Effects of repetitive transcranial magnetic stimulation combined with action-observation-execution on social interaction and communication in autism spectrum disorder: Feasibility study.

OBJECTIVE: To investigate the feasibility of a combined high-frequency rTMS (HF-rTMS) with action observation and execution (AOE) on social interaction and communication in children with Autistic Spectrum Disorder (ASD). MATERIALS AND METHODS: Fifteen children underwent 10 sessions of 5-Hz HF-rTMS on the right inferior frontal gyrus combined with AOE. An experimental group received the real HF-rTMS while the control group received the sham one. For the AOE protocol, they were instructed to watch and imitate a video showing the procedure, including reaching and grasping tasks, gustatory tasks, and facial expressions. Their behavioural outcomes were evaluated using the Vineland Adaptive Behaviour Scale (VABS) and electroencephalograms (EEGs) recorded at three time points: baseline, immediately after each treatment, and at the 1-week follow-up after the 10th treatment. RESULTS: There were increased VABS subitem scores in the experimental group, including the receptive, expressive, domestic, and community scores but no such increase was observed in the control group. For the EEG, the beta rhythm at C3 and C4 increased in the experimental group. Additionally, positive correlations were observed between changes in the scores for the expressive subitem and changes in the beta rhythm on the C4 electrode at baseline and immediately after treatment in the experimental group. The control group showed no significant differences in any items for both observation and imitation times. CONCLUSION: Ten sessions of HF-rTMS combined with AOE could improve both the subitems of communication and daily living skills domain in children aged 7-12 years with ASD. Although it is still inconclusive, this behavioural improvement may be partly attributable to increased cortical activity, as evidenced by beta rhythms.

Psychometric Assessment of the Handwriting Proficiency Screening Questionnaire (HPSQ)-Thai Version for Primary School-Aged Children.

In this study, the original Handwriting Proficiency Screening Questionnaire (HPSQ) was translated into Thai and cross-culturally adapted for use among school-aged children in Thailand. Additionally, the initial psychometric properties of the new Thai version were assessed, including internal consistency, construct validity, and content validity. The original HPSQ was forward-translated by two independent translators from English to Thai and then back-translated. A final consolidation was conducted by an expert committee to develop the Thai HPSQ. In the psychometric evaluation, content validity was quantified using the item-objective congruence (IOC) value for each item. Intra-rater and inter-rater reliabilities were also assessed. Internal consistency was measured using Cronbach's alpha coefficient, and confirmatory factor analysis models were used to examine its construct validity. The Thai version of the HPSQ had excellent internal consistency (α = 0.92), good construct, and content validity (IOC value > 0.6). Intra-rater reliability was good (intraclass correlation coefficient (ICC) = 0.98), and inter-rater reliability ranged from fair to good (ICC = 0.46−0.77). Factor analysis revealed that a three-factor model best fitted the data. Thus, the Thai version of the HPSQ is a reliable and valid instrument for handwriting evaluation among Thai school-aged children. It can be useful for teachers and therapists to identify students with handwriting problems.

Inorganic arsenic contamination and the health of children living near an inactive mining site: northern Thailand.

Arsenic toxicity is a global health problem affecting millions of people. Contamination is caused by arsenic from natural geological sources leaching into aquifers, contaminating drinking water, and may also be caused by mining and other industrial processes. Acute arsenic poisoning is associated with nausea, vomiting, abdominal pain, and severe diarrhea. Chronic arsenic toxicity results in multisystemic diseases leading to central nervous system (CNS) impairments such as cognitive or intellectual deficits in children. Over the past ten years, arsenic contamination has been reported in northern Thailand. The Ministry of Public Health; Thailand, Forensic Science Institute Thammasat University, and the Research Center to Promote Safety and Prevent Injuries in Children at the Ramathibodi Hospital compiled a report on the health impact of the population within a 10 kilometer radius around a mine tailing in the Phichit, Phitsanulok, and Phetchabun Provinces of Thailand. It showed that more than 30 % of children (aged 8-13 years) had higher than normal arsenic contamination levels based on the Agency for Toxic Substances and Disease Registry (ATSDR). After the publication of that report, the mine was temporarily closed in 2016. Based on this data, this research aimed to follow arsenic contamination after the mining operation had stopped operation for three years. The study showed that 4.5 % of school aged children had levels of inorganic arsenic in their urine, higher than the normal range (ATSDR), showing clearly that inorganic arsenic contamination is still above the normal range in children living near an inactive mining site. Therefore, monitoring heavy metal contamination in Thailand and the health effects on vulnerable children who live near mines during regular operation or after being temporarily suspended can prevent and mitigate possible health impacts.

Earning Too Little And Worrying Too Much: The Role Of Income And Financial Worries On Parents' Well-Being In Hong Kong And Bangkok.

Research has shown that financial worries are key determinants of parents' well-being. However, less is known about the relative role of income and financial worries on parents' well-being; especially from a cross-cultural perspective. Guided by need and aspiration theories, we examined the roles of income and financial worries on happiness and distress among parents from Hong Kong (N = 258) and Bangkok (N = 190). Bayesian structural equation modelling revealed that greater income and lower financial worries were correlated, on a bivariate level, with higher levels of happiness and lower levels of distress in both societies. However, regressing happiness on both income and financial worries shows that income is uniquely associated with happiness in Bangkok, but not in Hong Kong. Financial worries uniquely explained variance in distress in both societies. These findings suggest that income and financial worries play different roles in parents' psychological well-being in the two cities. To promote parents' well-being, future policy or intervention programs should target financial worries in Hong Kong. Targeting income and financial worries are more likely to be efficacious in Bangkok.

Bridging the Gap between Clinical Service and Academic Education of Hand-Splinting Practice: Perspectives and Experiences of Thai Occupational Therapists.

A gap in knowledge about current splinting practice exists between the educational program and clinical service. To bridge this gap, we investigated the perspectives and experiences of Thai occupational therapists regarding contemporary hand splinting practices in clinical use. A mixed-method study was designed. An explanatory sequential mixed methods design was used. In the first quantitative phase, a survey questionnaire was mailed to occupational therapists. The questions were regarding contemporary hand splinting practices in clinical use at seven hospitals in the capital city of Bangkok and outskirt areas. In the second phase, semi-structured interviews were completed to explore expert occupational therapists' perspectives on practice in the same hospital settings. Transcripts were analyzed using thematic analysis. The results showed that most conditions receiving splints were nerve injuries, orthopedics, and stroke, which represented the service frequency of splint types: functional resting (100%), cock-up (93.3%), and thumb spica splints (80%). Bone and joint deformity prevention ranked first with muscle contracture prevention being ranked second, and the third-ranked was maintaining range of motion. Three themes emerged from the interviews: starting with the patient condition; effective function and value; knowledge and experiential skills. Perspectives and experiences of occupational therapists in splinting practice contribute to education based on the reality of practice. Integrated numerical and textual data of professional skills and knowledge in actual splinting practice can be reflected through splints and orthoses program revisions to meet future learning outcomes.

Effects of cathodal transcranial direct current stimulation on inhibitory and attention control in children and adolescents with attention-deficit hyperactivity disorder: A pilot randomized sham-controlled crossover study.

