IL-1ß and TNF-α play an important role in modulating the risk of periodontitis and Alzheimer's disease.

BACKGROUND: Systemic activation of the immune system can exert detrimental effects on the central nervous system. Periodontitis, a chronic disease of the oral cavity, is a common source of systemic inflammation. Neuroinflammation might be a result of this to accelerate progressive deterioration of neuronal functions during aging or exacerbate pre-existing neurodegenerative diseases, such as Alzheimer's disease. With advancing age, the progressive increase in the body's pro-inflammatory status favors the state of vulnerability to both periodontitis and Alzheimer's disease. In the present study, we sought to delineate the roles of cytokines in the pathogenesis of both diseases. METHODS: To examine the impacts of periodontitis on the onset and progression of Alzheimer's disease, 6-month-old female 3 × Tg-AD mice and their age-matched non-transgenic mice were employed. Periodontitis was induced using two different experimental models: heat-killed bacterial-induced periodontitis and ligature-induced periodontitis. To delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and Alzheimer's disease, interleukin 1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were also injected into the buccal mandibular vestibule of mice. RESULTS: Here, we show that IL-1ß and TNF-α were two of the most important and earliest cytokines upregulated upon periodontal infection. The systemic upregulation of these two cytokines promoted a pro-inflammatory environment in the brain contributing to the development of Alzheimer's disease-like pathology and cognitive dysfunctions. Periodontitis-induced systemic inflammation also enhanced brain inflammatory responses and subsequently exacerbated Alzheimer's disease pathology and cognitive impairment in 3 × Tg-AD mice. The role of inflammation in connecting periodontitis to Alzheimer's disease was further affirmed in the conventional magnetization transfer experiment in which increased glial responses resulting from periodontitis led to decreased magnetization transfer ratios in the brain of 3 × Tg-AD mice. CONCLUSIONS: Systemic inflammation resulting from periodontitis contributed to the development of Alzheimer's disease tau pathology and subsequently led to cognitive decline in non-transgenic mice. It also potentiated Alzheimer's disease pathological features and exacerbated impairment of cognitive function in 3 × Tg-AD mice. Taken together, this study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and Alzheimer's disease.

The pathogenic effects of particulate matter on neurodegeneration: a review.

The increasing amount of particulate matter (PM) in the ambient air is a pressing public health issue globally. Epidemiological studies involving data from millions of patients or volunteers have associated PM with increased risk of dementia and Alzheimer's disease in the elderly and cognitive dysfunction and neurodegenerative pathology across all age groups, suggesting that PM may be a risk factor for neurodegenerative diseases. Neurodegenerative diseases affect an increasing population in this aging society, putting a heavy burden on economics and family. Therefore, understanding the mechanism by which PM contributes to neurodegeneration is essential to develop effective interventions. Evidence in human and animal studies suggested that PM induced neurodenegerative-like pathology including neurotoxicity, neuroinflammation, oxidative stress, and damage in blood-brain barrier and neurovascular units, which may contribute to the increased risk of neurodegeneration. Interestingly, antagonizing oxidative stress alleviated the neurotoxicity of PM, which may underlie the essential role of oxidative stress in PM's potential effect in neurodegeneration. This review summarized up-to-date epidemiological and experimental studies on the pathogenic role of PM in neurodegenerative diseases and discussed the possible underlying mechanisms.

Optimised tissue clearing minimises distortion and destruction during tissue delipidation.

