments associated with presbycusis and may serve as a potential imaging biomarker for investigating and predicting cognitive difficulties.

Aberrant Functional Network of Small-World in Sudden Sensorineural Hearing Loss With Tinnitus.

Few researchers investigated the topological properties and relationships with cognitive deficits in sudden sensorineural hearing loss (SNHL) with tinnitus. To explore the topological characteristics of the brain connectome following SNHL from the global level and nodal level, we recruited 36 bilateral SNHL patients with tinnitus and 37 well-matched healthy controls. Every subject underwent pure tone audiometry tests, neuropsychological assessments, and MRI scanning. AAL atlas was employed to divide a brain into 90 cortical and subcortical regions of interest, then investigated the global and nodal properties of "small world" network in SNHL and control groups using a graph-theory analysis. The global characteristics include small worldness, cluster coefficient, characteristic path length, local efficiency, and global efficiency. Node properties include degree centrality, betweenness centrality, nodal efficiency, and nodal clustering coefficient. Interregional connectivity analysis was also computed among 90 nodes. We found that the SNHL group had significantly higher hearing thresholds and cognitive impairments, as well as disrupted internal connections among 90 nodes. SNHL group displayed lower AUC of cluster coefficient and path length lambda, but increased global efficiency. The opercular and triangular parts of the inferior frontal gyrus, rectus gyrus, parahippocampal gyrus, precuneus, and amygdala showed abnormal local features. Some of these connectome alterations were correlated with cognitive ability and the duration of SNHL. This study may prove potential imaging biomarkers and treatment targets for future studies.

Disrupted Topological Organization of Resting-State Functional Brain Networks in Age-Related Hearing Loss.

Purpose: Age-related hearing loss (ARHL), associated with the function of speech perception decreases characterized by bilateral sensorineural hearing loss at high frequencies, has become an increasingly critical public health problem. This study aimed to investigate the topological features of the brain functional network and structural dysfunction of the central nervous system in ARHL using graph theory. Methods: Forty-six patients with ARHL and forty-five age, sex, and education-matched healthy controls were recruited to undergo a resting-state functional magnetic resonance imaging (fMRI) scan in this study. Graph theory was applied to analyze the topological properties of the functional connectomes by studying the local and global organization of neural networks. Results: Compared with healthy controls, the patient group showed increased local efficiency (Eloc) and clustering coefficient (Cp) of the small-world network. Besides, the degree centrality (Dc) and nodal efficiency (Ne) values of the left inferior occipital gyrus (IOG) in the patient group showed a decrease in contrast with the healthy control group. In addition, the intra-modular interaction of the occipital lobe module and the inter-modular interaction of the parietal occipital module decreased in the patient group, which was positively correlated with Dc and Ne. The intra-modular interaction of the occipital lobe module decreased in the patient group, which was negatively correlated with the Eloc. Conclusion: Based on fMRI and graph theory, we indicate the aberrant small-world network topology in ARHL and dysfunctional interaction of the occipital lobe and parietal lobe, emphasizing the importance of dysfunctional left IOG. These results suggest that early diagnosis and treatment of patients with ARHL is necessary, which can avoid the transformation of brain topology and decreased brain function.

Aberrant Modulations of Neurocognitive Network Dynamics in Migraine Comorbid With Tinnitus.

Purpose: The possible relationship between migraine and tinnitus still remains elusive although migraine is often accompanied by chronic tinnitus. Several neuroimaging studies have reinforced the cognitive network abnormality in migraine and probably as well as tinnitus. The present work aims to investigate the dynamic neurocognitive network alterations of migraine comorbid with tinnitus. Materials and Methods: Participants included migraine patients (n = 32), tinnitus patients (n = 20), migraine with tinnitus (n = 27), and healthy controls (n = 47), matched for age and gender. Resting-state functional magnetic resonance imaging (rs-fMRI) with independent component analysis (ICA), sliding window cross-correlation, and clustering state analysis was used to detect the dynamic functional network connectivity (dFNC) of each group. Correlation analyses illustrated the association between clinical symptoms and abnormal dFNC in migraine as well as tinnitus. Results: Compared with healthy controls, migraine patients exhibited decreased cerebellar network and visual network (CN-VN) connectivity in State 2; migraine with tinnitus patients showed not only decreased CN-VN connectivity in State 2 but also decreased cerebellar network and executive control network (CN-ECN) connectivity in State 2 and increased cerebellar network and somatomotor network (SMN-VN) connectivity in State 1. The abnormal cerebellum dFNC with the executive control network (CN-ECN) was negatively correlated with headache frequency of migraine (rho = -0.776, p = 0.005). Conclusion: Brain network characteristics of migraine with tinnitus patients may indicate different mechanisms for migraine and tinnitus. Our results demonstrated a transient pathologic state with atypical cerebellar-cortical connectivity in migraine with tinnitus patients, which might be used to identify the neuro-pathophysiological mechanisms in migraine accompanied by tinnitus.

Topological features of limbic dysfunction in chronicity of tinnitus with intact hearing: New hypothesis for 'noise-cancellation' mechanism.

