Advances in functional MRI research in bipolar disorder:from the perspective of mood states

Bipolar disorder is characterised by recurrent and alternating episodes of mania/hypomania and depression.Current breakthroughs in functional MRI techniques have uncovered the functional neuroanatomy of bipolar disorder.However,the pathophysiology underlying mood instability,mood switching and the development of extreme mood states is less well understood.This reviewpresents a comprehensive overviewof current evidence from functional MRI studies from the perspective of mood states.We first summarise the disrupted brain activation patterns and functional connectivity that have been reported in bipolar disorder,irrespective of the mood state.We next focus on research that solely included patients in a single mood state for a better understanding of the pathophysiology of bipolar disorder and research comparing patients with different mood states to dissect mood state-related effects.Finally,we briefly summarise current theoretical models and conclude this review by proposing potential avenues for future research.A comprehensive understanding of the pathophysiology with consideration of mood states could not only deepen our understanding of how acute mood episodes develop at a neurophysiological level but could also facilitate the identification of biological targets for personalised treatment and the development of new interventions for bipolar disorder.

Association between abnormal default mode network homogeneity and sleep disturbances in major depressive disorder

Background Sleep disturbance is a common comorbidity of major depressive disorder(MDD).However,network homogeneity(NH)changes of the default mode network(DMN)in MDD with sleep disturbances are unclear.Aims The purpose of this study was to probe the abnormal NH in the DMN in MDD with sleep disturbances and to reveal the differences between MDD with or without sleep disturbances.Methods Twenty-four patients with MDD and sleep disturbances(Pa_s),33 patients with MDD without sleep disturbances(Pa_ns)and 32 healthy controls(HCs)were recruited in this study.Resting-state functional imaging data were analysed using NH.Results Compared with Pa_ns and HCs,Pa_s showed decreased NH in the left superior medial prefrontal cortex and increased NH in the right precuneus.There was a negative correlation between NH in the left superior medial prefrontal cortex and sleep disturbances(r=−0.42,p=0.001)as well as a positive correlation between NH in the right precuneus and sleep disturbances(r=0.41,p=0.002)in patients with MDD.Conclusions MDD with sleep disturbances is associated with abnormal NH in the DMN,which could differentiate pa_s from pa_ns.The DMN may play a crucial role in the neurobiological mechanisms of MDD with sleep disturbances.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Clinical application of repetitive transcranial magnetic stimulation for post-traumatic stress disorder:A literature review

The efficacy of traditional treatment for post-traumatic stress disorder(PTSD)is still unsatisfactory.Repetitive transcranial magnetic stimulation(rTMS)has been widely used in the treatment of various types of mental disorders,including PTSD.Although rTMS has been demonstrated to be effective in many cases,there are still arguments regarding its mechanism and protocol.This review aims to summarize the origin,development,principle,and future direction of rTMS and introduce this neuro-stimulation therapy to relevant clinicians.

Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder

There is an increasing heavy disease burden of major depressive disorder(MDD)globally.Both high diagnostic heterogeneity and complicated pathological mechanisms of MDD pose significant challenges.There is much evidence to support anhedonia as a core feature of MDD.In the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition,anhedonia is further emphasised as a key item in the diagnosis of major depression with melancholic features.Anhedonia is a multifaceted symptom that includes deficits in various aspects of reward processing,such as anticipatory anhedonia,consummatory anhedonia,and decision-making anhedonia.Anhedonia is expected to become an important clinicopathological sign for predicting the treatment outcome of MDD and assisting clinical decision making.However,the precise neurobiological mechanisms of anhedonia in MDD are not clearly understood.In this paper,we reviewed(1)the current understanding of the link between anhedonia and MDD;(2)the biological basis of the pathological mechanism of anhedonia in MDD;and(3)challenges in research on the pathological mechanisms of anhedonia in MDD.A more in-depth understanding of anhedonia associated with MDD will improve the diagnosis,prediction,and treatment of patients with MDD in the future.

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

Oligodendrocytes in central nervous system diseases:the effect of cytokine regulation

Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.