The pathophysiological of attention-deficit hyperactivity disorder (ADHD) includes hypoactivation of the dorso-lateral prefrontal cortex (DLPFC). Most studies have used anodal (excitatory) transcranial direct current stimulation (tDCS) to improve ADHD symptoms, however, a meta-analysis showed limited effect on improving inhibition, and no evidence of attention improvement. We thus present a pilot protocol for investigating the effect of other montage i.e. cathodal (inhibitory) tDCS on neurophysiological and behavioral measures in ADHD. Eleven participants underwent active (1.5 mA, 20 min) and sham cathodal tDCS over the left DLPFC for 5 consecutive days at a 1-month interval. Quantitative electroencephalography was recorded in a resting state with the eyes opened and closed during visual go/no-go and auditory continuous performance tasks at baseline, after five sessions, and at 1-week and 1-month follow-ups. Correct responses and omission errors were recorded. After five active sessions, alpha power increased in the right frontal area when the eyes were opened, and delta power in the left frontal area and omission errors decreased during go/no-go tasks, with no differences at follow-ups. The results revealed improvements in inhibitory control, but not for attention. No aftereffects were observed in either outcomes. However, the changes found in both hemispheres would probably support the hypothesis that cathodal stimulation over the left DLPFC may increase the activity of the right DLPFC via transcallosal inhibition. Results of this pilot trial would help to design and implement a full-scale randomized control trials for further ADHD research. This study was registered on ClinicalTrials.gov (NCT03955692).

Protective Effects of Melatonin on Methamphetamine-Induced Blood-Brain Barrier Dysfunction in Rat Model.

The specialized brain endothelial cells interconnected by unique junctions and adhesion molecules are distinctive features of the blood-brain barrier (BBB), maintaining the homeostasis of the cerebral microenvironment. This study was designed to investigate the protective effects of melatonin on methamphetamine (METH)-induced alterations of BBB integrity. Wistar rats were randomly distributed into groups and underwent melatonin pretreatment and escalating-high doses of METH treatment. Immunohistochemistry was performed to demonstrate the BBB leakage. Protein and RNA samples were isolated from hippocampal and prefrontal cortical tissues and measured expression levels of molecular markers associated with BBB structural components and inflammatory processes. METH provoked the loss of zonula occludens (ZO)-1, occludin, and claudin-5 tight junction proteins. Furthermore, METH caused an excessive increase in matrix metalloproteinase-9 (MMP-9) enzyme, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) and the increase in NAD(P)H oxidase 2 (NOX2). Melatonin exerted the protective effects by recovering tight junction loss; attenuating excessive MMP-9, NOX2, and cell adhesion molecule expression; and reducing serum albumin in the brain. Our results also showed the protective effects of melatonin against METH neurotoxic profiles, characterized by reactive gliosis: microglia (integrin-αM) and astrocyte (GFAP); an excessive upregulation of primary pro-inflammatory cytokines: interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α); activation of neuroinflammatory signaling: nuclear factor-kappa B (NF-κB); and suppression of anti-oxidative signaling: nuclear factor erythroid 2-related factor (Nrf2), that may exacerbate BBB structural impairment. Our results provide insights into the beneficial effects of melatonin against METH-induced BBB disruption and mechanisms that play detrimental roles in BBB impairment by in vivo design.

Long-term administration of melatonin attenuates neuroinflammation in the aged mouse brain.

Aging is often accompanied by a decline in cognitive function in conjunction with a variety of neurobiological changes, including neuroinflammation. Melatonin is a key endogenous indoleamine secreted by the pineal gland that plays a crucial role in the regulation of circadian rhythms, is a potent free radical scavenger, has anti-inflammatory activity and serves numerous other functions. However, the role of melatonin in sterile inflammation in the brain has not been fully investigated. In the present study, we investigated the neuroinflammation status in aged mouse brains. The results showed that the protein levels of integrin αM (CD11b), glial fibrillary acidic protein (GFAP), the major pro-inflammatory cytokines (interleukin-1 beta [IL-1ß], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNF-α]) and phosphor-nuclear factor kappa B (pNFκB) were significantly increased, while N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and brain-derived neurotrophic factor (BDNF) were down-regulated in the hippocampus and prefrontal cortex (PFC) of 22-months-old (aged) mice compared with 2-months-old (young adult) mice. Melatonin was administered in the drinking water to a cohort of the aged mice at a dose of 10 mg/kg/day, beginning at an age of 16 months for 6 months. Our results revealed that melatonin significantly attenuated the alterations in these protein levels. The present study suggests an advantageous role for melatonin in anti-inflammation, and this may lead to the prevention of memory impairment in aging.

A Study of the Correlation between VEP and Clinical Severity in Children with Autism Spectrum Disorder.

Visual evoked potential (VEP) is a technique used to assess the brain's electrical response to visual stimuli. The aims of this study were to examine neural transmission within the visual pathway through VEP testing in preschool children with autism spectrum disorder (ASD) and compare it to age-matched controls, as well as search for a correlation between the VEP parameters and the symptoms of ASD. Participants were composed of ASD children (9 males) and typically developing children (8 males and 4 females), aged between 3 and 5 years. Checkerboards were chosen as the pattern-reversal VEP. The clinical severity of ASD was assessed using the Autism Treatment Evaluation Checklist (ATEC) and the Vineland Adaptive Behavior Scales 2nd edition (VABS-II). Our findings demonstrated that children with ASD had significantly longer N145 latency compared to the controls. A longer N145 latency correlated with a higher score of ATEC within the sensory/cognitive awareness subdomain. In addition, a slower N145 response was also associated with a lower VABS-II score within the socialization domain. The correlation between longer VEP latency and abnormal behaviors in children with ASD suggests a delayed neural communication within other neural circuits, apart from the visual pathway. These lines of evidence support the possibility of using VEP, along with clinical parameters, for the assessment of ASD severity.

The anti-inflammatory effect of melatonin in SH-SY5Y neuroblastoma cells exposed to sublethal dose of hydrogen peroxide.

Brain inflammaging is considered as one of the underlying factors of neurodegenerative diseases. The present study aimed to investigate the effects of melatonin, an endogenous indoleamine mainly synthesized by the pineal gland, on hydrogen peroxide (H2O2)-induced inflammaging state in SH-SY5Y cells. Our data showed that p21Cip1 and p16INK4a, cell cycle arrest markers, and the number of senescence-associated ß-galactosidase (SA-ßgal) staining increased significantly in H2O2-treated cells. Melatonin treatment could reverse this effect. Flow cytometry analysis showed a significantly higher percentage in the G0/G1 phase and a lower proportion in the S phase of H2O2 treated cells. Cells pretreated with H2O2 showed a dramatic decrease in the formation of Ki67 immunoactivity while the treatment with melatonin increased Ki67-positive cell. Both mRNA and protein expression levels of the pro-inflammatory cytokines, interleukin-1ß (IL-1ß), IL-6 and, tumor necrosis factor-α (TNF-α) which were increased after induction with H2O2, could be attenuated by melatonin. In addition, melatonin decreased the phospho-nuclear factor kappa B (pNF-κB) expression and prevented its nuclear translocation, as well as abrogated the reduction of nuclear factor erythroid 2-related factor 2 (Nrf2) in SH-SY5Y cells exposed to H2O2. The present data suggested the importance of melatonin on ameliorating inflammation in SH-SY5Y cells.

Calcitonin gene-related peptide mediates an inflammatory response in Schwann cells via cAMP-dependent ERK signaling cascade.

AIMS: Calcitonin gene-related peptides (CGRP), an endogenous neuropeptide, play an important role in the development of neuroinflammation by acting upon its receptor. The CGRP receptor immunoreactivity was identified on Schwann cells. However the effects of CGRP on Schwann cells are unknown and the exact signaling mechanisms associated with CGRP receptor activation related to Schwann cells inflammatory responses are not well understood. We investigated the effect of CGRP on CGRP receptor activation mediates a proinflammatory signaling response in Schwann cells. MAIN METHODS: CGRP-induced ERK-MAPK phosphorylation and proinflammatory cytokines, interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) expressions were measured by immune blotting. We also used specific antagonist and inhibitors to confirm the exactly signaling pathway including CGRP (8-37), SQ 22536 and H-89. KEY FINDINGS: Treatment with CGRP demonstrated a significant generation of IL-1ß and IL-6 but not in the level of TNF-α. In addition, there was a temporal increase in the activated form of ERK caused by CGRP that was prevented after pretreatment with CGRP (8-37), SQ 22536 and H-89. Furthermore, use of the CGRP (8-37), ERK inhibitor PD 98059, SQ 22536 or H-89 abolished the CGRP mediated increase in IL-1ß. SIGNIFICANCE: This investigation provides evidence for a novel CGRP activation on Schwann cells that mediates inflammatory response by increasing of IL-1ß and IL-6 expression. CGRP activates the cAMP-PKA-ERK signaling cascade leading to IL-1ß production. These results support the notion that CGRP may play a direct role to initiate inflammatory processes in the peripheral nervous system.