AIMS: A variety of tissue clearing techniques have been developed to render intact tissue transparent. For thicker samples, additional partial tissue delipidation is required before immersion into the final refractive index (RI)-matching solution, which alone is often inadequate to achieve full tissue transparency. However, it is difficult to determine a sufficient degree of tissue delipidation, excess of which can result in tissue distortion and protein loss. Here, we aim to develop a clearing strategy that allows better monitoring and more precise determination of delipidation progress. METHODS: We combined the detergent sodium dodecyl sulphate (SDS) with OPTIClear, a RI-matching solution, to form a strategy termed Accurate delipidation with Optimal Clearing (Accu-OptiClearing). Accu-OptiClearing allows for a better preview of the final tissue transparency achieved when immersed in OPTIClear alone just before imaging. We assessed for the changes in clearing rate, protein loss, degree of tissue distortion, and preservation of antigens. RESULTS: Partial delipidation using Accu-OptiClearing accelerated tissue clearing and better preserved tissue structure and antigens than delipidation with SDS alone. Despite achieving similar transparency in the final OPTIClear solution, more lipids were retained in samples cleared with Accu-OptiClearing compared to SDS. CONCLUSIONS: Combining the RI-matching solution OPTIClear with detergents, Accu-OptiClearing, can avoid excessive delipidation, leading to accelerated tissue clearing, less tissue damage and better preserved antigens.

The role of sleep deprivation and circadian rhythm disruption as risk factors of Alzheimer's disease.

Emerging evidence suggests that sleep deprivation (SD) and circadian rhythm disruption (CRD) may interact and increase the risk for the development of Alzheimer's disease (AD). This review inspects different pathophysiological aspects of SD and CRD, and shows that the two may impair the glymphatic-vascular-lymphatic clearance of brain macromolecules (e.g., ß-amyloid and microtubule associated protein tau), increase local brain oxidative stress and diminish circulatory melatonin levels. Lastly, this review looks into the potential association between sleep and circadian rhythm with stress granule formation, which might be a new mechanism along the AD pathogenic pathway. In summary, SD and CRD is likely to be associated with a positive risk in developing Alzheimer's disease in humans.

The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases.

Growing evidence has shown the beneficial influence of exercise on humans. Apart from classic cardioprotection, numerous studies have demonstrated that different exercise regimes provide a substantial improvement in various brain functions. Although the underlying mechanism is yet to be determined, emerging evidence for neuroprotection has been established in both humans and experimental animals, with most of the valuable findings in the field of mental health, neurodegenerative diseases, and acquired brain injuries. This review will discuss the recent findings of how exercise could ameliorate brain function in neuropathological states, demonstrated by either clinical or laboratory animal studies. Simultaneously, state-of-the-art molecular mechanisms underlying the exercise-induced neuroprotective effects and comparison between different types of exercise will be discussed in detail. A majority of reports show that physical exercise is associated with enhanced cognition throughout different populations and remains as a fascinating area in scientific research because of its universal protective effects in different brain domain functions. This article is to review what we know about how physical exercise modulates the pathophysiological mechanisms of neurodegeneration.

Systemic inflammation linking chronic periodontitis to cognitive decline.

Persistent inflammation in the systemic immune system can impose detrimental effects on the central nervous system (CNS). Neuroinflammation might be a result of this to accelerate the progressive deterioration of neuronal functions during aging. In this regard, controlling inflammation through delaying and/or preventing chronic inflammatory diseases may be a potential strategy to prevent or modify the progression of Alzheimer's Disease (AD). Periodontitis is a chronic inflammatory disease of the oral cavity that is common among the elderly, especially for those who have decline in cognitive functions. While epidemiological findings support the association of chronic periodontitis and cognitive decline, whether they have causal relationship remains unclear. Nonetheless, the possibility that periodontopathogens, systemic immune cells and inflammatory cytokines could reach the CNS should not be overlooked. The impacts of periodontitis on CNS homeostasis and inflammation as a pathophysiological factor concerning the association between periodontitis and AD will be discussed in this review. Future work should elucidate the pathological pathways involved in periodontitis-induced cerebral infections and inflammation, and define the role of the latter in AD progression.

Silica nanoparticles induce neurodegeneration-like changes in behavior, neuropathology, and affect synapse through MAPK activation.

BACKGROUND: Silica nanoparticles (SiO2-NPs) are naturally enriched and broadly utilized in the manufacturing industry. While previous studies have demonstrated toxicity in neuronal cell lines after SiO2-NPs exposure, the role of SiO2-NPs in neurodegeneration is largely unknown. Here, we evaluated the effects of SiO2-NPs-exposure on behavior, neuropathology, and synapse in young adult mice and primary cortical neuron cultures. RESULTS: Male C57BL/6 N mice (3 months old) were exposed to either vehicle (sterile PBS) or fluorescein isothiocyanate (FITC)-tagged SiO2-NPs (NP) using intranasal instillation. Behavioral tests were performed after 1 and 2 months of exposure. We observed decreased social activity at both time points as well as anxiety and cognitive impairment after 2 months in the NP-exposed mice. NP deposition was primarily detected in the medial prefrontal cortex and the hippocampus. Neurodegeneration-like pathological changes, including reduced Nissl staining, increased tau phosphorylation, and neuroinflammation, were also present in the brains of NP-exposed mice. Furthermore, we observed NP-induced impairment in exocytosis along with decreased synapsin I and increased synaptophysin expression in the synaptosome fractions isolated from the frontal cortex as well as primary neuronal cultures. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were also activated in the frontal cortex of NP-exposed mice. Moreover, inhibition of ERK activation prevented NP-mediated changes in exocytosis in cultured neurons, highlighting a key role in the changes induced by NP exposure. CONCLUSIONS: Intranasal instillation of SiO2-NPs results in mood dysfunction and cognitive impairment in young adult mice and causes neurodegeneration-like pathology and synaptic changes via ERK activation.

The Protective Effects of Icariin against the Homocysteine-Induced Neurotoxicity in the Primary Embryonic Cultures of Rat Cortical Neurons.

Icariin, an ingredient in the medicinal herb Epimedium brevicornum Maxim (EbM), has been considered as a potential therapeutic agent for neurodegenerative diseases such as Alzheimer's disease (AD). Hyperhomocysteinaemia is a risk factor for AD and other associated neurological diseases. In this study we aim to investigate whether icariin can reverse homocysteine (Hcy)-induced neurotoxicity in primary embryonic cultures of rat cortical neurons. Our findings demonstrated that icariin might be able restore the cytoskeleton network damaged by Hcy through the modulation of acetyl-α-tubulin, tyrosinated-α-tubulin, and phosphorylation of the tubulin-binding protein Tau. In addition, icariin downregulated p-extracellular signal-regulated kinase (ERK) which is a kinase targeting tau protein. Furthermore, icariin effectively restored the neuroprotective protein p-Akt that was downregulated by Hcy. We also applied RT² Profiler PCR Arrays focused on genes related to AD and neurotoxicity to examine genes differentially altered by Hcy or icariin. Among the altered genes from the arrays, ADAM9 was downregulated 15 folds in cells treated with Hcy, but markedly restored by icariin. ADAM family, encoded α-secreatase, plays a protective role in AD. Overall, our findings demonstrated that icariin exhibits a strong neuroprotective function and have potential for future development for drug treating neurological disorders, such as AD.

PKR deficiency alters E. coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load.

