Olfactory dysfunction: A plausible source of COVID-19-induced neuropsychiatric symptoms.

Olfactory dysfunction and neuropsychiatric symptoms are commonly reported by patients of coronavirus disease 2019 (COVID-19), a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence from recent research suggests linkages between altered or loss of smell and neuropsychiatric symptoms after infection with the coronavirus. Systemic inflammation and ischemic injury are believed to be the major cause of COVID-19-related CNS manifestation. Yet, some evidence suggest a neurotropic property of SARS-CoV-2. This mini-review article summarizes the neural correlates of olfaction and discusses the potential of trans-neuronal transmission of SARS-CoV-2 or its particles within the olfactory connections in the brain. The impact of the dysfunction in the olfactory network on the neuropsychiatric symptoms associated with COVID-19 will also be discussed.

Revisit the Effectiveness of Educational Kinesiology on Stress and Anxiety Amelioration in Kindergarteners With Special Needs Using Biological Measures.

Background: Educational kinesiology is a popular intervention that aims to improve brain functioning via physical movements. Yet, it lacks supporting scientific evidence and is regarded as pseudoscience. Given the popularity of educational kinesiology in school settings, it is important to revisit its effectiveness through scientific research. Previous studies that evaluated the effectiveness of educational kinesiology relied mainly on subjective measures, in which subjective bias is inevitable. Cortisol and oxytocin levels in saliva have been reported to be reliable stress and anxiety markers that provide unbiased objective data. This study explores the effect of educational kinesiology on the changes in salivary cortisol and oxytocin levels in kindergarteners with special needs. Methods: A quasi-experimental design was adopted in this study. Thirty-seven kindergarteners (3.5-6.5 years old) who were either diagnosed with one type of special needs or referred by school principals due to the requirement of special supports at school were assigned to either the intervention group, which received 1-h educational kinesiology intervention weekly for a total of 10 weeks, or the wait-list control group. Saliva samples were collected at baseline and after the completion of intervention programme for the measurement of cortisol and oxytocin levels. Scores of Parent-rated Preschool Anxiety Scale (PAS-TC) were also collected at pre- and post-intervention. Because of the small samples, non-parametric tests such as Mann-Whitney U test, Quade test, and Fisher's exact tests were used in this study where appropriate. Results: After controlled for the effect at baseline, gender and types of special needs, the changes in oxytocin levels were significantly higher in the intervention group compared with control [F (1, 35) = 4.747, p = 0.036, eta2 = 0.119], whereas no significant between-group difference in changes of cortisol levels was observed [F (1, 35) = 0.306, p = 0.584, eta2 = 0.009]. Results from PAS-TC showed significant improvement in anxiety levels after the intervention in the intervention group (p = 0.048, ϕ = 0.344, p = 0.037). Conclusions: Our findings suggest a plausible anti-anxiety effect of educational kinesiology in kindergarteners with special needs by elevating the oxytocin levels. Future studies are warranted to further confirm our findings with a larger sample.

Impact of COVID-19 on pornography use: Evidence from big data analyses.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has led to radical changes in social distancing awareness and affected social relationships. Owing to large-scale lockdown, home quarantine and social distancing requirements, it was anticipated that sexual activities would be severely impacted. However, retrospective self-report studies showed that pornography use and autoerotism increased during the pandemic. AIM: This study used big-data databases available on the Internet to investigate factors that modulated pornography use during the pandemic. METHODS: Daily relative search volume (RSV) data from Google Trends for the period from 24 February 2020 to 13 July 2020 were extracted. Pornhub traffic data were extracted from the Pornhub Insights website, for the period from 24 February 2020 to 13 July 2020. The parameter was defined as 'percent change in traffic compared to an average day in 2019'. The number of daily new cases of COVID-19 was extracted from the database on Our World in Data. OUTCOME MEASURES: The normality of the data was examined using the Shapiro-Wilk test. All variables included in this study were non-normally distributed. Therefore, non-parametric tests or parametric tests with bootstrapping were adopted where appropriate. RESULTS: According to Google Trends, the RSV for 'pornography' increased after late March 2020, which is close to the date when the World Health Organization declared COVID-19 a global pandemic. The number of daily new cases of COVID-19 was positively correlated with the traffic of Pornhub, a popular pornography website, and the RSV for 'pornography'. Moderation analysis demonstrated a significant main effect of daily new cases of COVID-19 and the RSV for 'social distancing' in predicting Pornhub traffic/RSV for 'pornography'. Furthermore, the RSV for 'social distancing' significantly moderated the relationship between daily new cases and Pornhub traffic/RSV for 'pornography'. A stronger COVID-pornography use association was observed with increased social distancing awareness. CONCLUSION: Increased pornography consumption during the pandemic was observed, and it was associated with the severity of the pandemic. Social distancing awareness could be a key factor influencing interest in and use of pornography. Further studies on the changes in sexual desire and birth-rate control are worthwhile because long-term public health may be affected by the changes in sexual behaviour during the pandemic.

Music therapy as social skill intervention for children with comorbid ASD and ID: study protocol for a randomized controlled trial.

BACKGROUND: Autism spectrum disorder (ASD) is a developmental impairment characterized by persistent deficits in social communication and interactions, and over half of children with ASD possess below average intellectual ability (IQ < 85). The social development and response to social skill interventions among children with ASD and comorbid intellectual disability (ID) is not well understood. Music therapy is a systematic process of intervention, wherein a therapist may help clients promote their social skills by using musical experience. The proposed study will address limited research evidence on music therapy as an intervention for social functioning in children with ASD with mild to borderline ID. METHOD: A randomized controlled trial (RCT) with two parallel groups of 40 children each (1:1 allocation ratio) is planned. Participants will receive 45 min of music therapy or non-musical intervention targeting social skills once a week for 12 weeks. Primary outcome measures will be independent ratings on the Childhood Autism Rating Scale and parent ratings on the Social Responsiveness Scale-2. Linear mixed-effects models for these two outcome measures will be created for data collected at 2-week pre-intervention, 2-week post-intervention, and 4-month post-intervention sessions. In-session behaviors at the first and last intervention will be videotaped and coded offline and compared. Pretreatment neural response of quantitative electroencephalograms (qEEG) to social scenes will be used to predict the outcomes of musical and non-musical social skill interventions, whereas qEEG responses to music will be used to predict the effectiveness of musical social skill intervention. DISCUSSION: If neural markers of social skill development are found, then the long-term goal is to develop individualized intervention based on pre-treatment markers to maximize treatment efficacy. The proposed study's results may also suggest directions to development and provision of music therapy services in Hong Kong. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04557488 ). Registered September 21, 2020.

Resting-state abnormalities of posterior cingulate in autism spectrum disorder.

The posterior cingulate cortex (PCC) plays pivotal roles in cognitive, social and emotional processing, as well as early neural development that supports complex interactions among different neural networks. Alterations in its local and long-range connectivity during resting state are often implicated in neuropathology of neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is characterized by social and communication deficits, as well as restricted and repetitive behaviors and interests. Individuals with ASD demonstrate persistent disturbances in cognitive and social-emotional functioning, and their PCC exhibits both local and long-range resting state abnormalities compared to typically developing healthy controls. In terms of regional metrics, only the dorsal part of the PCC showed local underconnectivity. As to long-range connectivity measures, the most replicated finding in ASD studies is the reduced functional coupling between the PCC and medial prefrontal cortex (MPFC), which may represent a core neuropathology of ASD unrelated to medication effects. Functional importance of these resting state abnormalities to ASD and directions of future study are discussed at the end of this chapter.

Endothelin type B receptor promotes cofilin rod formation and dendritic loss in neurons by inducing oxidative stress and cofilin activation.

Endothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress- or cofilin activation-driven cofilin rod formation. Here, we demonstrate that exposure to 100 nm ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nm IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 µm VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nm FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.

Lavender essential oil ameliorates depression-like behavior and increases neurogenesis and dendritic complexity in rats.

Depression is a major health issue that causes severe societal economic and health burden. Aromatherapy, a practice that uses essential oils for preventive and therapeutic purposes, represents a promising therapeutic alternative for the alleviation of depressive symptoms. Lavender essential oil (LEO) has been the focus of clinical studies due to its positive effect on mood. An animal model of chronic administration of high dose corticosterone to induce depression- and anxiety-like behavior and reduced neurogenesis was used to explore the biological changes brought by aromatherapy. Twenty-four adult male Sprague Dawley rats were randomly assigned into four groups: Control, corticosterone (Cort) group with high dose of corticosterone, LEO group with daily exposure to LEO by inhalation, and LEO + Cort. At the end of the 14-day treatment period, behavioral tests were carried out. Serum samples were collected 2-3 days after the 14-day period treatment and before perfusion to carry out biochemical analyses to measure BDNF, corticosterone and oxytocin. After perfusion, brains were collected for immunohistochemical analysis to detect BrdU and DCX positive cells in the hippocampus and subventricular zone. Results showed that treatment with LEO ameliorated the depression-like behavior induced by the chronic administration of corticosterone as observed in the LEO + Cort group. Cort treatment reduced the number of BrdU positive cells in the hippocampus and the subventricular zone. Treatment with LEO prevented the corticosterone-induced reduction in the number of BrdU positive cells (LEO + Cort group) demonstrating the neurogenic effect of LEO under high corticosterone conditions. Chronic administration of high dose of corticosterone significantly reduced the dendritic complexity of immature neurons. On the contrary, treatment with LEO increased dendritic complexity of immature neurons under high corticosterone conditions (LEO + Cort group). The improved neurogenesis and dendritic complexity observed in the LEO + Cort group demonstrated a clear restorative effect of LEO under high corticosterone conditions. However, 2-3 days after the treatment, the levels of BDNF were upregulated in the LEO and LEO + Cort groups. Furthermore, the concentration of oxytocin in serum, 2-3 days after the treatment, showed to be upregulated in the LEO group alone. The present study has provided evidence of the biological effect of LEO on neuroplasticity and neurogenesis. Also, this study contributes to the understanding of the mechanism of action of LEO in an animal model where depression- and anxiety-like behavior and reduced neurogenesis were induced by high corticosterone administration.

The presence of serotonin in cigarette smoke - a possible mechanistic link to 5-HT-induced airway inflammation.

We previously reported the involvement of serotonin (5-HT) metabolism in cigarette smoke-induced oxidative stress in rat lung in vivo. Here, we report cigarette smoke as a source of serotonin (5-HT) to the airways and aim at investigating the effects of 5-HT on oxidative stress and inflammation in human bronchial epithelial cells (BEAS-2B). A 5-HT analog was identified to be present in aqueous phase cigarette smoke using the LC-MS/MS approach, which was later confirmed by a 5-HT enzyme-linked immune assay (EIA). Furthermore, exposure to 5-HT caused a time-dependent elevation of intracellular ROS level, which was blocked in the presence of apocynin (a NOX inhibitor). In support, the immunoblot analysis indicated that there was an increase in the expression of NOX2 time-dependently. 5-HT-induced elevation of IL-8 at both mRNA and protein levels was observed, which was inhibited by TEMPOL (a free radical scavenger), and inhibitors for p38 MAPK (SB203580) and ERK (U0126), in line with the time-dependent phosphorylation of p38 MAPK and ERK. In conclusion, our findings suggest that 5-HT presented in bronchial epithelium of smokers may be involved in cigarette smoke-induced oxidative stress and inflammation via activation of p38 MAPK and ERK pathway after the formation of free radicals.

The involvement of serotonin metabolism in cigarette smoke-induced oxidative stress in rat lung in vivo.