The anti-inflammatory effect of melatonin on methamphetamine-induced proinflammatory mediators in human neuroblastoma dopamine SH-SY5Y cell lines.

Methamphetamine (METH) is a highly addictive drug that is commonly abused worldwide. This psychostimulant drug causes the disturbances in the dopaminergic and serotonergic neurons of several brain areas. Exposure to METH has been shown to induce oxidative stress, reactive oxygen species, reactive nitrogen species, and neuroinflammation. However, the mechanism underlying METH-induced inflammation in neurons is still unclear. In this study, we investigated whether METH caused inflammatory effects in human dopaminergic neuroblastoma SH-SY5Y cells and whether this effect involved the nuclear factor-κB (NF-κB) transcription factor pathway. The present results showed that METH significantly increased inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner and significantly increased the levels of tumor necrosis factor (TNF)-α mRNA and phosphorylated NF-κB, which is translocated into the nucleus. Moreover, our results also show that METH downregulated another transcription factor, the nuclear factor erythroid 2-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Furthermore, we also examined the anti-inflammatory effect of melatonin against these METH-induced neuroinflammatory functions. The results show that melatonin significantly decreases the iNOS protein expression and TNF-α mRNA levels caused by METH. The activation and the level of pNF-κB were decreased while Nrf2 expression was increased when cells were pre-incubated with 100 nM of melatonin. In order to show the relationship between cell death and the increase of iNOS, 100 µM of L-NAME, an iNOS inhibitor pretreatment significantly prevented cell death caused by METH. These results demonstrate, for the first time, that METH directly induces inflammation in neurons via an NF-κB-dependent pathway and that the anti-neuroinflammatory effects of melatonin result from the inhibition of activated NF-κB in parallel with potentiated antioxidant/detoxificant defense by activated Nrf2 pathway.

Effect of melatonin on D-amphetamine-induced neuroglial alterations in postnatal rat hippocampus and prefrontal cortex.

Amphetamine is a psychostimulant drug that produces long-lasting neurotoxic effects on the central nervous system. Recent studies suggested that glia might contribute to amphetamine-induced neuropathy. Excessive activation of astrocytes can be deleterious to the neuron. Amphetamine-induced lesions during development have the potential to produce numerous permanent abnormalities in neural circuitry and function, including memory deficit. In the present study, postnatal rats were injected with either saline or d-amphetamine for 7 consecutive days, starting on postnatal day 4 (P4). Our results found that d-amphetamine caused a marked increase in glia fibrillary acidic protein (GFAP), an astroglia marker, expression that implicated astrogliosis in both hippocampus and prefrontal cortex. The effect of d-amphetamine on hippocampal and prefrontal cortex neurons was also investigated, and we detected a downregulation of ßIII-tubulin, a marker of premature neuron expression. Furthermore, we found that pretreatment with melatonin, a major hormone secreted from the pineal gland, prevented glial cell activation and ßIII-tubulin reduction, caused by d-amphetamine in both hippocampus and prefrontal cortex. The present study suggests that melatonin can attenuate the detrimental effect of d-amphetamine on glial and neuronal cells.

Noradrenergic depression of neuronal excitability in the entorhinal cortex via activation of TREK-2 K+ channels.

The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia, and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by alpha(2A) adrenergic receptors and required the functions of Galpha(i) proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated by activation of TREK-2, a type of two-pore domain K(+) channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine. Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels.