Top-down and bottom-up alterations of connectivity patterns of the suprachiasmatic nucleus in chronic insomnia disorder.

The importance of the suprachiasmatic nucleus (SCN, also called the master circadian clock) in regulating sleep and wakefulness has been confirmed by multiple animal research. However, human studies of SCN in vivo are still nascent. Recently, the development of resting-state functional magnetic resonance imaging (fMRI) has made it possible to study SCN-related connectivity changes in patients with chronic insomnia disorder (CID). Hence, this study aimed to explore whether sleep-wake circuitry (i.e., communication between the SCN and other brain regions) is disrupted in human insomnia. Forty-two patients with CID and 37 healthy controls (HCs) underwent fMRI scanning. Resting-state functional connectivity (rsFC) and Granger causality analysis (GCA) were performed to find abnormal functional and causal connectivity of the SCN in CID patients. In addition, correlation analyses were conducted to detect associations between features of disrupted connectivity and clinical symptoms. Compared to HCs, CID patients showed enhanced rsFC of the SCN-left dorsolateral prefrontal cortex (DLPFC), as well as reduced rsFC of the SCN-bilateral medial prefrontal cortex (MPFC); these altered cortical regions belong to the "top-down" circuit. Moreover, CID patients exhibited disrupted functional and causal connectivity between the SCN and the locus coeruleus (LC) and the raphe nucleus (RN); these altered subcortical regions constitute the "bottom-up" pathway. Importantly, the decreased causal connectivity from the LC-to-SCN was associated with the duration of disease in CID patients. These findings suggest that the disruption of the SCN-centered "top-down" cognitive process and "bottom-up" wake-promoting pathway may be intimately tied to the neuropathology of CID.

Deficits in brain default mode network connectivity mediate the relationship between poor sleep quality and anxiety severity.

STUDY OBJECTIVES: Chronic insomnia disorder (CID) is a prevalent sleep disorder that frequently cooccurs with anxiety. The association between insomnia and anxiety has been established; however, the neurobiological basis of this relationship remains unclear. This study aimed to investigate the neural markers of CID patients with and without anxiety and to determine whether specific neural connectivity mediates the relationship between insomnia and anxiety. METHODS: This study included 180 participants, comprising CID patients with anxiety (CID-A), CID patients without anxiety (CID-NA), and good sleep controls. All participants completed self-reported measures of sleep quality and anxiety severity and underwent functional magnetic resonance imaging. Brain functional integration was measured using functional connectivity density (FCD) and resting-state functional connectivity (rsFC). Correlation and mediation analyses were used to examine the relationships among brain connectivity, sleep quality, and anxiety severity. RESULTS: The CID-NA and CID-A groups showed decreased local FCD in the medial prefrontal cortex (mPFC) and disrupted rsFC between the precuneus and other brain regions. Only the CID-A group exhibited altered long-range FCD in the precuneus and the rsFC between the anterior default mode network (DMN, e.g. mPFC) and posterior DMN (e.g. precuneus). Mediation analysis revealed DMN dysconnectivity underlying the association between poor sleep quality and anxiety symptoms. CONCLUSIONS: This study identified shared and distinct brain circuit disruptions in the CID-NA and CID-A groups, with deficits in DMN connectivity as a potential neural mechanism through which disrupted sleep augments anxiety. These findings may facilitate the development of personalized therapies for insomnia and associated anxiety problems.

Neural mechanisms of working memory dysfunction in patients with chronic insomnia disorder.