PURPOSE: The reorganization of the limbic regions extend to general cognitive network is believed to exist in the chronicity of tinnitus with particular 'hubs' contributing to a 'noise-cancellation' mechanism. To test this hypothesis, we investigated the topological brain network of tinnitus in different periods. METHODS: Resting-state functional magnetic resonance imaging were obtained from 32 patients with acute tinnitus, 41 patients with chronic tinnitus and 60 age- and gender- matched healthy controls (HC). The topological features of their brain networks were explored using graph theory analysis. RESULTS: Common small-world attributes were compared between the three groups, all showed a significantly increased values in Cp, Lp, λ (all p < 0.05). Significantly increased nodal centralities in the left superior frontal gyrus and the right precuneus, significantly decreased nodal centralities in the right inferior temporal gyrus were observed for acute tinnitus patients compared to HC. While for chronic tinnitus patients, there were significant increased nodal centralities in the left hippocampus, amygdala, and temporal pole, but decreased nodal centralities in the right inferior temporal gyrus. Additionally, significant higher nodal centralities were found in bilateral medial superior frontal gyrus for acute tinnitus patients compared to chronic tinnitus patients. Besides, alterations in rich-club organization were found in acute tinnitus patients and chronic tinnitus patients compared with HC, with increased functional connections among rich-club nodes and peripheral nodes in patients with tinnitus. CONCLUSIONS: Brain network topological properties altered across prefrontal-limbic-subcortical regions in tinnitus. The existed hubs in tinnitus might indicate an emotional and cognitive burden in 'noise-cancellation' mechanism.

Reorganized Brain Functional Network Topology in Presbycusis.

Purpose: Presbycusis is characterized by bilateral sensorineural hearing loss at high frequencies and is often accompanied by cognitive decline. This study aimed to identify the topological reorganization of brain functional network in presbycusis with/without cognitive decline by using graph theory analysis approaches based on resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Resting-state fMRI scans were obtained from 30 presbycusis patients with cognitive decline, 30 presbycusis patients without cognitive decline, and 50 age-, sex-, and education-matched healthy controls. Graph theory was applied to analyze the topological properties of brain functional networks including global and nodal metrics, modularity, and rich-club organization. Results: At the global level, the brain functional networks of all participants were found to possess small-world properties. Also, significant group differences in global network metrics were observed among the three groups such as clustering coefficient, characteristic path length, normalized characteristic path length, and small-worldness. At the nodal level, several nodes with abnormal betweenness centrality, degree centrality, nodal efficiency, and nodal local efficiency were detected in presbycusis patients with/without cognitive decline. Changes in intra-modular connections in frontal lobe module and inter-modular connections in prefrontal subcortical lobe module were found in presbycusis patients exposed to modularity analysis. Rich-club nodes were reorganized in presbycusis patients, while the connections among them had no significant group differences. Conclusion: Presbycusis patients exhibited topological reorganization of the whole-brain functional network, and presbycusis patients with cognitive decline showed more obvious changes in these topological properties than those without cognitive decline. Abnormal changes of these properties in presbycusis patients may compensate for cognitive impairment by mobilizing additional neural resources.

Specific brain network predictors of interventions with different mechanisms for tinnitus patients.

BACKGROUND: The aberrant brain network that gives rise to the phantom sound of tinnitus is believed to determine the effectiveness of tinnitus therapies involving neuromodulation with repetitive transcranial magnetic stimulation (rTMS) and sound therapy utilizing tailor-made notch music training (TMNMT). To test this hypothesis, we determined how effective rTMS or TMNMT were in ameliorating tinnitus in patients with different functional brain networks. METHODS: Resting-state functional MRI was used to construct brain functional networks in patients with tinnitus (41 males/45 females, mean age 49.53±11.19 years) and gender-matched healthy controls (22 males/35 females, mean age 46.23±10.23 years) with independent component analysis (ICA). A 2 × 2 analysis of variance with treatment outcomes (Effective group, EG/Ineffective group, IG) and treatment types (rTMS/TMNMT) was used to test the interaction between outcomes and treatment types associated with functional network connections (FNCs). FINDINGS: The optimal neuroimaging indicator for responding to rTMS (AUC 0.804, sensitivity 0.700, specificity 0.913) was FNCs in the salience network-right frontoparietal network (SN-RFPN) while for responding to TMNMT (AUC 0.764, sensitivity 0.864, specificity 0.667) was the combination of FNCs in the auditory network- salience network (AUN-SN) and auditory network-cerebellar network (AUN-CN). INTERPRETATION: Tinnitus patients with higher FNCs in the SN-RFPN is associated with a recommendation for rTMS whereas patients with lower FNCs in the AUN-SN and AUN-CN would suggest TMNMT as the better choice. These results indicate that brain network-based measures aid in the selection of the optimal form of treatment for a patient contributing to advances in precision medicine. FUNDING: Yuexin Cai is supported by Key R&D Program of Guangdong Province, China (Grant No. 2018B030339001), National Natural Science Foundation of China (82071062), Natural Science Foundation of Guangdong province (2021A1515012038), the Fundamental Research Funds for the Central Universities (20ykpy91), and Sun Yat-Sen Clinical Research Cultivating Program (SYS-Q-201903). Yu-Chen Chen is supported by Medical Science and Technology Development Foundation of Nanjing Department of Health (No. ZKX20037), and Natural Science Foundation of Jiangsu Province (No. BK20211008).