Systemic low-grade inflammation associated with specific depressive symptoms:insights from network analyses of five independent NHANES samples

To the editor:Major depressive disorder(MDD)is a heterogeneous disorder with varying symptom presentations and underlying biological mechanisms.1 The mainstream neurobiological hypotheses of depression involve monoamine neurotransmitters,hypothalamic-pituitary-adrenal axis,immune-inflammation and the glutamate system.

Network analysis of suicide ideation and depression-anxiety symptoms among Chinese adolescents

Background The co-occurrence of depression and anxiety among adolescents is typically associated with suicide ideation.Aims The study aimed to investigate the symptom-level relationship between suicide ideation and the comorbidity of depression and anxiety.Methods 1501 adolescents aged 12-19 years were assessed using the Patient Health Questionnaire(PHQ-9)and the Generalized Anxiety Disorder Scale,and 716 adolescents who scored≥5 on both scales were selected as participants.Network analysis was used to identify the network structure of depressive symptoms and anxiety symptoms.Participants were categorised into either the suicide ideation or non-suicide ideation groups based on their scoring on the suicide-related item in PHQ-9.A comparison was made between the depression-anxiety symptom networks of the two groups.Results‘Restlessness’,‘sad mood’and‘trouble relaxing’were the most prominent central symptoms in the depression-anxiety symptom network,and‘restlessness’,‘nervousness’and‘reduced movement’were the bridge symptoms in this network.‘Sad mood’was found to be directly related to‘suicide ideation’with the highest variance.The network structure was significantly different in properties between the suicide ideation group and the non-suicide ideation group,with‘restlessness’and‘sad mood’exhibiting significantly higher influence in the network of the suicide ideation group than that in the non-suicide ideation group.Conclusion Restlessness and sad mood could be targeted for the intervention of depression-anxiety symptoms among adolescents with suicide ideation.

Gut microbiota-derived short-chain fatty acids and depression:deep insight into biological mechanisms and potential

The gut microbiota is a complex and dynamic ecosystem known as the second brain'.Composing the microbiota-gut-brain axis,the gut microbiota and its metabolites regulate the central nervous system through neural,endocrine and immune pathways to ensure the normal functioning of the organism,tuning individuals'health and disease status.Short-chain fatty acids(SCFAs),the main bioactive metabolites of the gut microbiota,are involved in several neuropsychiatric disorders,including depression.SCFAs have essential effects on each component of the microbiota-gut-brain axis in depression.In the present review,the roles of major SCFAs(acetate,propionate and butyrate)in the pathophysiology of depression are summarised with respect to chronic cerebral hypoperfusion,neuroinflammation,host epigenome and neuroendocrine alterations.Concluding remarks on the biological mechanisms related to gut microbiota will hopefully address the clinical value of microbiota-related treatments for depression.

Development and challenges of mental health in China

With the socioeconomic development and the acceleration of the ageing process of the population, the incidence rates of mental disorders and psycho-behavioural problems have become higher and higher worldwide. So far, the disease burden caused by mental disorders has ranked second in the world.1 In China, the disease burden caused by mental disorders accounts for 13% of all non-communicable diseases burden.2 Hence, mental health has become a major public health problem and social problem. In order to promote mental health, the Chinese government has promulgated a series of policies and regulations, as well as reform measures. Moreover, the upcoming 'China Brain Project' will also focus on some mental disorders such as autism, depression and dementia to improve mental health research in China.

High‑Performance Flexible Microneedle Array as a Low‑Impedance Surface Biopotential Dry Electrode for Wearable Electrophysiological Recording and Polysomnography

Microneedle array(MNA)electrodes are an effective solution to achieve high-quality surface biopotential recording without the coordination of conductive gel and are thus very suitable for long-term wearable applications.Existing schemes are limited by flexibility,biosafety,and manufacturing costs,which create large barriers for wider applications.Here,we present a novel flexible MNA electrode that can simultaneously achieve flexibility of the substrate to fit a curved body surface,robustness of microneedles to penetrate the skin without fracture,and a simplified process to allow mass production.The compatibility with wearable wireless systems and the short preparation time of the electrodes significantly improves the comfort and convenience of electrophysiological recording.The normalized electrode–skin contact impedance reaches 0.98 kΩcm^(2)at 1 kHz and 1.50 kΩcm^(2)at 10 Hz,a record low value compared to previous reports and approximately 1/250 of the standard electrodes.The morphology,biosafety,and electrical/mechanical properties are fully characterized,and wearable recordings with a high signal-to-noise ratio and low motion artifacts are realized.The first reported clinical study of microneedle electrodes for surface electrophysiological monitoring was conducted in tens of healthy and sleep-disordered subjects with 44 nights of recording(over 8 h per night),providing substantial evidence that the electrodes can be leveraged to substitute for clinical standard electrodes.

Cross-sectional survey following a longitudinal study on mental health and insomnia of people with sporadic COVID-19

BACKGROUNDIn the post-pandemic era, the emergence of sporadic cases of coronavirus disease 2019 (COVID-19) and the scale of the pandemic are unpredictable. Therefore, the impact ofsporadic cases of COVID-19 and isolation measures on mental health and sleep in different groupsof people need to be analyzed.AIMTo clarify the severity of psychological problems and insomnia of staff and community residentsaround a hospital with sporadic cases of COVID-19, and their relationship with quarantinelocation and long-term changes.METHODSA cross-sectional survey was conducted on community residents and medical staff. Many of thesemedical staff had been subjected to different places of quarantine. Community residents did notexperience quarantine. Hospital anxiety and depression scale (HADS), acute stress disorder scale(ASDS) and insomnia severity index (ISI) were used to evaluate anxiety and depression, acutestress disorder symptoms, and the severity of insomnia. Additionally, we conducted a 1-yearfollow-up study on medical staff, with related scales measurement immediately after and one yearafter the 2-wk quarantine period.RESULTSWe included 406 medical staff and 226 community residents. The total scores of ISI and subscale inHADS of community residents were significantly higher than that of medical staff. Furtheranalysis of medical staff who experienced quarantine showed that 134 were quarantined in hotels,70 in hospitals and 48 at home. Among all subjects, the proportions of HADS, ASDS and ISI scoresabove normal cutoff value were 51.94%, 19.17% and 31.11%, respectively. Multivariable logisticregression analysis found that subjects with higher total ASDS scores had a greater risk to developanxiety and depression. The total ISI score for medical staff in hotel quarantine was significantlyhigher than those in home quarantine. Total 199 doctors and nurses who completed the 1-yearfollow-up study. Compared with baseline, HADS and ASDS scores decreased significantly oneyear after the end of quarantine, while ISI scores did not change significantly.CONCLUSIONSporadic COVID-19 cases had a greater psychological impact on residents in surroundingcommunities, mainly manifested as insomnia and depressive symptoms. Hotel quarantineaggravated the severity of insomnia in medical staff, whose symptoms lasted ≥ 1 year.

Using eye movements in the dot-probe paradigm to investigate attention bias in illness anxiety disorder

BACKGROUND Illness anxiety disorder(IAD)is a common,distressing,and debilitating condition with the key feature being a persistent conviction of the possibility of having one or more serious or progressive physical disorders.Because eye movements are guided by visual-spatial attention,eye-tracking technology is a comparatively direct,continuous measure of attention direction and speed when stimuli are oriented.Researchers have tried to identify selective visual attention biases by tracking eye movements within dot-probe paradigms because dot-probe paradigm can distinguish these attentional biases more clearly.AIM To examine the association between IAD and biased processing of illness-related information.METHODS A case-control study design was used to record eye movements of individuals with IAD and healthy controls while participants viewed a set of pictures from four categories(illness-related,socially threatening,positive,and neutral images).Biases in initial orienting were assessed from the location of the initial shift in gaze,and biases in the maintenance of attention were assessed from the duration of gaze that was initially fixated on the picture per image category.RESULTS The eye movement of the participants in the IAD group was characterized by an avoidance bias in initial orienting to illness-related pictures.There was no evidence of individuals with IAD spending significantly more time viewing illness-related images compared with other images.Patients with IAD had an attention bias at the early stage and overall attentional avoidance.In addition,this study found that patients with significant anxiety symptoms showed attention bias in the late stages of attention processing.CONCLUSION Illness-related information processing biases appear to be a robust feature of IAD and may have an important role in explaining the etiology and maintenance of the disorder.

The Effect of Case Management for Schizophrenia Clients in China

Background: The aim at this study is to establish the effectiveness of case management (CM) compared to care as usual (CAU) in patients with schizophrenia. Methods: 128 patients with schizophrenia were recruited from the community of Haidian District (Beijing, China), 68 patients in the CM group and 60 patients in the CAU group. Efficacy and safety information were assessed at one year follow-up. The relapse rate was similar in both groups after 12 months followed up (7% and 5%). The withdraw rate was significant lower in CM group compared with CAU group (10% and 36%). Results: There is no significant difference in PANSS, PSP and SSMI score between 2 groups at each visit. Between endpoint and baseline, there is a significant improvement on PANSS negative score and PSP in patients treated with CM, while CAU group was not significantly changed. Conclusions: There is a possible effectiveness of CM group of improving negative symptoms and social function in schizophrenia clients.

A review of methylenetetrahydrofolate reductase in one-carbon metabolism and psychiatric disorders

Methylenetetrahydrofolate reductase(MTHFR)is a key enzyme for the critical process of one-carbon circulation,which convert5,10-methylenetetrahydrofolate to5-methyltetrahydrofolate and participate in folate and homocysteine conversion correlated to methyl group supply.The enzyme activity decline depends on the gene polymorphism.MTHFR impacts on the methylation process which is related to psychiatric diseases.Studies have shown association between MTHFR gene polymorphisms and mental disorders,some of which stratified by folate and cobalamin levels.In this review,we will summarize the testimony on the relationship between methylation and MTHFR polymorphism as well as the implication on psychiatric diseases by MTHFR mutation.

Prevalence of dementia and the attributable contributions of modifiable risk factors in China

With the largest ageing population in the world,China is faced with the huge chal-lenge of dementia.-However,previously reported estimates on the prevalence of dementia among Chinese older adults were inconsistent,varying from 2%to 13%.5°It is crucial for dementia prevention to determine the number of cases that could be delayed or prevented,but how to do this remains unclear.To address these research gaps,we aimed to provide population estimates of the prevalence of dementia in China and estimate the population attributable fractions(PAFs)of potentially modifiable risk factors.

Effect of an Ecological Executive Skill Training Program for School-aged Children with Attention Deficit Hyperactivity Disorder： A Randomized Controlled Clinical Trial

Background： As medication does not normalize outcomes of children with attention deficit hyperactivity disorder （ADHD）, especially in real-life functioning, nonpharmacological methods are important to target this field. This randomized controlled clinical trial was designed to evaluate the effects of a comprehensive executive skill training program for school-aged children with ADHD in a relatively large sample. Methods： The children （aged 6-12 years） with ADHD were randomized to the intervention or waitlist groups. A healthy control group was composed of gender- and age-matched healthy children. The intervention group received a 12-session training program lbr multiple executive skills. Executive function （EF）, ADHD symptoms, and social functioning in the intervention and waitlist groups were evaluated at baseline and the end of the final training session. The healthy controls （HCs） were only assessed once at baseline. Repeated measures analyses of variance were used to compare EF, ADHD symptoms, and social function between intervention and waitlist groups. Results： Thirty-eight children with ADH D in intervention group, 30 in waitlist group, and 23 healthy children in healthy control group were included in final analysis. At posttreatment, intervention group showed significantly lower Behavior Rating Inventory of Executive Function （BRIEF） total score （135.89 ±16.80 vs. 146.09 ± 23.92, P = 0.04） and monitoring score （18.05 ± 2.67 vs. 19.77 ± 3.10, P = 0.02）, ADHD-IV overall score （41.11 ± 7.48 vs. 47.20 ± 8.47, P 〈 0.01 ）, hyperactivity-impulsivity （HI） subscale score （ 18.92 ± 5.09 vs. 21.93 ± 4.93, P = 0.02）, and inattentive subscale score （22.18 ±3.56 vs. 25.27± 5.06, P 〈 0.01 ）, compared with the waitlist group. Repeated measures analyses of variance revealed significant interactions between time and group on the BRIEF inhibition subscale （F = 5.06, P 0.03）, working memory （F- 4.48, P = 0.04）, A DH D-IV overall score （F = 21.72, P 〈 0.01）, HI subscale score （F = 19.08, P 〈 0.01）, and inattentive subscale score （F- 12,40, P 〈 0.01 ）. Multiple-way analysis of variance showed significant differences on all variables of BRIEF, ADHD-rating scale-IV, and WEISS Functional Impairment Scale-Parent form （WFIRS-P） among the intervention and waitlist groups at posttreatment and HCs at baseline. Conclusions： This randomized controlled study on executive skill training in a relatively large sample provided some evidences that the training could improve EF deficits, reduce problematic symptoms, and potentially enhance the social thnctioning in school-aged children with ADHD.

Therapy of replenishing Yin and regulating Yang for manic episode in bipolar disorder:study protocol for a prospective,double-blind,randomized controlled trial

Bipolar disorder(BD) is a chronic and recurrent disorder characterized by biphasic mood episodes of mania or hypomania and depression.It affects more than 1% of the global population and is a leading cause of disability in young people.Currently available treatments for BD are still fairly limited in terms of efficacy,with high rates of non-adherence,non-response,and undesirable side effects.Traditional Chinese medicine(TCM) has a long history and rich experience in stabilizing mania and improving quality of life.Aiming at rebalancing Yin and Yang in BD,therapy of replenishing Yin and regulating Yang(RYRY therapy) has been in clinical use for years in China.The present prospective,double-blind,randomized controlled trial is designed to investigate the efficacy and safety of RYRY therapy for bipolar mania and its possible mechanism from the point of regulating gut microbiota and anti-inflammation.A total of 60 eligible participants will be recruited from Beijing Anding Hospital.They will be randomized to either the study group or the control group in a ratio of 1∶1.Participants allocated to the study group will receive RYRY granule,while placebo granule will be applied in the control group.Participants in both groups will be prescribed conventional therapy for manic episode in BD.Four scheduled visits will be conducted over 4 weeks.Outcome measurements include Young Mania Rating Scale,TCM Symptom Pattern Rating Scale,Treatment Emergent Symptom Scale,levels of C-reactive protein,interleukin-6 and tumor necrosis factor-α and the gut microbial community profile of stool samples.Safety outcomes and adverse events will also be recorded.In this study,we set a number of scientific and objective assessments to evaluate the efficacy of RYRY therapy and study into its possible mechanism,hopefully offering clinicians an alternative approach to BD.

Antidepressant treatment strategy with an early onset of action improves the clinical outcome in patients with major depressive disorder and high anxiety: a multicenter and 6-week follow-up study

Major depressive disorder(MDD)is a prevalent,often chronic,and highly disabling multidimensional psychiatric illness.[1] Moreover,co-occurring anxiety symptoms are extremely common among patients with MDD;up to 90%of patients present with anxiety symptoms.[2]Notably,high levels of anxiety symptoms may predict worse clinical outcomes because of poor response to pharmacotherapy for MDD.[3]So use of augmentation or combination strategies during early course of treatment could be necessary,but ensuring the accurate and timely change is difficult because of the lack of consensus to assess the early improvement of initial treatment.To date,replicated evidence indicates that the lack of early improvement(eg,<20% reduction in a depression scale score)in 2 weeks can be an accurate predictor to identify eventual non?responders?4*This study aimed to evaluate the early onset of antidepressant action and clinical outcomes in patients with MDD and high anxiety,and to explore the potential influencing factors of early onset improvement.