OBJECTIVE: This study aimed to investigate the neural mechanisms underlying working memory impairment in patients with chronic insomnia disorder (CID) using event-related potentials (ERP) and resting-state functional connectivity (rsFC) approaches. METHODS: Participants, including CID patients and healthy controls (HCs), completed clinical scales and underwent electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). EEG analysis compared reaction times, P3 amplitudes, event-related spectral perturbations (ERSP), and inter-trial phase synchronisation (ITPS) between CID patients and HCs. Subsequently, frontal regions (i.e., the Superior Frontal Gyrus [SFG] and Middle Frontal Gyrus [MFG]) corresponding to the EEG were selected as seeds for rsFC analysis. Correlation analyses were conducted to further investigate the relationship between functional connectivity abnormalities in brain regions and clinical symptom severity and P3 amplitude in CID patients. RESULTS: Compared to HCs, CID patients exhibited slower reaction times across all working memory conditions, with the deficits becoming more pronounced as memory load increased. ERP analysis revealed increased P3 amplitude, theta wave power, and reduced inter-trial synchrony in CID patients. rsFC analysis showed decreased connectivity of SFG-posterior cingulated cortex (PCC), SFG-MFG, and MFG-frontal pole (FP), and increased connectivity of MFG- Middle Temporal Gyrus (MTG)in CID patients. Importantly, a significant correlation was found between the rsFC of SFG-MTG and P3 amplitude during 1-back. CONCLUSION: This study confirms deficits in working memory capacity in patients with CID, specifically in the neural mechanisms of cognitive processing that vary depending on the level of cognitive load. Alterations in connectivity patterns within and between the frontal and temporal regions may be the neural basis of the cognitive impairment.

Classification of primary dysmenorrhea by brain effective connectivity of the amygdala: a machine learning study.

BACKGROUND: The amygdala plays a crucial role in the central pathogenesis mechanism of primary dysmenorrhea (PDM). However, the detailed pain modulation principles of the amygdala in PDM remain unclear. Here, we applied the Granger causality analysis (GCA) to investigate the directional effective connectivity (EC) alterations in the amygdala network of PDM patients. METHODS: Thirty-seven patients with PDM and 38 healthy controls were enrolled in this study and underwent resting-state functional magnetic resonance imaging scans during the pain-free stage. GCA was employed to explore the amygdala-based EC network alteration in PDM. A multivariate pattern analysis (MVPA)-based machine learning approach was used to explore whether the altered amygdala EC could serve as an fMRI-based marker for classifying PDM and HC participants. RESULTS: Compared to the healthy control group, patients with PDM showed significantly decreased EC from the amygdala to the right superior frontal gyrus (SFG), right superior parietal lobe/middle occipital gyrus, and left middle cingulate cortex, whereas increased EC was found from the amygdala to the bilateral medial orbitofrontal cortex. In addition, increased EC was found from the bilateral SFG to the amygdala, and decreased EC was found from the medial orbitofrontal cortex, caudate nucleus to the amygdala. The increased EC from the right SFG to the amygdala was associated with a plasma prostaglandin E2 level in PDM. The MVPA based on an altered amygdala EC pattern yielded a total accuracy of 86.84% for classifying the patients with PDM and HC. CONCLUSION: Our study is the first to combine MVPA and EC to explore brain function alteration in PDM. The results could advance understanding of the neural theory of PDM in specifying the pain-free period.

Acupuncture modulates the frequency-specific functional connectivity density in primary dysmenorrhea.

Background: The study aimed to investigate how acupuncture modulates brain activities across multiple frequency bands to achieve therapeutic effects in PDM. Methods: A total of 47 patients with PDM were randomly assigned to the verum acupuncture group and sham acupuncture group with three menstrual cycles of the acupuncture course. The fMRI scans, visual analog scale (VAS) scores, and other clinical evaluations were assessed at baseline and after three menstrual-cycles treatments. The global functional connectivity density (gFCD) analyses were performed between the pre-and post-acupuncture course of two groups at full-low frequency band, Slow-3 band, Slow-4 band, and Slow-5 band. Results: After the acupuncture treatments, the patients with PDM in the verum acupuncture group showed significantly decreased VAS scores (p < 0.05). The frequency-dependent gFCD alternations were found in the verum acupuncture group, altered regions including DLPFC, somatosensory cortex, anterior cingulate cortex (ACC), middle cingulate cortex (MCC), precuneus, hippocampus, and insula. The sham acupuncture modulated regions including angular gyrus, inferior frontal gyrus, and hippocampus. The gFCD alternation in DLPFC at the Slow-5 band was negatively in the patients with PDM following verum acupuncture, and S2 at the Slow-4 band was positively correlated with VAS scores. Conclusion: These findings supported that verum acupuncture could effectively modulate frequency-dependent gFCD in PDM by influencing abnormal DLPFC at Slow-5 band and hippocampus at the Slow-3 band. The outcome of this study may shed light on enhancing the potency of acupuncture in clinical practice.

Moxibustion for primary dysmenorrhea: A resting-state functional magnetic resonance imaging study exploring the alteration of functional connectivity strength and functional connectivity.

Introduction: Primary dysmenorrhea (PDM) is a common gynecological disease and chronic pain disorder. Moxibustion, a form of traditional Chinese medicine therapy, has proven to be effective for PDM. However, the central mechanisms of PDM and moxibustion for PDM are still unclear. This study aims to explore the potential central mechanism of PDM and clarify the possible mechanism of moxibustion for relieving pain. Materials and methods: A total of 23 PDM patients and 23 matched healthy controls (HCs) were enrolled. For PDM patients, resting-state functional magnetic resonance imaging (rs-fMRI) data were collected pre- and post-moxibustion treatment of 3 consecutive menstrual cycles, respectively. For HCs, rs-fMRI data were collected in the baseline. The resting-state functional connectivity strength (rs-FCS) analysis and the resting-state functional connectivity (rs-FC) analysis based on the region of interest (ROI) were combined to be conducted. Results: Compared to HCs, PDM patients showed weaker rs-FCS in the left inferior frontal gyrus (IFG). After the moxibustion treatment, rs-FCS in the left IFG was increased with clinical improvement. Then, the left IFG was chosen as ROI, and the rs-FC analysis was conducted. It showed that the left IFG rs-FC in the bilateral anterior cingulate cortex (ACC)/middle cingulate cortex (MCC), the left posterior cingulate cortex (PCC)/precuneus (PCU), and the left parahippocampal gyrus (PHG) decreased after moxibustion treatment, most of which belong to the default mode network (DMN). Conclusion: Our results highlight the role of the left IFG and the DMN in PDM. Specifically, the central mechanism of moxibustion for analgesia may be related to modulating the disorders of the reappraisal and processing of pain stimuli through influencing the cognition of pain.

[Effect of acupuncture on brain functional connectivity strength in patients with primary dysmenorrhea].

OBJECTIVE: To investigate the effect of acupuncture on the brain functional activities of the patients with primary dysmenorrhea based on the resting-state functional magnetic resonance imaging (rs-fMRI), and to provide visual evidence for the central mechanism of acupuncture in treatment of primary dysmenorrhea. METHODS: Forty-two patients of primary dysmenorrhea were enrolled and randomly divided into an observation group (21 cases, 1 case dropped off) and a control group (21 cases, 2 cases dropped off, 3 cases withdrawal). In the observation group, acupuncture was exerted at Sanyinjiao (SP 6) and Guanyuan (CV 4), started 5-7 days before menstrual flow, once a day till menstrual onset, for a total of 3 menstrual cycles. No intervention was applied in the control group. The scores of visual analogue scale (VAS) and Cox menstrual symptom scale (CMSS) were observed in both groups before and after treatment. Based on rs-fMRI, the data of resting-state functional magnetic resonance were collected from two groups before and after treatment. Combined with functional connectivity strength (FCS) and functional connectivity (FC) analysis, the differences of brain regions before and after treatment were compared between the two groups and the correlation was analyzed between their functional connectivity changes and the improvements in VAS and CMSS scores of the patients in the observation group. RESULTS: In the observation group, the scores of VAS and CMSS were all decreased after treatment (P<0.05), while the scores related to the symptom time in CMSS was reduced in comparison with that before treatment in the control group (P<0.05). The score reducing ranges of VAS and CMSS in the observation group were larger than the control group (P<0.05). Compared before treatment, FCS of the right middle cingulate cortex and the left cuneus was increased, while FCS of the left inferior parietal lobule was decreased after treatment in the observation group. In the control group, FCS of the left orbital frontal cortex was increased after treatment. Compared with the control group, FCS of the left anterior insula was increased in the observation group after treatment. FC analysis was performed using the left anterior insula as the seed point. In comparison with the control group, FC of the left anterior insula was increased either with the inferior temporal gyrus or with the right hippocampus; and was decreased either with the middle occipital lobe or with the right dorsolateral prefrontal cortex in the observation group after treatment. In the observation group, FC between the left anterior insula and the right hippocampus was positively correlated with the improvements in symptom severity (r =0.385, P<0.05) and symptom time (r =0.510, P<0.05) of CMSS, and FC between the right dorsolateral prefrontal cortex and the left anterior insula was negatively correlated with the improvement in symptom severity of CMSS after treatment (r =-0.373, P<0.05). CONCLUSION: The anterior insula may be the key brain region in treatment of primary dysmenorrhea with acupuncture. Acupuncture may relieve dysmenorrhea and the related symptoms through strengthening the functional connectivity of anterior insula-limbic system and anterior insula-control network.

The hypertrophic amygdala shape associated with anxiety in patients with primary dysmenorrhea during pain-free phase: insight from surface-based shape analysis.

BACKGROUND: Primary dysmenorrhea (PDM) is highly associated with mood symptoms. However, the neuropathology of these comorbidities is unclear. In the present study, we aimed to investigate the structural changes in the amygdala of patients with PDM during the pain-free phase using a surface-based shape analysis. METHODS: Forty-three PDM patients and forty healthy controls were recruited in the study, and all participants underwent structural magnetic resonance imaging scans during their periovulatory phase. FMRIB's Integrated Registration and Segmentation Tool (FIRST) was employed to assess the subcortical volumetric and surface alterations in patients with PDM. Moreover, correlation and mediation analyses were used to detect the clinical significance of the subcortical morphometry alteration. RESULTS: PDM patients showed hypertrophic alteration of the amygdala in the left superficial nuclei and right basolateral and superficial nuclei but not for the whole amygdala volume. The hypertrophic amygdala was associated with disease duration, pain severity and anxiety symptoms during the menstrual period. Furthermore, the hypertrophic left amygdala could mediate the association between disease duration and anxiety severity. CONCLUSIONS: The results of the current study demonstrated that the localized amygdala shape hypertrophy was present in PDM patients even in the pain-free phase. In addition, the mediator role of the hypertrophic amygdala indicates the potential target of amygdala for anxiety treatment in PDM treatment in the pain-free phase.

Brain Mechanism of Acupuncture Treatment of Chronic Pain: An Individual-Level Positron Emission Tomography Study.

Objective: Acupuncture has been shown to be effective in the treatment of chronic pain. However, their neural mechanism underlying the effective acupuncture response to chronic pain is still unclear. We investigated whether metabolic patterns in the pain matrix network might predict acupuncture therapy responses in patients with primary dysmenorrhea (PDM) using a machine-learning-based multivariate pattern analysis (MVPA) on positron emission tomography data (PET). Methods: Forty-two patients with PDM were selected and randomized into two groups: real acupuncture and sham acupuncture (three menstrual cycles). Brain metabolic data from the three special brain networks (the sensorimotor network (SMN), default mode network (DMN), and salience network (SN)) were extracted at the individual level by using PETSurfer in fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) data. MVPA analysis based on metabolic network features was employed to predict the pain relief after treatment in the pooled group and real acupuncture treatment, separately. Results: Paired t-tests revealed significant alterations in pain intensity after real but not sham acupuncture treatment. Traditional mass-univariate correlations between brain metabolic and alterations in pain intensity were not significant. The MVPA results showed that the brain metabolic pattern in the DMN and SMN did predict the pain relief in the pooled group of patients with PDM (R 2 = 0.25, p = 0.005). In addition, the metabolic pattern in the DMN could predict the pain relief after treatment in the real acupuncture treatment group (R 2 = 0.40, p = 0.01). Conclusion: This study indicates that the individual-level metabolic patterns in DMN is associated with real acupuncture treatment response in chronic pain. The present findings advanced the knowledge of the brain mechanism of the acupuncture treatment in chronic pain.

Frequency-Specific Alterations in Brain Function in Patients with Primary Dysmenorrhea.

OBJECTIVE: Recent neuroimaging studies have found that brain function is abnormal in primary dysmenorrhea (PDM). The present study aimed to explore frequency-specific brain alterations and their occurrence in the PDM. METHODS: Forty-seven patients with PDM and 36 matched healthy controls were enrolled in the study and underwent resting-state functional magnetic resonance imaging. The alterations in brain function in patients with PDM were assessed with different frequency filter bands (Slow5, Slow4, Slow3, and full low frequency) and a functional connectivity density (FCD) approach. The clinical significance of the altered FCD was then explored. Additionally, mediation analysis was used to detect the altered FCD-mediated clinical relationships in PDM. RESULTS: Frequency-specific FCD alterations have been observed in patients with PDM, especially in the central executive, default mode, and sensorimotor networks and in the hippocampus. The altered full low-frequency FCD in the hippocampus was associated with the duration of disease and pain severity scores. The altered Slow5 FCD in the second somatosensory area (S2) was associated with the severity of pain in PDM. Furthermore, the FCD in S2 mediated the duration associated with pain symptoms in PDM. CONCLUSION: The present study identified frequency-specific FCD alterations in PDM and suggested that the S2 area is a potential treatment target for PDM.

The cerebral mechanism of acupuncture for chronic insomnia with gastrointestinal disorder: protocol for a randomized controlled trial.

BACKGROUND: Many patients with chronic insomnia disorder (CID) have gastrointestinal (GI) symptoms. First-line insomnia medications do not treat GI problems. Acupuncture has a comprehensive regulative action on both CID and GI disorder and is receiving increasing attention. Recent studies indicate that both CID and GI diseases may cause abnormal brain activity. However, the neurological mechanism underlying the effect of acupuncture on such diseases is still unclear. The aim of this study is to explore the pathological mechanisms of CID with GI discomfort, as well as the main response characteristics of acupuncture treatment from multiple perspectives using multimodal magnetic resonance imaging (MRI). METHODS: A total of 60 participants with CID and GI disorders will be randomly divided into two groups (real acupuncture group and sham acupuncture group; ratio of 1:1). Patients will receive 20 sessions (five sessions per week) of real acupuncture treatment or sham acupuncture treatment. The primary outcome is the aggregate score on the Pittsburgh Sleep Quality Index. Secondary outcomes are scores on the Gastrointestinal Symptom Rating Scale, Self-Rating Anxiety Scale, and Self-Rating Depression Scale. Multimodal MRI scans and clinical assessments will be performed both at baseline and post-treatment. Another 30 age-, sex-, and education-matched healthy subjects will be recruited as controls and will receive MRI scans and clinical evaluations. DISCUSSION: This study aims to provide scientific evidence for the mechanism of acupuncture in treating CID with GI disorder using multimodal MRI imaging data on brain structure, function, and metabolism. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017092 (URL: http://www.chictr.org.cn/showproj.aspx?proj=27173 ). Registered on July 11, 2018.

Gray matter hypertrophy in primary insomnia: a surface-based morphometric study.

