• Molecules and Cells
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• v.40 no.2
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• pp.151-161
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• 2017

Proper synaptic function in neural circuits requires precise pairings between correct pre- and post-synaptic partners. Errors in this process may underlie development of neuropsychiatric disorders, such as autism spectrum disorder (ASD). Development of ASD can be influenced by genetic factors, including copy number variations (CNVs). In this study, we focused on a CNV occurring at the 16p11.2 locus in the human genome and investigated potential defects in synaptic connectivity caused by reduced activities of genes located in this region at Drosophila larval neuromuscular junctions, a well-established model synapse with stereotypic synaptic structures. A mutation of rolled, a Drosophila homolog of human mitogen-activated protein kinase 3 (MAPK3) at the 16p11.2 locus, caused ectopic innervation of axonal branches and their abnormal defasciculation. The specificity of these phenotypes was confirmed by expression of wild-type rolled in the mutant background. Albeit to a lesser extent, we also observed ectopic innervation patterns in mutants defective in Cdk2, Gq, and Gp93, all of which were expected to interact with Rolled MAPK3. A further genetic analysis in double heterozygous combinations revealed a synergistic interaction between rolled and Gp93. In addition, results from RT-qPCR analyses indicated consistently reduced rolled mRNA levels in Cdk2, Gq, and Gp93 mutants. Taken together, these data suggest a central role of MAPK3 in regulating the precise targeting of presynaptic axons to proper postsynaptic targets, a critical step that may be altered significantly in ASD.

• Korean Journal of Biological Psychiatry
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• v.19 no.4
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• pp.205-210
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• 2012

Objectives The purpose of this study was to investigate clinical profile, efficacy, and safety of long-term treatment with selective serotonin reuptake inhibitors (SSRIs) in Korean autism spectrum disorders (ASDs) patients. Methods Effectiveness was assessed through a retrospective review of self-reported target symptom improvement at the last follow-up visit. Changes in illness severity and improvement were measured using the Clinical Global Impression-Severity (CGI-S) of illness and Clinical Global Impression-Improvement (CGI-I) Scales. Tolerability was assessed through a review of the reason for discontinuation of SSRI and documented adverse events. Results A total of 21 ASDs patients (aged 9 to 19 years) treated with SSRI during July 2010 to July 2011 in department of child and adolescent psychiatry of Seoul National Hospital were identified. The mean duration of SSRI treatment was 47.9 (standard deviation = 36.9) months (range 0.7-114.5), and the mean fluoxetine equivalent dosage of SSRIs was $27.1{\pm}10.8$ mg. Nineteen (90.5%) patients were using concomitant medication. We found that SSRIs were prescribed for symptoms of agitation, stereotyped behavior, aggression, depression, impulsivity and self-injury in ASDs. Ten patients (47.6%) reported improvement in their target symptom after SSRI treatment based on CGI-I scores (CGI-I ${\leq}$ 2). The side effects were reported in 5 patients (23.8%) ; vomiting (n = 2, 9.5%), excessive mood elevation (n = 1, 4.8%), insomnia (n = 1, 4.8%), somnolence (n = 1, 4.8%) and decreased appetite (n = 1, 4.8%). Self-injurious behavior was reported in one patient (4.8%). Conclusions The results of this study suggest that SSRIs may be used effectively in children and adolescents diagnosed with ASDs. However, safety issues need to be considered carefully when choosing SSRIs for treatment. Future controlled trials are needed to confirm these findings.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.23 no.3
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• pp.154-160
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• 2012

Objectives : The purpose of this study was to investigate clinical characteristics of children and adolescents with autism spectrum disorders (ASDs) using methylphenidate (MPH). Methods : Retrospective review of the charts of 79 children and adolescents with ASDs, who visited the Department of Child and Adolescent Psychiatry of Seoul National Hospital, from July 2010 to July 2011, was conducted. Changes in illness severity and improvement were measured using the Clinical Global Impression-Severity of illness (CGI-S) and Clinical Global Impression-Improvement (CGI-I) Scales. Results : We found that MPH was prescribed in 23 (29.1%) children and adolescents. Of the 23 patients on MPH, 4 patients (17.4%) were on MPH monotherapy and 18 patients (78.3%) were using risperidone concomitantly. MPH was prescribed primarily for symptoms of hyperactivity and impulsivity in ASDs patients. The mean dosage of MPH was $26.2{\pm}11.1$mg/day and mean duration of treatment was $31.9{\pm}28.7$ months. Mean CGI-S score improved significantly from baseline to endpoint (from $5.4{\pm}0.6$ to $4.1{\pm}0.9$ ; p<.01). MPH was reported to be effective in 17 patients (17/23, 73.9%), and 10 patients (10/23, 43.5%) reported side effects. Side effects included decreased appetite (4/23, 17.4%), tic (2/23, 8.6%), sleep disturbances (2/23, 8.6%), headache (1/23, 4.3%) and irritability (1/23, 4.3%). Conclusion : The results of this study demonstrate that MPH may be used effectively and safely in children and adolescents with ASDs with hyperactivity and impulsivity. Future controlled trials are needed to confirm these findings.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.24 no.3
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• pp.109-123
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• 2013

The discovery of the mirror neuron system (MNS) is one of the most important neuroscientific achievements in the 20th century. Some researchers had reported that MNS dysfunction was discovered in autism spectrum disorders (ASD). Finally, the 'broken mirror' theory of ASD was announced in the mid 2000's. According to this theory, ASD cannot simulate the mind and behavior of others due to MNS dysfunction; therefore, they cannot imitate the behaviors and empathized with the mind of others. However, ASD does not always show imitation problems. The researchers who have criticized the 'broken mirror' theory proposed the 'social top-down response modulation (STORM)' theory. On STORM theory, the medial prefrontal cortex or temporo-parietal junction, brain areas related with mentalising, might modulate MNS according to social context. We compared the strengths and weaknesses of each theory.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.26 no.4
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• pp.273-278
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• 2015

Objectives : We retrospectively investigated the efficacy and tolerability of risperidone monotherapy in subjects with autism spectrum disorder (ASD). In addition, we did mixed effect model analysis of the effects of risperidone in patients with ASDs naturalistically treated in a routine clinical setting to determine whether the clinical effects were maintained and the side effects were tolerable. Methods : This retrospective study assessed children and adolescents with ASD, who were on risperidone monotherapy from July 2010 to July 2011 at the Child and Adolescent ASD Clinic at Seoul National Hospital. Outcome measures included the Clinical Global Impression-Severity of Illness (CGI-S) and the CGI-Improvement (CGI-I) scales along with other clinical indices: dosage, target symptoms, and side effects. Results : The mean dose of risperidone in 47 children and adolescents with ASD (40 males, 7 females; age range 5-19 years) who were on risperidone monotherapy was $1.6{\pm}0.8mg/day$, and the mean duration of the treatment period was $20.2{\pm}17.3months$. Aggressive behavior, stereotypic behavior, irritability, and self-injurious behavior were the most frequent target symptoms of risperidone. The most common side effects were weight gain followed by somnolence and extrapyramidal symptoms. In a mixed effects model analysis of CGI-I scores, the mean CGI-I score at the 1 month follow-up was significantly different from the mean CGI-I score of the 3-month follow-up (p=.046), and the CGI-I scores were equally maintained over 3 to 48 months [F(6, 28.9)=4.393, p=.003]. Of the 47 patients, 33 patients (70.2%) were identified as the response group, showing an end point CGI-I rating of 3 or under and having continued risperidone treatment for at least 6 months. The baseline CGI-S score showed significant association with clinical response to risperidone (p=.005), the mean baseline CGI-S was higher in the response group compared to the non-response group. Conclusion : In this study, clinical improvement of risperidone stabilized around 3 months and was equally maintained up to 48 months with tolerable side effects, supporting maintenance of risperidone treatment in children and adolescents with ASDs.

• Journal of Music and Human Behavior
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• v.13 no.1
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• pp.61-87
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• 2016

With broad individual variability in social communication skills of children with autism spectrum disorders and increasing focus on interventions targeting social communication of this population, there is a need for systematic analysis of how social communication outcomes are measured. This study aimed to systematically analyze the measurement tools used in the music therapy interventions for improving social communication of children with ASD. Electronic databases and music therapy journals were searched for controlled studies published between 1980 and 2015. A total of 21 studies were included for the analysis. The results demonstrated that direct observation of behaviors was the most frequently used and the combination of targeted social communication areas and specific measurements used for a specific skill varied among the studies. In addition, 90.4% of studies reported interrater reliability. These results indicate that there has been a diversity in approaches to measure social communication skills despite increasing attempts for systematic measurements. In consideration of the nature of social communication development in children with ASD, multifaceted strategy to understand and assess the target skills in terms of specific behavior acquisition, social functioning in general, and social cognition was recommended.

• Proceedings of the Korea Information Processing Society Conference
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• 2021.05a
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• pp.351-353
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• 2021

자폐 스펙트럼 장애는 이질적인 신경 발달 장애로, 뇌기능영상에 기반한 기능적 연결성 행렬을 이용해 연구가 활발하게 진행된다. 기능적 연결성 행렬을 분석하기 위해 주성분 분석방법을 이용하며, 이를 통해 뇌의 기능적 경향성 패턴을 확인할 수 있다. 이 때, 서로 다른 연결성 성분 비율과 주성분 벡터를 이용해서 다양한 기능적 경향성 패턴을 얻을 수 있다. 패턴에 따른 랜덤 포레스트 분류 모델의 성능이 달라지는데 이를 비교해본 결과, 상위 50%의 성분을 이용하여 만든 기능적 경향성 패턴 1 이 데이터의 설명 비율도 높고, 우수한 분류 성능을 보이는 것을 확인했다.

• Phonetics and Speech Sciences
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• v.12 no.2
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• pp.39-49
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• 2020

The prosody of children with autism spectrum disorders (ASD) has several abnormal features, including monotonous speech. The purpose of this study was to compare acoustic features between an ASD group and a typically developing (TD) group and within the ASD group. The study also examined audience perceptions of the lengthening effect of increasing the number of syllables. 50 participants were divided into two groups (20 with ASD and 30 TD), and they were asked to imitate a total of 28 sentences. In the auditory-perceptual evaluation, seven participants chose sentence types in 115 sentences. Pitch, intensity, speech rate, and pitch slope were used to analyze the significant differences. In conclusion, the ASD group showed higher pitch and intensity and a lower overall speaking rate than the TD group. Moreover, there were significant differences in s2 slope of interrogative sentences. Finally, based on the auditory-perceptual evaluation, only 4.3% of interrogative sentences produced by participants with ASD were perceived as declarative sentences. The cause of this abnormal prosody has not been clearly identified; however, pragmatic ability and other characteristics of autism are related to ASD prosody. This study identified prosodic ASD patterns and suggested the need to develop treatments to improve prosody.

• Biomolecules & Therapeutics
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• v.28 no.5
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• pp.389-396
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• 2020

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.

• Biomolecules & Therapeutics
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• v.27 no.2
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• pp.168-177
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• 2019

Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.