BACKGROUND: Systemic inflammation induces neuroimmune activation, ultimately leading to sickness (e.g., fever, anorexia, motor impairments, exploratory deficits, and social withdrawal). In this study, we evaluated the role of protein kinase R (PKR), a serine-threonine kinase that can control systemic inflammation, on neuroimmune responses and sickness. METHODS: Wild-type (WT) PKR+/+ mice and PKR-/- mice were subcutaneously injected with live Escherichia coli (E. coli) or vehicle. Food consumption, rotarod test performance, burrowing, open field activity, object investigation, and social interaction were monitored. Plasma TNF-α and corticosterone were measured by ELISA. The percentage of neutrophils in blood was deduced from blood smears. Inflammatory gene expression (IL-1ß, TNF-α, IL-6, cyclooxygenase (COX)-2, iNOS) in the liver and the brain (hypothalamus and hippocampus) were quantified by real-time PCR. Blood and lavage fluid (injection site) were collected for microbiological plate count and for real-time PCR of bacterial 16S ribosomal DNA (rDNA). Corticotrophin-releasing hormone (CRH) expression in the hypothalamus was also determined by real-time PCR. RESULTS: Deficiency of PKR diminished peripheral inflammatory responses following E. coli challenge. However, while the core components of sickness (anorexia and motor impairments) were similar between both strains of mice, the behavioral components of sickness (reduced burrowing, exploratory activity deficits, and social withdrawal) were only observable in PKR-/- mice but not in WT mice. Such alteration of behavioral components was unlikely to be caused by exaggerated neuroimmune activation, by an impaired host defense to the infection, or due to a dysregulated corticosterone response, because both strains of mice displayed similar neuroimmune responses, bacterial titers, and plasma corticosterone profiles throughout the course of infection. Nevertheless, the induction of hypothalamic corticotrophin-releasing hormone (CRH) by E. coli was delayed in PKR-/- mice relative to WT mice, suggesting that PKR deficiency may postpone the CRH response during systemic inflammation. CONCLUSIONS: Taken together, our findings show that (1) loss of PKR could alter E. coli-induced sickness behaviors and (2) this was unlikely to be due to exacerbated neuroimmune activation, (3) elevated bacterial load, or (4) dysregulation in the corticosterone response. Further studies can address the role of PKR in the CRH response together with its consequence on sickness.

Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: implications for depression and Alzheimer's disease.

The relationship between Alzheimer's disease (AD) and depression has been well established in terms of epidemiological and clinical observations. Depression has been considered to be both a symptom and risk factor of AD. Several genetic and neurobiological mechanisms have been described to underlie these two disorders. Despite the accumulating knowledge on this topic, the precise neuropathological mechanisms remain to be elucidated. In this study, we propose that synaptic degeneration plays an important role in the disease progression of depression and AD. Using primary culture of hippocampal neurons treated with oligomeric Aß and corticosterone as model agents for AD and depression, respectively, we found significant changes in the pre-synaptic vesicle proteins synaptophysin and synaptotagmin. We further investigated whether the observed protein changes affected synaptic functions. By using FM(®)4-64 fluorescent probe, we showed that synaptic functions were compromised in treated neurons. Our findings led us to investigate the involvement of protein degradation mechanisms in mediating the observed synaptic protein abnormalities, namely, the ubiquitin-proteasome system and autophagy. We found up-regulation of ubiquitin-mediated protein degradation, and the preferential signaling for the autophagic-lysosomal degradation pathway. Lastly, we investigated the neuroprotective role of different classes of antidepressants. Our findings demonstrated that the antidepressants Imipramine and Escitalopram were able to rescue the observed synaptic protein damage. In conclusion, our study shows that synaptic degeneration is an important common denominator underlying depression and AD, and alleviation of this pathology by antidepressants may be therapeutically beneficial.

Neuropathology of cigarette smoking.

It is well established that cigarette smoking is hazardous to health and is a risk factor for many chronic diseases. However, its impact on the brain, whether it be from prenatal exposure to maternal cigarette smoking, cerebrovascular disease, Alzheimer's disease (AD) or Parkinson's disease, is still not very clear. Neuroimaging and neuropathological investigations suggest that there are heterogeneous effects of cigarette smoking on the brain. On the one hand, it is quite clear that cigarette smoking causes damage to endothelial cells, resulting in increased risk of cerebrovascular disease. On the other hand, it seems to be associated with different Alzheimer's pathologies in post-mortem brains and experimental models, despite the fact that epidemiological studies clearly indicate a positive correlation between cigarette smoking and increased risk for AD. Interestingly, cigarette smoking appears to be associated with reduced Parkinson's pathology in post-mortem brains. However, although nicotine in cigarettes may have some neuroprotective actions, the effects of all the other toxic compounds in cigarettes cannot be ignored. It is, therefore, our aim to summarize what is known about the neuropathology of cigarette smoking and, in particular, its implications for neurodegenerative diseases.

Views of Hong Kong Chinese medicine practitioners on the application of the "Chinese Medicine Anti-epidemic Plans" prepared by the Chinese medicine expert group of central authorities: a focus group study.

BACKGROUND: Drawing on the extensive utilization of traditional Chinese medicine (TCM) to combat COVID-19 in Mainland China, experts designed a series of TCM anti-epidemic strategies. This study aims to understand Hong Kong CM practitioners' application of and opinions on the "Chinese Medicine Anti-epidemic Plans." METHODS: Online focus group interviews were conducted, and purposive sampling was employed to invite 22 CM practitioners to voluntarily participate in three interview sessions. The interviews were audio recorded, then transcribed verbatim. The transcripts were analyzed using template analysis. RESULTS: Three themes were derived: (1) facilitators of the "Chinese Medicine Anti-epidemic Plans," (2) barriers of the "Chinese Medicine Anti-epidemic Plans," and (3) expectations on improving the "Chinese Medicine Anti-epidemic Plans." The participants could obtain relevant information from various sources, which highlights the value of the plans for TCM medicinal cuisine and non-pharmacologic therapies and guiding junior CM practitioners, supplementing Western medicine interventions, and managing Chinese herb reserves in clinics. However, the barriers included the lack of a specialized platform for timely information release, defective plan content, limited reference value to experienced CM practitioners, and lack of applicability to Hong Kong. The expectations of the CM practitioners for improving the plans were identified based on the barriers. CONCLUSIONS: To enhance the implementation of the anti-epidemic plans, CM practitioners in Hong Kong expect to utilize a specific CM platform and refine the plans to ensure that they are realistic, focused, comprehensive, and tailored to the local context.

Commercial Chinese polyherbal preparation Zao Ren An Shen prescription for primary insomnia: a systematic review with meta-analysis and trial sequential analysis.

Background: Natural products are widely used for primary insomnia (PI). This systematic review with trial sequential analysis (TSA) aimed to summarize evidence pertaining to the effectiveness and safety of Zao Ren An Shen (ZRAS) prescription, a commercial Chinese polyherbal preparation, for treating PI. Methods: Controlled clinical trials appraising ZRAS compared to controls or as an add-on treatment were systematically searched across seven databases until January 2024. Cochrane ROB 2.0 and ROBINS-I tools were adopted to determine risk of bias. Quality of evidence was assessed using the GRADE framework. Results: We analyzed 22 studies, involving 2,142 participants. The effect of ZRAS in reducing Pittsburgh Sleep Quality Index scores was found to be comparable to benzodiazepines [MD = 0.39, 95%CI (-0.12, 0.91), p = 0.13] and superior to Z-drugs [MD = -1.31, 95%CI (-2.37, -0.24), p = 0.02]. The addition of ZRAS to hypnotics more significantly reduced polysomnographically-recorded sleep onset latency [MD = -4.44 min, 95%CI (-7.98, -0.91), p = 0.01] and number of awakenings [MD = -0.89 times, 95%CI (-1.67, -0.10), p = 0.03], and increased total sleep time [MD = 40.72 min, 95%CI (25.14, 56.30), p < 0.01], with fewer adverse events than hypnotics alone. TSA validated the robustness of these quantitative synthesis results. However, the quality of evidence ranged from very low to low. The limited data available for follow-up did not support meta-synthesis. Conclusion: While ZRAS prescription shows promising effectiveness in treating PI, the overall quality of evidence is limited. Rigorously-designed randomized control trials are warranted to confirm the short-term efficacy of ZRAS and explore its medium-to-long-term efficacy. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=471497), identifier (CRD42023471497).

Career Considerations in Nurse-Led Traditional Chinese Medicine Clinics: a Two-Center Qualitative Study.

Background: Growing demand exists for high-quality Traditional Chinese Medicine (TCM) care, particularly through Nurse-led TCM clinics (TCM-NLCs). Nurses with extensive experience in TCM departments represent a potential workforce for this healthcare model. This qualitative study aims to investigate the willingness of these candidates to engage in TCM-NLCs, with a specific focus on their main concerns and apprehensions when facing new challenges. Methods: Individual semi-structured face to face interviews were conducted with senior nurses from two TCM hospitals in Shanghai. Each participant had a minimum of three years of work experience in a TCM related department. Conventional qualitative content analysis was utilized. Results: Fourteen participants were interviewed and data saturation was achieved. Nurses exhibited strong interest in practicing in TCM-NLCs. They believed that such innovative TCM nursing service model not only extends nursing role, provides greater empowerment and opportunities for professional development but also meets patients' diverse healthcare needs, reduces reliance on other healthcare providers such as doctors, and increases hospital revenue. However, challenges such as deficiencies in evidence-based TCM nursing education, the absence of standardized practice guidelines, and limited prescriptive privileges were identified as primary obstacles to engaging in TCM-NLCs practice, potentially undermining the specialization of this advanced nursing practice model. Conclusion: Although the nurses interviewed were highly motivated, they generally lacked confidence to practice independently in TCM-NLCs. A pressing priority is to address their concerns by providing appropriate resources as well as education and policy support to enhance their competency and ensure their practice autonomy, therefore building a more qualified pool of professionals for advanced TCM nursing practice.

Self-Administered Acupressure for Probable Knee Osteoarthritis in Middle-Aged and Older Adults: A Randomized Clinical Trial.

Importance: The effects of self-administered acupressure (SAA) on knee osteoarthritis (OA) pain remain unclear. Objective: To evaluate the effectiveness of SAA taught via a short training course on reducing knee OA pain in middle-aged and older adults. Design, Setting, and Participants: This randomized clinical trial was conducted among community-dwelling individuals in Hong Kong who were aged 50 years or older with probable knee OA from September 2019 to May 2022. Interventions: The intervention included 2 training sessions for SAA with a brief knee health education (KHE) session, in which participants practiced acupressure twice daily for 12 weeks. The control group (KHE only) received only education about maintaining knee health on the same schedule and duration. Main Outcomes and Measures: The primary outcome was the numerical rating scale (NRS) pain score at 12 weeks. Other outcomes included Western Ontario and McMaster University Osteoarthritis Index, Short Form 6 Dimensions (SF-6D), Timed Up and Go, and Fast Gait Speed tests. Results: A total of 314 participants (mean [SD] age, 62.7 [4.5] years; 246 [78.3%] female; mean [SD] knee pain duration, 7.3 [7.6] years) were randomized into intervention and KHE-only groups (each 157). At week 12, compared with the KHE-only group, the intervention group had a significantly greater reduction in NRS pain score (mean difference [MD], -0.54 points; 95% CI, -0.97 to -0.10 points; P = .02) and higher enhancement in SF-6D utility score (MD, 0.03 points; 95% CI, 0.003 to 0.01 points; P = .03) but did not have significant differences in other outcome measures. The cost-effectiveness acceptability curve demonstrated a greater than 90% probability that the intervention is cost-effective at a willingness to pay threshold of 1 GDP per capita. Conclusions and Relevance: In this randomized clinical trial, SAA with a brief KHE program was efficacious and cost-effective in relieving knee pain and improving mobility in middle-aged and older adults with probable knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT04191837.

Acupuncture for primary insomnia: Effectiveness, safety, mechanisms and recommendations for clinical practice.