Studies have explored brain structural abnormalities in patients with primary insomnia (PI). However, most of them are based on volumetric measures, in a specific region of interest, and have small sample sizes. Here, we investigated changes in cortical morphology (thickness and volume) in PI using an advanced surface-based morphometric method. Sixty-seven patients with PI and 55 matched healthy controls were recruited for this study and underwent a structural magnetic resonance imaging scan. The reconstructed cortical surface was processed by Freesurfer 6.0. A general linear model was used to explore group differences in surface-based morphometric features. Furthermore, the association between these cortical features and clinical characteristics were assessed in the PI group. Compared to controls, PI patients showed cortical thickening in the left orbital frontal cortex (OFC), right rostral anterior cingulate cortex (rACC), left middle cingulate cortex (MCC), bilateral insula, left superior parietal lobule (SPL), and right fusiform area (FFA), and showed increased cortical volume in the left OFC, right rACC, bilateral rostral middle frontal gyrus, and right FFA. Cortical thickness in the right OFC and FFA was positively correlated with the severity of insomnia in the PI group, suggesting a right-lateralized relationship. This study was the first to explore multiple-scale cortical morphometric changes in a relatively large sample of PI patients. Our results suggest that hypertrophic cortical morphology may underlie the neuropathology of primary insomnia.

Effects of acupuncture in treating insomnia due to spleen-stomach disharmony syndrome and its influence on intestinal microbiome: Study protocol for a randomized controlled trial.

BACKGROUND: Insomnia is a common complaint that is closely related to gastrointestinal symptoms, which is consistent with the traditional Chinese medicine classical theory of "stomach disharmony leading to restless sleep." Acupuncture is an effective complementary and alternative medicine therapy to improve gastrointestinal function and restore the normal sleep-wake cycle. However, studies on the effectiveness of acupuncture for insomnia due to spleen-stomach disharmony syndrome are limited to case reports and few randomized controlled trials; deeper research on its mechanism is still lacking. This randomized controlled trial aims to assess the treatment efficacy of "harmonizing stomach to tranquilize mind" acupuncture for insomnia and its influence on the intestinal microbiome. METHODS/DESIGN: This is a randomized, single-blind, parallel-group study. Sixty eligible patients with insomnia due to spleen-stomach disharmony syndrome will be randomly divided into two groups (1:1 allocation ratio). The intervention group will use "harmonizing stomach to tranquilize mind" acupuncture, and the control group will receive sham acupuncture. Participants will receive 5 acupuncture treatment sessions per week for 4 consecutive weeks. The Pittsburgh Sleep Quality Index will be used to evaluate the clinical efficacy of acupuncture treatment by making assessments at baseline, the end of treatment and the end of the follow-up. High-throughput 16S ribosomal ribonucleic acid gene sequencing will be performed to detect changes in the intestinal microbial composition before and after treatment. DISCUSSION: The results of this trial are expected to confirm that "harmonizing stomach to tranquilize mind" acupuncture can effectively relieve insomnia and alter the intestinal microbiome. TRIAL REGISTRATION: Chinese Clinical Trials Registry: ChiCTR1800017092.

Abnormal amygdala resting-state functional connectivity in primary dysmenorrhea.

Neuroimaging studies have manifested functional abnormalities in pain-related brain regions in patients with primary dysmenorrhea (PDM). However, as the key region in brain pain matrix, whether and how the amygdala functional network alteration in PDM is unclear. In this study, we aimed to investigate the intrinsic amygdala functional connectivity (AFC) network alteration in patients with PDM during ovulatory period. Thirty-six PDM patients and 35 matched healthy controls were enrolled in this study. The AFC was constructed using amygdala-based functional connectivity using resting-state functional MRI data. The plasma prostaglandin E2 level was measured during ovulatory period. The group difference on AFC network was conducted and further explored the clinical significant of the abnormal AFC network in PDM patients. Compared to the healthy control group, PDM patients showed increased left AFC in default mode network, including medial prefrontal cortex, posterior cingulate cortex/precuneus, angular gyrus, and inferior temporal gyrus, while, decreased left AFC at bilateral nucleus accumbens/orbital frontal cortex, and decreased right AFC network in right orbital frontal cortex and insula, ventral tegmental area (VTA), left hippocampal, and insula. In addition, the decreased right AFC in VTA was associated with higher plasma prostaglandin E2 level in the PDM group. The AFC network was disrupted in PDM patients, mainly in default mode network and reward system. The disrupted connectivity between amygdala and VTA might contribute to the prostaglandins associated pathological mechanism of PDM.

The Orbitofrontal Cortex Gray Matter Is Associated With the Interaction Between Insomnia and Depression.

Insomnia and depression are highly comorbid symptoms in both primary insomnia (PI) and major depressive disorder (MDD). In the current study, we aimed at exploring both the homogeneous and heterogeneous brain structure alteration in PI and MDD patients. Sixty-five MDD patients and 67 matched PI patients were recruited and underwent a structural MRI scan. The subjects were sub-divided into four groups, namely MDD patients with higher or lower insomnia, and PI patients with higher or lower severe depression. A general linear model was employed to explore the changes in cortical thickness and volume as a result of depression or insomnia, and their interaction. In addition, partial correlation analysis was conducted to detect the clinical significance of the altered brain structural regions. A main effect of depression on cortical thickness was seen in the superior parietal lobe, middle cingulate cortex, and parahippocampal gyrus, while a main effect of insomnia on cortical thickness was found in the posterior cingulate cortex. Importantly, the interaction between depression and insomnia was associated with decreased gray matter volume in the right orbitofrontal cortex, i.e., patients with co-occurring depression and insomnia showed smaller brain volume in the right orbitofrontal cortex when compared to patients with lower insomnia/depression. These findings highlighted the role of the orbitofrontal cortex in the neuropathology of the comorbidity of insomnia and depression. Our findings provide new insights into the understanding of the brain mechanism underlying comorbidity of insomnia and depression.

The imbalanced anterior and posterior default mode network in the primary insomnia.

Neuroimaging studies have demonstrated that the brain is altered both structurally and functionally in patients with primary insomnia (PI). However, most previous hypothesis-driven studies of PI might bias observations. Here, we use global functional connectivity density (gFCD), a hypothesis-free approach, to investigate the brain functional alteration in patients with PI. Forty-eight patients with PI and 51 matched healthy control (HC) subjects were recruited and underwent a resting state functional magnetic resonance imaging (fMRI) scan. Analyses of group differences of gFCD in the whole brain and the clinical significances of abnormal brain function were conducted. Compared with the HC group, patients with PI showed increased gFCD in the executive control network, salience network, dorsal attention network, and visual network. Interestingly, the gFCD in the anterior default mode network (DMN) is increased in the PI group, whereas the gFCD in the posterior DMN is decreased. In addition, the increased gFCD in the insula is associated with higher Pittsburgh Sleep Quality Index scores in the PI group. The gender and duration of disease have no significant effects on abnormal gFCD network. This study is the first attempt to explore the gFCD feature in patients with PI. Our findings support the hyperarousal model of insomnia and suggest an imbalanced neural spontaneous fluctuation between anterior and posterior DMN in the resting state in patients with PI. These findings expand our understanding of the neuropathological mechanism of primary insomnia.

Acupuncture for stable angina pectoris: a systematic review protocol.

INTRODUCTION: Previous reviews indicate that the effect of acupuncture on stable angina pectoris (SAP) remains controversial. The results of trials published in the past 5 years may possibly change this situation, but an updated systematic review is not available. We therefore designed this study to systematically assess the efficacy and safety of acupuncture for treating SAP. METHODS AND ANALYSIS: Nine online databases will be searched without language or publication status restrictions from their inception to September 2017. Randomised controlled trials that include patients with stable angina receiving acupuncture therapy versus a control group will be deemed eligible. The selection of studies, data extraction and risk of bias assessment will be carried out by two independent reviewers. Data synthesis will be performed using RevMan V.5.3 software with either a fixed effects model or random effects model, depending on the heterogeneity test. Evidence quality will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. The efficacy-effectiveness spectrum for each included trial will be rated using the Rating of Included Trials on the Efficacy-effectiveness Spectrum tool. Outcomes of interest include the improvement of weekly angina attacks and reduction of nitroglycerin medication use after receiving acupuncture treatment, the incidence of cardiovascular events, heart rate variability, pain intensity measured on a visual analogue scale, total workload and exercise duration at peak exercise, safety and adverse events. A meta-analysis will be conducted if no considerable heterogeneity is detected. The results will be presented as risk ratios with 95% CIs for dichotomous data and weighted mean differences or standardised mean differences with 95% CIs for continuous data. ETHICS AND DISSEMINATION: This systematic review will not involve private information from individuals or endanger their rights, and therefore does not necessarily require ethical approval. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. TRIAL REGISTRATION NUMBER: CRD42015016201.

[Effect of Acupuncture at Points in Heel Vessel for Circadian Clock Genes of Period 1 and Period 2 mRNAs in the Suprachiasmatic Nucleus in Insomnia Rats].

OBJECTIVE: To investigate the influence and mechanism of acupuncture at the points in Heel Vessel for the circadian clock genes of Period (Per) 1 and Per 2 mRNAs in the suprachiasmatic nucleus (SCN) in insomnia rats. METHODS: Thirty male SD rats were randomly divided into blank, model, acupuncture groups, 10 rats in each group. Insomnia model was established by intraperitoneal injection of PCPA (suspension, 1 mL/100 g). Acupuncture at "Shenmai" (BL 62) and "Zhaohai" (KI 6) was used in the acupuncture group for continuous 7 days, 15 min/day and once daily. The circadian rhythm was observed; the expressions of Per 1 and Per 2 mRNAs in SCN were examined with real time-PCR. RESULTS: The activity in the model group in rest period everyday increased compared with that in the blank group, and the expressions of Per 1 and Per 2 mRNAs in SCN decreased (P<0.05). Compared with the model group, the activity in the acupuncture group in rest period decreased and the expressions of Per 1 and Per 2 mRNAs in the SCN increased (P<0.05). CONCLUSIONS: Acupuncture at BL 62 and KI 6 can increase the expressions of Per 1 and Per 2 mRNAs in the SCN, so as to decrease the activity in rest period, and improve the quality of sleep in insomnia rats.

[Moving cupping at Hechelu combined with rubbing method for depression of diabetes mellitus].

OBJECTIVE: To compare the efficacy between moving cupping at Hechelu combined with rubbing method and western medication for depression of diabetes mellitus (DM). METHODS: Two hundred and sixteen patients were randomly divided into an observation group and a control group, 108 cases in each group. Patients in the observation group were treated with moving cupping at Hechelu combined with rubbing method, once every: other day; six treatments were considered as one course, and totally two courses were given with an interval of: 4 days between courses. Patients in the control group were treated with oral administration of fluoxetine hydrochloride capsules, once a day for consecutive 4 weeks. The Hamilton depression scale (HAMD), self-rating depression scale (SDS) and TCM symptom score were measured before treatment, after the treatment and in follow-up visit one and a half months after treatment. The fasting blood glucose was tested before and after treatment. The glycosylated hemoglobin (HbA1c) was tested in the follow-up visit. RESULTS: The total effective rate was 90.9% (90/99) in the observation group, which was superior to 73.7% (70/95) in the control group (P < 0.05). After the treatment, HAMD, SDS and TCM symptom scores were all reduced apparently in the observation group and the control group (all P < 0.05). After the treatment and the follow-up visit, the TCM symptom score in the observation group was lower than that in the control group (P < 0.05). The levels of HbA1c and GLU were stable in the observation group, and were decreased compared with those before treatment; but the difference between the, two groups was not significant (P > 0.05). CONCLUSION: The Hechelu theory-based TCM treatment has better: efficacy for depression of diabetes mellitus than fluoxetine hydrochloride capsule, which has less adverse effects.