Hyperactive Behavior Research Articles

Identification of curcumin analogues with anti-seizure potential in vivo using chemical and genetic zebrafish larva seizure models

Seizures are the outward manifestation of abnormally excessive or synchronous brain activity. While seizures can be somewhat symptomatically managed with anti-epileptic drugs (AEDs), many patients are still refractory to the currently available AEDs. As a result, there is a need to identify new molecules with anti-seizure properties. Curcumin is the principle curcuminoid of Curcuma longa, or colloquially turmeric, and has been experimentally proven to have anti-convulsive properties, but its poor bioavailability has dampened further therapeutic interest. Hence, this study aimed to ask if structural analogues of curcumin with an adequate bioavailability could have an anti-seizure effect in vivo. To do so, we tested these analogues following a multipronged approach combining the use of several zebrafish seizure models (chemically-induced and genetic) and complementary assays (behavioural and brain activity). Overall, from the 68 analogues tested, we found 15 different derivatives that were able to significantly decrease the behavioural hyperactivity induced by pentylenetetrazol. Of those, only a few showed an effect on the hyperactivity phenotype of two genetic models of brain seizures that are the gabra1 and gabrg2 knockouts. Two analogues, CA 80(1) and CA 74(1), were able to significantly alleviate brain seizures of gabrg2-mutant larvae. As a result, these analogues are good candidates as novel anti-seizure agents.

Ubtor Mutation Causes Motor Hyperactivity by Activating mTOR Signaling in Zebrafish

Mechanistic target of rapamycin (mTOR) signaling governs important physiological and pathological processes key to cellular life. Loss of mTOR negative regulators and subsequent over-activation of mTOR signaling are major causes underlying epileptic encephalopathy. Our previous studies showed that UBTOR/KIAA1024/MINAR1 acts as a negative regulator of mTOR signaling, but whether UBTOR plays a role in neurological diseases remains largely unknown. We therefore examined a zebrafish model and found that ubtor disruption caused increased spontaneous embryonic movement and neuronal activity in spinal interneurons, as well as the expected hyperactivation of mTOR signaling in early zebrafish embryos. In addition, mutant ubtor larvae showed increased sensitivity to the convulsant pentylenetetrazol, and both the motor activity and the neuronal activity were up-regulated. These phenotypic abnormalities in zebrafish embryos and larvae were rescued by treatment with the mTORC1 inhibitor rapamycin. Taken together, our findings show that ubtor regulates motor hyperactivity and epilepsy-like behaviors by elevating neuronal activity and activating mTOR signaling.

Bromide toxicosis (bromism) secondary to a decreased chloride intake after dietary transition in a dog with idiopathic epilepsy: a case report

BackgroundBromide is a halide ion of the element bromine usually administered in the form of potassium salt as monotherapy or add-on treatment in epileptic dogs. It is excreted unchanged in the urine and undergoes tubular reabsorption in competition with chloride. Thus, dietary chloride content affects serum bromide concentrations. This is the first published clinical report of bromide toxicosis secondary to a dietary modification of chloride content in an epileptic dog treated with potassium bromide.Case presentationA 3-year-old 55-kg neutered male Tibetan Mastiff was evaluated because of a 1-month history of progressive signs including ataxia, lethargy and behaviour changes. The dog was successfully treated for idiopathic epilepsy since the age of 1-year-old with phenobarbital and potassium bromide. Two months prior to presentation, the owners decided to change the dog’s diet without veterinary advice. Physical examination was unremarkable. A 12-kg weight gain was recorded since last follow-up (8 months). Neurological examination revealed severe symmetric 4-limbs ataxia with altered vigilance and intermittent episodes of hyperactivity and aggressive behaviour without significant abnormality of cranial nerves. Serum bromide concentration was high and increased by 103 % since last follow-up. Nutritional evaluation revealed a 53 % decrease of chloride content in the diet before and after dietary transition. Bromide toxicosis was suspected, due to bromide reduced clearance secondary to the decreased dietary chloride content. Potassium bromide treatment was lowered by 15 % without further dietary changes. Neurologic signs progressively improved over the next month, without any seizure. After two months, the serum bromide concentration lowered to the same level measured before dietary modification. After four months, neurological examination was unremarkable.ConclusionsDietary chloride content can directly influence serum bromide concentrations, therefore affecting seizure control or contributing to unexpected adverse effects. In the present case, a reduction in chloride intake markedly increased serum bromide concentrations causing bromism. Dietary changes should be avoided in dogs treated with potassium bromide to maintain stable serum bromide levels.

Social impairments in mice lacking the voltage-gated potassium channel Kv3.1

Parvalbumin (PV)-expressing neurons have been implicated in the pathology of autism spectrum disorders (ASD). Loss of PV expression and/or reduced number of PV-expressing neurons have been reported not only in genetic and environmental rodent models of ASD, but also in post-mortem analyses of brain tissues from ASD vs. healthy control human subjects. PV-expressing neurons play a pivotal role in the maintenance of the balance between excitation and inhibition within neural circuits in part because of their fast-spiking properties. Their high firing rate is mostly regulated by the voltage-gated potassium channel Kv3.1. It is yet unknown whether disturbances in the electrophysiological properties of PV-expressing neurons per se can lead to behavioral disturbances. We assessed locomotor activity, social interaction, recognition and memory, and stereotypic behaviors in Kv3.1 wild-type (WT) and knockout (KO) mice. We then used Western Blot analyses to measure the impact of Kv3.1 deficiency on markers of GABA transmission (PV and GAD67) and neural circuit activity (Egr1). Deficiency in Kv3.1 channel is sufficient to induce social deficits, hyperactivity and stereotypic behaviors. These behavioral changes were independent of changes in GAD67 levels and associated with increased levels of PV protein in the prefrontal cortex and striatum. These findings reveal that a loss of PV expression is not a necessary factor to induce an ASD-like phenotype in mice and support the need for further investigation to fully understand the contribution of PV-expressing neurons to ASD pathology.

Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder

RationaleAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted.ObjectivesThe aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD.MethodsTo induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment.ResultsCariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine.ConclusionsIn the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.

A Cluster Randomized Trial of Promoting Alternative Thinking Strategies (PATHS®) With Swedish Preschool Children.

The preschool edition of Promoting Alternative THinking Strategies (PATHS®) is a school-based, teacher implemented universal intervention developed in the United States designed to promote social emotional competence (SEC) in children as a foundation for improved mental health. PATHS is delivered as a curriculum and it is based on theories and research regarding SEC, brain development, and optimal school environments. A majority of children in Sweden attend preschool, which is government-subsidized and follows a national curriculum focusing on both academic and social emotional learning. However, there is not so much focus on formal instruction nor manual-based lessons. The purpose of this study was to assess the short-term (pre- to post-test) effects of PATHS in the Swedish preschool setting. Using a two-wave cluster randomized trial with multi-method and informant assessment (N = 285 4 and 5-year-old Swedish children; n = 145 wait-list control; n = 140 intervention; K = 26 preschools; k = 13 intervention; k = 13 control) we assessed changes in child emotional knowledge, emotional awareness, social problem solving, prosocial play, inhibitory control, and working memory using structural equation modeling (SEM). We included schools with at least one classroom of 4–5-year-old children from three municipalities. We excluded open preschools, parent cooperative preschools, and family day homes. After random assignment, schools were informed of condition assignment. Research team members were not blind to assignment. We hypothesized that relative to children in control schools, children in intervention schools would evidence improvements in social emotional competence as well as other outcomes. Children in PATHS, relative to children in the control, evidenced improvements in working memory and prosocial play, but also showed an increase in hyperactive behaviors. Girls in PATHS, relative to girls in the control, showed improvement in emotional knowledge and reduced anxiety. These results are considered in light of efforts to promote positive development and mental health. The trial registration number at ClinicalTrials.gov is NCT04512157. Main funding was from Swedish Council for Working Life and Social Research, the Swedish Research Council, Formas, and VINNOVA (dnr: 259-2012-71).

Factors associated with the decision to prescribe and administer antipsychotics for older people with delirium: a qualitative descriptive study

ObjectivesTo explore factors associated with decision-making of nurses and doctors in prescribing and administering as required antipsychotic medications to older people with delirium.DesignQualitative descriptive.SettingTwo acute care hospital organisations in Melbourne,...

Altering the development of the dopaminergic system through social play in rats: Implications for anxiety, depression, hyperactivity, and compulsivity

Dopamine is essential to many functions like reward, motivation, and attention; when its neural pathways do not function properly, various disorders (e.g., anxiety, depression, hyperactivity, compulsions) can arise. Truncated-DAT rats display persistent stereotypies and aggressiveness; hence they are a new valuable animal model to study the pathogenesis of these disorders. The focus of research is often on the individual epigenetic determinants and much less on the impact of social experiences. Here, we investigate the developmental impact of the social environment on adolescent wild type (WT) rats. We divided subjects at weaning into three groups: living with another adolescent (WT Peer), with a WT adult, or with a truncated-DAT one, and we observed homecage social behavior of these pairs (play, jump, victory, and “bullying”) during whole adolescence. When adult, we observed the same subjects in plus maze, forced swim, and social preference tests to measure levels of anxiety, depression, and quality of social interactions. Compared to the other groups, WT rats that had spent their adolescence with a truncated-DAT adult as companion show more anxious, depressive, hyperactive, impulsive, and compulsive behaviours. Results confirm that social interactions and healthy play (i.e., when play has behavioural, social, and psychomotor rewards that support the cognitive, emotional and physical development of the individual) are essential to neurobehavioral maturation. Conversely, anomalous interactions like poor play and “bullying” in developing rats may impact onto their dopaminergic system. Consequently, an impoverished social play could be one of the factors contributing to the appearance of putative indexes of attention deficit hyperactivity disorder (ADHD) and\\or obsessive–compulsive disorder (OCD).

High dose genistein in Sanfilippo syndrome: A randomised controlled trial.

The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P=.26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P=.0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

Does a Behavioral Parent Training Program for Parents of ADHD Children Improve Outcomes? A Pilot Project

ABSTRACT Attention Deficit Hyperactivity Disorder (ADHD) is the most common chronic neurobehavioral disorder of childhood. Research suggests increased parent–child conflict exists in families with an ADHD child. The evidence indicates links between child behavior problems and parenting practices. Behavioral Parent Training (BPT) is an evidence-based intervention recommended for the treatment of ADHD. BPT is recommended as first-line treatment in ADHD children under age six and as a combination treatment approach for children older than the age six. BPT programs have demonstrated significant improvement in frequency of the problem behaviors of inattention, hyperactivity, and impulsivity associated with ADHD. Pre- and Post-BPT Parenting Scales and Vanderbilt ADHD Diagnostic Rating Scales for Parents and Teachers were used to evaluate the efficacy of the BPT program. Percent changes for each participant pre- and post-BPT were calculated. The Parenting Scale overall score and overreactivity factor score showed significant improvement post-BPT (p = .05). