Altered effective connectivity among face-processing systems in major depressive disorder.

BACKGROUND: Neuroimaging studies have revealed abnormal functional interaction during the processing of emotional faces in patients with major depressive disorder (MDD), thereby enhancing our comprehension of the pathophysiology of MDD. However, it is unclear whether there is abnormal directional interaction among face-processing systems in patients with MDD. METHODS: A group of patients with MDD and a healthy control group underwent a face-matching task during functional magnetic resonance imaging. Dynamic causal modelling (DCM) analysis was used to investigate effective connectivity between 7 regions in the face-processing systems. We used a Parametric Empirical Bayes model to compare effective connectivity between patients with MDD and controls. RESULTS: We included 48 patients and 44 healthy controls in our analyses. Both groups showed higher accuracy and faster reaction time in the shape-matching condition than in the face-matching condition. However, no significant behavioural or brain activation differences were found between the groups. Using DCM, we found that, compared with controls, patients with MDD showed decreased self-connection in the right dorsolateral prefrontal cortex (DLPFC), amygdala, and fusiform face area (FFA) across task conditions; increased intrinsic connectivity from the right amygdala to the bilateral DLPFC, right FFA, and left amygdala, suggesting an increased intrinsic connectivity centred in the amygdala in the right side of the face-processing systems; both increased and decreased positive intrinsic connectivity in the left side of the face-processing systems; and comparable task modulation effect on connectivity. LIMITATIONS: Our study did not include longitudinal neuroimaging data, and there was limited region of interest selection in the DCM analysis. CONCLUSION: Our findings provide evidence for a complex pattern of alterations in the face-processing systems in patients with MDD, potentially involving the right amygdala to a greater extent. The results confirm some previous findings and highlight the crucial role of the regions on both sides of face-processing systems in the pathophysiology of MDD.

Online and offline effects of parietal 10 Hz repetitive transcranial magnetic stimulation on working memory in healthy controls.

Parietal alpha activity shows a specific pattern of phasic changes during working memory. It decreases during the encoding and recall phases but increases during the maintenance phase. This study tested whether online rTMS delivered to the parietal cortex during the maintenance phase of a working memory task would increase alpha activity and hence improve working memory. Then, 46 healthy volunteers were randomly assigned to two groups to receive 3-day parietal 10 Hz online rTMS (either real or sham, 3600 pulses in total) that were time-locked to the maintenance phase of a spatial span task (180 trials in total). Behavioral performance on another spatial span task and EEG signals during a change detection task were recorded on the day before the first rTMS (pretest) and the day after the last rTMS (posttest). We found that rTMS improved performance on both online and offline spatial span tasks. For the offline change detection task, rTMS enhanced alpha activity within the maintenance phase and improved interference control of working memory at both behavioral (K score) and neural (contralateral delay activity) levels. These results suggested that rTMS with alpha frequency time-locked to the maintenance phase is a promising way to boost working memory.

Effects of escitalopram therapy on effective connectivity among core brain networks in major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) have abnormal functional interaction among large-scale brain networks, indicated by aberrant effective connectivity of the default mode network (DMN), salience network (SN), and dorsal attention network (DAN). However, it remains unclear whether antidepressants can normalize the altered effective connectivity in MDD. METHODS: In this study, we collected resting-state functional magnetic resonance imaging data from 46 unmedicated patients with MDD at baseline and after 12 weeks of escitalopram treatment. We also collected data from 58 healthy controls (HCs) at the same time point with the same interval. Using spectral dynamic causal modeling and parametric empirical Bayes, we examined group differences, time effect and their interaction on the casual interactions among the regions of interest in the three networks. RESULTS: Compared with HCs, patients with MDD showed increased positive (excitatory) connections within the DMN, decreased positive connections within the SN and DAN, decreased absolute value of negative (inhibitory) connectivity from the SN and DAN to the DMN, and decreased positive connections between the DAN and the SN. Furthermore, we found that six connections related to the DAN showed decreased group differences in effective connectivity between MDD and HCs during follow-up compared to the baseline. CONCLUSIONS: Our findings suggest that escitalopram therapy can partly improve the disrupted effective connectivity among high-order brain functional networks in MDD. These findings deepened our understanding of the neural basis of antidepressants' effect on brain function in patients with MDD.

Neuroanatomical and functional substrates of the hypomanic personality trait and its prediction on aggression

Hypomanic personality manifests a close link with several psychiatric disorders and its abnormality is a risk indicator for developing bipolar disorders. We systematically investigated the potential neuroanatomical and functional substrates underlying hypomanic personality trait (HPT) and its sub-dimensions (i.e., Social Vitality, Mood Volatility, and Excitement) combined with structural and functional imaging data as well as their corresponding brain networks in a large non-clinical sample across two studies (n = 464). Behaviorally, HPT, specifically Mood Volatility and Excitement, was positively associated with aggressive behaviors in both studies. Structurally, sex-specific morphological characteristics were further observed in the motor and top-down control networks especially for Mood Volatility, although HPT was generally positively associated with grey matter volumes (GMVs) in the prefrontal, temporal, visual, and limbic systems. Functionally, brain activations related to immediate or delayed losses were found to predict individual variability in HPT, specifically Social Vitality and Excitement, on the motor and prefrontal-parietal cortices. Topologically, connectome-based prediction model analysis further revealed the predictive role of individual-level morphological and resting-state functional connectivity on HPT and its sub-dimensions, although it did not reveal any links with general brain topological properties. GMVs in the temporal, limbic (e.g., amygdala), and visual cortices mediated the effects of HPT on behavioral aggression. These findings suggest that the imbalance between motor and control circuits may be critical for HPT and provide novel insights into the neuroanatomical, functional, and topological mechanisms underlying the specific temperament and its impacts on aggression. (AU)

Neuroanatomical and functional substrates of the hypomanic personality trait and its prediction on aggression.

Hypomanic personality manifests a close link with several psychiatric disorders and its abnormality is a risk indicator for developing bipolar disorders. We systematically investigated the potential neuroanatomical and functional substrates underlying hypomanic personality trait (HPT) and its sub-dimensions (i.e., Social Vitality, Mood Volatility, and Excitement) combined with structural and functional imaging data as well as their corresponding brain networks in a large non-clinical sample across two studies (n = 464). Behaviorally, HPT, specifically Mood Volatility and Excitement, was positively associated with aggressive behaviors in both studies. Structurally, sex-specific morphological characteristics were further observed in the motor and top-down control networks especially for Mood Volatility, although HPT was generally positively associated with grey matter volumes (GMVs) in the prefrontal, temporal, visual, and limbic systems. Functionally, brain activations related to immediate or delayed losses were found to predict individual variability in HPT, specifically Social Vitality and Excitement, on the motor and prefrontal-parietal cortices. Topologically, connectome-based prediction model analysis further revealed the predictive role of individual-level morphological and resting-state functional connectivity on HPT and its sub-dimensions, although it did not reveal any links with general brain topological properties. GMVs in the temporal, limbic (e.g., amygdala), and visual cortices mediated the effects of HPT on behavioral aggression. These findings suggest that the imbalance between motor and control circuits may be critical for HPT and provide novel insights into the neuroanatomical, functional, and topological mechanisms underlying the specific temperament and its impacts on aggression.

Cl- induces endothelium-dependent mesenteric arteriolar vasorelaxation through the NKCC1/TRPV4/NCX axis.

AIMS: Although absorbed NaCl increases intestinal blood flow to facilitate absorption and transportation, it is unclear if it can directly mediate mesenteric arterial relaxation. We aimed to investigate and test our hypothesis that Cl- induces mesenteric arterial vasorelaxation via endothelium-dependent hyperpolarization (EDH). MAIN METHODS: We used wire myograph to study NaCl-induced vasorelaxation of mesenteric arteries isolated from mice. Cl-, Ca2+ and K+ imaging was performed in human vascular endothelial cells pre-treated with pharmacological agents. KEY FINDINGS: The Cl- concentration-dependently induced vasorelaxation of mesenteric arteries likely through EDH. The Cl--induced vasorelaxation was attenuated in TRPV4 KO mice and inhibited by selective blockers of Na+-K+-2Cl- cotransporter 1 (NKCC1) (bumetanide, 10 µM), transient receptor potential vanilloid 4 (TRPV4) (RN-1734, 40 µM), and small conductance Ca2+-activated K+ channels (SKCa) (apamin, 3 µM)/ intermediate conductance Ca2+-activated K+ channels (IKCa) (TRAM-34, 10 µM) and myoendothelial gap junction (18α-glycyrrhetinic acid, 10 µM), but enhanced by a selective activator of IKCa/SKCa (SKA-31, 0.3 µM). Cl- decreased intracellular K+ concentrations in endothelial cells, which was reversed by apamin (200 nM) plus TRAM-34 (500 nM). Extracellular Cl- raised intracellular Cl- concentrations in endothelial cells, which was attenuated by bumetanide (10 µM). Finally, Cl- induced a transient Ca2+ signaling via TRPV4 in endothelial cells, which became sustained when the Ca2+ exit mode of Na+-Ca2+ exchanger (NCX) was blocked. SIGNIFICANCE: Cl- induces a pure EDH-mediated vasorelaxation of mesenteric arteries through activation of endothelial NKCC1/TRPV4/NCX axis. We have provided a novel insight into the role of Cl--induced vasorelaxation via EDH mechanism.

Divergent roles of estrogen receptor subtypes in regulating estrogen-modulated colonic ion transports and epithelial repair.

Although it was described previously for estrogen (E2) regulation of intestinal epithelial Cl- and HCO3- secretion in sex difference, almost nothing is known about the roles of estrogen receptor (ER) subtypes in regulating E2-modulated epithelial ion transports and epithelial restitution. Here, we aimed to investigate ERα and ERß subtypes in the regulation of E2-modulated colonic epithelial HCO3- and Cl- secretion and epithelial restitution. Through physiological and biochemical studies, in combination of genetic knockdown, we showed that ERα attenuated female colonic Cl- secretion but promoted Ca2+-dependent HCO3- secretion via store-operated calcium entry (SOCE) mechanism in mice. However, ERß attenuated HCO3- secretion by inhibiting Ca2+via the SOCE and inhibiting cAMP via protein kinases. Moreover, ERα but not ERß promoted epithelial cell restitution via SOCE/Ca2+ signaling. ERα also enhanced cyclin D1, proliferating cell nuclear antigen, and ß-catenin expression in normal human colonic epithelial cells. All ERα-mediated biological effects could be attenuated by its selective antagonist and genetic knockdown. Finally, both ERα and ERß were expressed in human colonic epithelial cells and mouse colonic tissues. We therefore conclude that E2 modulates complex colonic epithelial HCO3- and Cl- secretion via ER subtype-dependent mechanisms and that ERα is specifically responsible for colonic epithelial regeneration. This study provides novel insights into the molecular mechanisms of how ERα and ERß subtypes orchestrate functional homeostasis of normal colonic epithelial cells.

Effects of 12-week escitalopram treatment on resting-state functional connectivity of large-scale brain networks in major depressive disorder.

In this study, the effects of antidepressants on large-scale brain networks and the neural basis of individual differences in response were explored. A total of 41 patients with major depressive disorder (MDD) and 42 matched healthy controls (HCs) were scanned by resting-state functional magnetic resonance imaging separately at baseline and after a 12-week follow-up. The patients with MDD received escitalopram for 12 weeks. After treatment, patients were classified into those with MDD in remission [MDDr, endpoint 17-item Hamilton Depression Rating Scale (HAMD) total score ≤7] and those in nonremission (MDDnr). The human Brainnetome Atlas was used to define large-scale networks and compute within- and between-network resting-state functional connectivity (rsFC). Results showed the decreased subcortical network (SCN)-ventral attention network (VAN) connectivity at baseline increased in patients with MDD after 12-week treatment, and it was comparable with that of HCs. This change was only observed in patients with MDDr. However, the decreased within-network rsFC in SCN and default mode network (DMN) persisted in all patients with MDD, including those with MDDr and MDDnr, after treatment. The strength of SCN-VAN connectivity at baseline was significantly negatively correlated with the reduction rate of HAMD score in all patients with MDD. Thus, SCN-VAN connectivity may be an antidepressant target associated with depressive state changes and a predictor of treatment response to serotonin reuptake inhibitors. The within-network rsFC in SCN and DMN may reflect a trait-like abnormality in MDD. These findings provide further insights into the mechanism of antidepressants and their individual differences in response. The trial name is "Appropriate technology study of MDD diagnosis and treatment based on objective indicators and measurement" (URL: http://www.chictr.org.cn/showproj.aspx?proj=21377; registration number: ChiCTR-OOC-17012566).

The CaSR/TRPV4 coupling mediates pro-inflammatory macrophage function.

AIM: Although calcium-sensing receptor (CaSR) and transient receptor potential vanilloid 4 (TRPV4) channels are functionally expressed on macrophages, it is unclear if they work coordinately to mediate macrophage function. The present study investigates whether CaSR couples to TRPV4 channels and mediates macrophage polarization via Ca2+ signaling. METHODS: The role of CaSR/TRPV4/Ca2+ signaling was assessed in lipopolysaccharide (LPS)-treated peritoneal macrophages (PMs) from wild-type (WT) and TRPV4 knockout (TRPV4 KO) mice. The expression and function of CaSR and TRPV4 in PMs were analyzed by immunofluorescence and digital Ca2+ imaging. The correlation factors of M1 polarization, CCR7, IL-1ß, and TNFα were detected using q-PCR, western blot, and ELISA. RESULTS: We found that PMs expressed CaSR and TRPV4, and CaSR activation-induced marked Ca2+ signaling predominately through extracellular Ca2+ entry, which was inhibited by selective pharmacological blockers of CaSR and TRPV4 channels. The CaSR activation-induced Ca2+ signaling was significantly attenuated in PMs from TRPV4 KO mice compared to those from WT mice. Moreover, the CaSR activation-induced Ca2+ entry via TRPV4 channels was inhibited by blocking phospholipases A2 (PLA2)/cytochromeP450 (CYP450) and phospholipase C (PLC)/Protein kinase C (PKC) pathways. Finally, CaSR activation promoted the expression and release of M1-associated cytokines IL-1ß and TNFɑ, which were attenuated in PMs from TRPV4 KO mice. CONCLUSION: We reveal a novel coupling of the CaSR and TRPV4 channels via PLA2/CYP450 and PLC/PKC pathways, promoting a Ca2+ -dependent M1 macrophage polarization. Modulation of this coupling and downstream pathways may become a potential strategy for the prevention/treatment of immune-related disease.

A prospective cohort study of depression (PROUD) in China: rationale and design.

Background: Major depressive disorder (MDD) imposes a heavy global disease burden. However, current etiology, diagnosis and treatment remain unsatisfactory and no previous study has resolved this problem. Building on the strengths and limitations of previous cohort studies of MDD, the prospective cohort study of depression (PROUD) is a 3-year large-scale cohort study designed to collect multidimensional data with a flexible follow-up schedule and strategy. The goal is to establish a nationally representative, high-quality, standardized depression cohort to support precise diagnosis and treatment of MDD and address the gap in current research. Methods: PROUD is a patient-based, nationally representative multicenter prospective cohort study with baseline and 3-year follow-up assessments. It will be carried out from January 2022 to December 2026 in 52 qualified tertiary hospitals in China. A total of 14,000 patients diagnosed with MDD, according to the DSM-5 criteria, and aged ≥ 16 years, will be recruited to PROUD. Participants aged 18-65 years who have not received any treatment during a depressive episode will be included in the precision medicine cohort (PMC) of PROUD (n=4,000). Patients who meet the general eligibility criteria but not the PMC criteria will be included in the naturalistic observation cohort (NOC) of PROUD (n=10,000). A multiple follow-up strategy, including scheduled, remote, telephone, external visits and patient self-reports, will be implemented to collect comprehensive sociodemographic, clinical information, biospecimens, neuroimaging, cognitive function and electrophysiology data and digital phenotypes according to strict standard operating procedures implemented across centers. Trial registration: ChiCTR2200059053, registered on 23 April 2022, http://www.chictr.org.cn/showproj.aspx?proj=165790. Conclusions: PROUD is a prospective cohort study of MDD patients in China. It will provide a comprehensive database facilitating further analyses and aiding the development of homeostatic and precision medicine in China.

Effects of working memory span training on top-down attentional asymmetry at both neural and behavioral levels.

The leftward asymmetry of the visual field and posterior brain regions, a feature of the normal attention process, can be strengthened by brain stimulation, e.g. administering alpha frequency stimulation to the left posterior cortex. However, whether it can be strengthened by cognitive training, especially with nonlateralized tasks, is unknown. We used a dataset from a 2-month-long randomized controlled trial and compared the control group with 2 training groups trained with backward or forward memory span tasks. A lateralized change detection task with varied memory loads was administered as the pre-, mid-, and post-tests with simultaneous electroencephalographic recording. Intrasubject response variability (IRV) and the alpha modulation index (MI) were calculated. Analysis of IRV showed more enhanced leftward attentional bias in the backward group than in the other groups. Consistently, analysis of MI found that its enhancements in the left hemisphere (but not the right hemisphere) of the backward group were significantly higher than those of the other groups. Further analysis revealed that left MI changes predicted left IRV improvement. All of these results indicated that backward memory span training enhanced leftward attentional asymmetry at both the behavioral and neural levels.

Effects of forward and backward span trainings on working memory: Evidence from a randomized controlled trial.

Both forward and backward working memory span tasks have been used in cognitive training, but no study has been conducted to test whether the two types of trainings are equally effective. Based on data from a randomized controlled trial, this study (N = 60 healthy college students) tested the effects of backward span training, forward span training, and no intervention. Event-related potential (ERP) signals were recorded at the pre-, mid-, and post-tests while the subjects were performing a distractor version of the change detection task, which included three conditions (2 targets and 0 distractor [2T0D]; 4 targets and 0 distractor [4T0D]; and 2 targets and 2 distractors [2T2D]). Behavioral data were collected from two additional tasks: a multi-object version of the change detection task, and a suppress task. Compared to no intervention, both forward and backward span trainings led to significantly greater improvement in working memory maintenance, based on indices from both behavioral (Kmax) and ERP data (CDA_2T0D and CDA_4T0D). Backward span training also improved interference control based on the ERP data (CDA_filtering efficiency) to a greater extent than did forward span training and no intervention, but the three groups did not differ in terms of behavioral indices of interference control. These results have potential implications for optimizing the current cognitive training on working memory.

Prediction of remission among patients with a major depressive disorder based on the resting-state functional connectivity of emotion regulation networks.

The prediction of antidepressant response is critical for psychiatrists to select the initial antidepressant drug for patients with major depressive disorders (MDD). The implicated brain networks supporting emotion regulation (ER) are critical in the pathophysiology of MDD and the prediction of antidepressant response. Therefore, the primary aim of the current study was to identify the neuroimaging biomarkers for the prediction of remission in patients with MDD based on the resting-state functional connectivity (rsFC) of the ER networks. A total of 81 unmedicated adult MDD patients were investigated and they underwent resting-state functional magnetic resonance imagining (fMRI) scans. The patients were treated with escitalopram for 12 weeks. The 17-item Hamilton depression rating scale was used for assessing remission. The 36 seed regions from predefined ER networks were selected and the rsFC matrix was caculated for each participant. The support vector machine algorithm was employed to construct prediction model, which separated the patients with remission from those with non-remission. And leave-one-out cross-validation and the area under the curve (AUC) of the receiver operating characteristic were used for evaluating the performance of the model. The accuracy of the prediction model was 82.08% (sensitivity = 71.43%, specificity = 89.74%, AUC = 0.86). The rsFC between the left medial superior frontal gyrus and the right inferior frontal gyrus as well as the precuneus were the features with the highest discrimination ability in predicting remission from escitalopram among the MDD patients. Results from our study demonstrated that rsFC of the ER brain networks are potential predictors for the response of antidepressant drugs. The trial name: appropriate technology study of MDD diagnosis and treatment based on objective indicators and measurement. URL: http://www.chictr.org.cn/showproj.aspx?proj=21377 . Registration number: ChiCTR-OOC-17012566.

Altered frequency-specific/universal amplitude characteristics of spontaneous brain oscillations in patients with bipolar disorder.

The human brain is a dynamic system with intrinsic oscillations in spontaneous neural activity. Whether the dynamic characteristics of these spontaneous oscillations are differentially altered across different frequency bands in patients with bipolar disorder (BD) remains unclear. This study recruited 65 patients with BD and 85 healthy controls (HCs). The entire frequency range of resting-state fMRI data was decomposed into four frequency intervals. Two-way repeated-measures ANCOVA was employed to detect frequency-specific/universal alterations in the dynamic oscillation amplitude in BD. The patients were then divided into two subgroups according to their mood states to explore whether these alterations were independent of their mood states. Finally, other window sizes, step sizes, and window types were tested to replicate all analyses. Frequency-specific abnormality of the dynamic oscillation amplitude was detected within the posterior medial parietal cortex (centered at the precuneus extending to the posterior cingulate cortex). This specific profile indicates decreased amplitudes in the lower frequency bands (slow-5/4) and no amplitude changes in the higher frequency bands (slow-3/2) compared with HCs. Frequency-universal abnormalities of the dynamic oscillation amplitude were also detectable, indicating increased amplitudes in the thalamus and left cerebellum anterior lobe but decreased amplitudes in the medial superior frontal gyrus. These alterations were independent of the patients' mood states and replicable across multiple analytic and parametric settings. In short, frequency-specific/universal amplitude characteristics of spontaneous oscillations were observed in patients with BD. These abnormal characteristics have important implications for specific functional changes in BD from multiple frequency and dynamic perspectives.

Effect of schizophrenia risk gene polymorphisms on cognitive and neural plasticity.

A recent Chinese genome-wide association study found evidence for 58 out of the 128 schizophrenia-associated variants previously discovered in Western samples by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). However, the functional impact of these trans-ancestry genome-wide single-nucleotide polymorphisms (SNPs) is not clear. In the current study, we examined the roles of trans-ancestry SNPs in cognitive and neural plasticity. We first performed a behavioral study of 547 healthy volunteers, who received month-long working memory training, and working memory capability assessment both before and after the training. A separate sample of 101 subjects received the same training and received fMRI scans during a working memory task, both before and after the training. The behavioral study found a significant association between the polygenic risk score (PRS) and behavioral plasticity, with higher schizophrenia risk scores being linked to less plasticity. At the SNP level, rs36068923 showed a significant signal, with the risk allele being associated with less plasticity. The fMRI study further found that the PRS and rs36068923 polymorphism were associated with training-induced changes in striatal activation, with higher PRS and the risk allele of rs36068923 being linked to less brain plasticity. In sum, this study found that a high genetic risk for schizophrenia was associated with less plasticity at both behavioral and neural levels. These results provide new insights into the neural and cognitive mechanisms linking genes to schizophrenia.

Evidence for the contribution of HCN1 gene polymorphism (rs1501357) to working memory at both behavioral and neural levels in schizophrenia patients and healthy controls.

Gene HCN1 polymorphism (rs1501357) has been proposed to be one of the candidate risk genes for schizophrenia in the second report of the Psychiatric Genomics Consortium-Schizophrenia Workgroup. Although animal studies repeatedly showed a role of this gene in working memory, its contribution to working memory in human samples, especially in schizophrenia patients, is still unknown. To explore the association between rs1501357 and working memory at both behavioral (Study 1) and neural (Study 2) levels, the current study involved two independent samples. Study 1 included 876 schizophrenia patients and 842 healthy controls, all of whom were assessed on a 2-back task, a dot pattern expectancy task (DPX), and a digit span task. Study 2 included 56 schizophrenia patients and 155 healthy controls, all of whom performed a 2-back task during functional magnetic resonance imaging (fMRI) scanning. In both studies, we consistently found significant genotype-by-diagnosis interaction effects. For Study 1, the interaction effects were significant for the three tasks. Patients carrying the risk allele performed worse than noncarriers, while healthy controls showed the opposite pattern. For Study 2, the interaction effects were observed at the parietal cortex and the medial frontal cortex. Patients carrying the risk allele showed increased activation at right parietal cortex and increased deactivation at the medial frontal cortex, while healthy controls showed the opposite pattern. These results suggest that the contributions of rs1501357 to working memory capability vary in different populations (i.e., schizophrenia patients vs. healthy controls), which expands our understanding of the functional impact of the HCN1 gene. Future studies should examine its associations with other cognitive functions.

Beneficial effect of capsaicin via TRPV4/EDH signals on mesenteric arterioles of normal and colitis mice.

INTRODUCTION: Although capsaicin has long been used as food additive and medication worldwide, its actions on gastrointestinal tract as its most delivery pathway have not been well addressed. OBJECTIVES: In the present study, we aimed to study GI actions of capsaicin on mesenteric arterioles in normal and colitis mice and to elucidate the underlying mechanisms. METHODS: Vasorelaxation of human submucosal arterioles and the mesenteric arterioles from wide-type (WT) mice, TRPV1-/- and TRPV4-/- (KO) mice were measured. The expression and function of TRPV channels in endothelial cells were examined by q-PCR, immunostaining, Ca2+ imaging and membrane potential measurements. RESULTS: Capsaicin dose-dependently induced vasorelaxation of human submucosal arterioles and mouse mesenteric arterioles in vitro and in vivo through endothelium-dependent hyperpolarization (EDH), nitric oxide (NO), and prostacyclin (PGI2). Using TRPV1 and TRPV4 KO mice, we found that capsaicin-induced vasorelaxation was predominately through TRPV4/EDH, but marginally through TRPV1/NO/PGI2. Capsaicin induced hyperpolarization through activation of endothelial TRPV4 channels and intermediate-conductance of Ca2+-activated K+ channels to finally stimulate vasorelaxation. Importantly, capsaicin exerted anti-colitis action by rescuing the impaired ACh-induced vasorelaxation in WT colitis mice but not in TRPV4 KO colitis mice. CONCLUSIONS: Capsaicin increases intestinal mucosal blood perfusion to potentially prevent/treat colitis through a novel TRPV4/EDH-dependent vasorelaxation of submucosal arterioles in health and colitis. This study further supports our previous notion that TRPV4/EDH in mesenteric circulation plays a critical role in the pathogenesis of colitis.

Altered effective connectivity among core brain networks in patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is increasingly being regarded as a dysconnection syndrome. Functional integration among the three core brain networks - executive control network (ECN), salience network (SN), and default mode network (DMN) - is abnormal in patients with BD; however, the causal relationship among the three networks in BD is largely unknown. It is also unclear whether patients with BD in different mood states show distinct effective connectivity patterns during rest. METHODS: Resting-state fMRI data were collected from 65 patients with BD and 85 healthy controls. Spectral dynamic causal modeling was applied to investigate the effective connectivity difference of the three brain networks between all patients with BD and healthy controls and between patients who were in euthymic mood state (euthymic BD) and depressed mood state (depressed BD). RESULTS: Compared with healthy controls, all patients with BD showed altered effective connectivity within and between the ECN and SN and from these two networks to the DMN. Compared with patients with depressed BD, patients with euthymic BD showed increased excitatory effects within the ECN and decreased inhibitory effects from the SN to the ECN and DMN. CONCLUSION: These results further confirmed that patients with BD show abnormal functional integration within and among the three core brain networks, and exhibit similar and different effective connectivity patterns in different mood states. Abnormal effective connectivity has the potential to be a critical index for diagnosing BD and differentiating between BD patients with different mood states.

Affective Representation of Early Relationships with Parents and Current Anxiety and Depression.

Research on the role of early relationships with parents on youth's anxiety and depression, especially in collectivist societies such as China, is limited. To fill this gap, we investigated the unique role of early relationship with mothers and fathers, respectively, in Chinese youth's anxiety and depression outcomes. The participants were 347 Chinese college students from 20 provinces. They first separately rated the frequency of experiencing 13 emotions (e.g., anger) from recalling early relationships with their mothers and fathers, then completed the Zung Self-Rating Anxiety Scale and the Zung Self-Rating Depression Scale. Logistic regression was performed to determine the unique contribution of early relationships with mothers and fathers, respectively, to the participants' clinical-level anxiety and depression. Based on the final model of our logistical regression, we found that an increase in negative affective representation of early relationship with the mother was associated with a higher likelihood of clinical level anxiety (OR = 3.58; 95% CI = 1.32-9.70), while an increase in positive affective representation of early relationship with the mother was associated with a lower likelihood of clinical-level depression (OR = 0.47; 95% CI = 0.25-0.87). Furthermore, an increase in negative affective representation of early relationship with the father was associated with a higher likelihood of clinical-level anxiety (OR = 3.36; 95% CI = 1.37-8.26) and depression (OR = 3.68; 95% CI = 1.59-8.52), above and beyond their affective representation of early relationship with the mother.

Intermittent theta burst stimulation over the parietal cortex has a significant neural effect on working memory.

The crucial role of the parietal cortex in working memory (WM) storage has been identified by fMRI studies. However, it remains unknown whether repeated parietal intermittent theta-burst stimulation (iTBS) can improve WM. In this within-subject randomized controlled study, under the guidance of fMRI-identified parietal activation in the left hemisphere, 22 healthy adults received real and sham iTBS sessions (five consecutive days, 600 pulses per day for each session) with an interval of 9 months between the two sessions. Electroencephalography signals of each subject before and after both iTBS sessions were collected during a change detection task. Changes in contralateral delay activity (CDA) and K-score were then calculated to reflect neural and behavioral WM improvement. Repeated-measures ANOVA suggested that real iTBS increased CDA more than the sham one (p = .011 for iTBS effect). Further analysis showed that this effect was more significant in the left hemisphere than in the right hemisphere (p = .029 for the hemisphere-by-iTBS interaction effect). Pearson correlation analyses showed significant correlations for two conditions between CDA changes in the left hemisphere and K score changes (ps <.05). In terms of the behavioral results, significant K score changes after real iTBS were observed for two conditions, but a repeated-measures ANOVA showed a nonsignificant main effect of iTBS (p = .826). These results indicate that the current iTBS protocol is a promising way to improve WM capability based on the neural indicator (CDA) but further optimization is needed to produce a behavioral effect.