Primary insomnia (PI) is an increasing concern in modern society. Cognitive-behavioral therapy for insomnia is the first-line recommendation, yet limited availability and cost impede its widespread use. While hypnotics are frequently used, balancing their benefits against the risk of adverse events poses challenges. This review summarizes the clinical and preclinical evidence of acupuncture as a treatment for PI, discussing its potential mechanisms and role in reliving insomnia. Clinical trials show that acupuncture improves subjective sleep quality, fatigue, cognitive impairments, and emotional symptoms with minimal adverse events. It also positively impacts objective sleep processes, including prolonging total sleep time, improving sleep efficiency, reducing sleep onset latency and wake after sleep onset, and enhancing sleep architecture/structure, including increasing N3% and REM%, and decreasing N1%. However, methodological shortcomings in some trials diminish the overall quality of evidence. Animal studies suggest that acupuncture restores circadian rhythms in sleep-deprived rodents and improves their performance in behavioral tests, possibly mediated by various clinical variables and pathways. These may involve neurotransmitters, brain-derived neurotrophic factors, inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, gut microbiota, and other cellular events. While the existing findings support acupuncture as a promising therapeutic strategy for PI, additional high-quality trials are required to validate its benefits.

The Effectiveness of Electrical Vestibular Stimulation (VeNS) on Symptoms of Anxiety: Study Protocol of a Randomized, Double-Blinded, Sham-Controlled Trial.

The prevalence of symptoms of anxiety is increasing, especially during the COVID-19 pandemic. A home use transdermal neurostimulation device might help to minimize the severity of anxiety disorder. To the best of our knowledge, there is no clinical trial using transdermal neurostimulation to treat individuals with symptoms of anxiety in Asia. This gives us the impetus to execute the first study which aims at evaluating the efficacy of Electrical Vestibular Stimulation (VeNS) on anxiety in Hong Kong. This study proposes a two-armed, double-blinded, randomized, sham-controlled trial including the active VeNS and sham VeNS group. Both groups will be measured at baseline (T1), immediately after the intervention (T2), and at the 1-month (T3) and 3-month follow-up (T4). A total of 66 community-dwelling adults aged 18 to 60 with anxiety symptoms will be recruited in this study. All subjects will be computer randomised into either the active VeNS group or the sham VeNS group in a 1:1 ratio. All subjects in each group will receive twenty 30 min VeNS sessions during weekdays, which will be completed in a 4-week period. Baseline measurements and post-VeNS evaluation of the psychological outcomes (i.e., anxiety, insomnia, and quality of life) will also be conducted on all participants. The 1-month and 3-month follow-up period will be used to assess the long-term sustainability of the VeNS intervention. For statistical analysis, ANOVA with repeated measures will be used to analyze data. Missing data were managed with multiple mutations. The level of significance will be set to p < 0.05. Results of this study will be used to determine whether this VeNS device can be considered as a self-help technological device to reduce perceived anxiety in the general population in the community setting. This clinical Trial was registered with the Clinical Trial government, identifier: NCT04999709.

Effects of transcranial pulse stimulation on autism spectrum disorder: a double-blind, randomized, sham-controlled trial.

Transcranial pulse stimulation has been proven effective to improve cognition, memory and depressive symptoms of Alzheimer's disease, but supporting evidence on other neurological diseases or neuropsychiatric disorders remains limited. This study aimed to investigate the effects of transcranial pulse stimulation on the right temporoparietal junction, which is a key node for social cognition for autism spectrum disorder, and to examine the association between transcranial pulse stimulation and executive and social functions. This double-blinded, randomized, sham-controlled trial included 32 participants (27 males), aged 12-17 years with autism spectrum disorder. All eligible participants were randomized into either the verum or sham transcranial pulse stimulation group, on a 1:1 ratio, based on the Childhood Autism Rating Scale screening score. Sixteen participants received six verum transcranial pulse stimulation sessions (energy level: 0.2-0.25 mJ/mm2; pulse frequency: 2.5-4.0 Hz, 800 pulse/session) in 2 weeks on alternate days. The remaining 16 participants received sham transcranial pulse stimulation. The primary outcome measure included Childhood Autism Rating Scale score changes, evaluated by parents, from baseline to 3-month follow-ups. Secondary outcomes included a self-reported questionnaire responded to by parents and cognitive tests responded to by participants. A licensed mental health professional evaluated clinical global impression severity, improvement, efficacy and total score. Results revealed significant interactions in Childhood Autism Rating Scale and other secondary outcomes. Significant group and time effects were found in most secondary outcomes. Additionally, significant differences were found between the transcranial pulse stimulation and sham transcranial pulse stimulation groups in Childhood Autism Rating Scale and clinical global impression improvement and total score immediately after 2 weeks of transcranial pulse stimulation intervention (all P < 0.05), and effects were sustainable at 1- and 3-month follow-up, compared with baseline. The effect size of Childhood Autism Rating Scale (d = 0.83-0.95) and clinical global impression improvement (d = 4.12-4.37) were large to medium immediately after intervention and sustained at 1-month post-stimulation; however, the effects were reduced to small at 3-month post-stimulation (d = 2.31). These findings indicated that transcranial pulse stimulation over right temporoparietal junction was effective to reduce the core symptoms of autism spectrum disorder, as evidenced by a 24% reduction in the total Childhood Autism Rating Scale score in the verum transcranial pulse stimulation group. Additionally, the clinical global impression total score was reduced by 53.7% in the verum transcranial pulse stimulation group at a 3-month follow-up, compared with the baseline. Participants in the verum transcranial pulse stimulation group had shown substantial improvement at 1- and 3-month follow-ups, compared with baseline, although some of the neuropsychological test results were deemed statistically insignificant. Future replication of this study should include a larger sample derived from multi-nations to determine transcranial pulse stimulation as an alternative top-on treatment option in neuropsychiatry.

Effects of Transcranial Pulse Stimulation (TPS) on Adults with Symptoms of Depression-A Pilot Randomized Controlled Trial.

Transcranial pulse stimulation (TPS) is a recent development in non-invasive brain stimulations (NIBS) that has been proven to be effective in terms of significantly improving Alzheimer patients' cognition, memory, and execution functions. Nonetheless, there is, currently, no trial evaluating the efficacy of TPS on adults with major depression disorder (MDD) nationwide. In this single-blinded, randomized controlled trial, a 2-week TPS treatment comprising six 30 min TPS sessions were administered to participants. Participants were randomized into either the TPS group or the Waitlist Control (WC) group, stratified by gender and age according to a 1:1 ratio. Our primary outcome was evaluated by the Hamilton depression rating scale-17 (HDRS-17). We recruited 30 participants that were aged between 18 and 54 years, predominantly female (73%), and ethnic Chinese from 1 August to 31 October 2021. Moreover, there was a significant group x time interaction (F(1, 28) = 18.8, p < 0.001). Further, when compared with the WC group, there was a significant reduction in the depressive symptom severity in the TPS group (mean difference = -6.60, p = 0.02, and Cohen's d = -0.93). The results showed a significant intervention effect; in addition, the effect was large and sustainable at the 3-month follow-up. In this trial, it was found that TPS is effective in reducing depressive symptoms among adults with MDD.

Linking circadian rhythms to microbiome-gut-brain axis in aging-associated neurodegenerative diseases.

Emerging evidence suggests that both disruption of circadian rhythms and gut dysbiosis are closely related to aging-associated neurodegenerative diseases. Over the last decade, the microbiota-gut-brain axis has been an emerging field and revolutionized studies in pathology, diagnosis, and treatment of neurological disorders. Crosstalk between the brain and gut microbiota can be accomplished via the endocrine, immune, and nervous system. Recent studies have shown that the composition and diurnal oscillation of gut microbiota are influenced by host circadian rhythms. This provides a new perspective for investigating the microbiome-gut-brain axis. We aim to review current understanding and research on the dynamic interaction between circadian rhythms and the microbiome-gut-brain axis. Furthermore, we will address the possible neurodegenerative disease contribution through circadian rhythms and microbiome-gut-brain axis crosstalk.