Recently, we have reported the dysregulation of circulating serotonin (5-hydroxytryptamine, 5-HT) homeostasis in patients with chronic obstructive pulmonary disease (COPD). An increase in metabolism of 5-HT has been reported to induce oxidative stress via monoamine oxidase (MAO)-dependent pathway. The present study aimed at investigating the effect of cigarette smoke exposure on the systemic circulation and local airway 5-HT levels as well as MAO-mediated oxidative pathway using a cigarette smoke-exposed rat model. Male Sprague-Dawley rats (150-200 g) were exposed to either sham air or 4% (v/v, smoke/air) cigarette smoke for 1 hour daily for 56 consecutive days. Sera, bronchoalveolar larvage (BAL) and lung tissues were collected 24 hours after the last exposure. We found a significant reduction in the reduced glutathione (rGSH) and an elevation in advanced oxidation protein products (AOPP), a protein oxidation marker, in the lung of cigarette smoke-exposed group (p < 0.05). A significant increase in 5-HT was found in serum (p < 0.05), but not in the BAL or lung, after cigarette smoke exposure. MAO-A activity was significantly elevated in the lung of cigarette smoke-exposed group (p < 0.05). Furthermore, increased superoxide anion levels were found in lung homogenates of cigarette smoke-exposed rats after incubation with 5-HT (p < 0.05), which was positively associated with the increase in MAO-A activity (r = 0.639, p < 0.05). Our findings supported the presence of GSH disruption and protein oxidation in the lung after cigarette smoke exposure. The metabolism of 5-HT by MAO-A in the lung enhanced cigarette smoke-induced superoxides, which might contribute to the pathogenesis of COPD.

The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced IL-8 production in human bronchial epithelial cells.

Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR(2A)) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD.

Cigarette smoke-induced cerebral cortical interleukin-6 elevation is not mediated through oxidative stress.

The author group has previously established an in vivo subchronic cigarette smoke (CS) exposure rat model, in which the systemic oxidative burden as well as the modulation of local anti-oxidative enzymes in the lung has been demonstrated. Oxidative stress has been shown to induce pro-inflammatory cytokine release, including interleukin (IL)-6 in the airways. In this study, we aimed to investigate the changes in IL-6 production, as well as the oxidative/anti-oxidative responses in the cerebral cortex using the same in vivo model. IL-6 was determined by RT-PCR and western-blot analysis. Local oxidative and anti-oxidative responses were determined by measuring cerebral cortical malondialdehyde (MDA) and advanced oxidation protein product (AOPP) levels, superoxide dismutase (SOD) and catalase activities, and the reduced to oxidized glutathione (GSH/GSSG) ratio. Nitrite level was measured by fluorescent spectrophotometry. Our results demonstrated a significant increase in both IL-6 mRNA and protein levels. Reductions of SOD activity and manganese (Mn)SOD protein level were observed together with the increased level of superoxide measured by chemiluminescent signal, after 56 days of CS exposure. There were no significant changes in the cerebral cortical levels of MDA, AOPP, catalase activity, and the GSH/GSSG ratio. Nitrite level was significantly reduced, together with the decreased protein level of nNOS in the cerebral cortex, after 56 days of CS exposure. Our results suggest that exposure to CS induces IL-6 expression in the cerebral cortex, which is not mediated by the oxidative/anti-oxidative imbalance.

A pro-drug of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine.

Regular consumption of green tea benefits people in prevention from cardiovascular disorders, obesity as well as neurodegenerative diseases. (-)-Epigallocatechin-3-gallate (EGCG) is regarded as the most biologically active catechin in green tea. However, the stability and bioavailability of EGCG are restricted. The purpose of the present study was to investigate whether a pro-drug, a fully acetylated EGCG (pEGCG), could be more effective in neuroprotection in Parkinsonism mimic cellular model. Retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cells were pre-treated with different concentrations of EGCG and pEGCG for 30 min and followed by incubation of 25 microM 6-hydroxydopamine (6-OHDA) for 24h. We found that a broad dosage range of pEGCG (from 0.1 to 10 microM) could significantly reduce lactate dehydrogenase release. Likewise, 10 microM of pEGCG was effective in reducing caspase-3 activity, while EGCG at all concentrations tested in the model failed to attenuate caspase-3 activity induced by 6-OHDA. Furthermore, Western-blot analysis showed that Akt could be one of the specific signaling pathways stimulated by pEGCG in neuroprotection. It was demonstrated that 25 microM of 6-OHDA significantly suppressed the phosphorylation level of Akt. Only pEGCG at 10 microM markedly increased its phosphorylation level compared to 6-OHDA alone. Taken together, as pEGCG has higher stability and bioavailability for further investigation, it could be a potential neuroprotective agent and our current findings may offer certain clues for optimizing its application in future.

Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research.

Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity experiments. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic associated protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in experimental Parkinson's disease research.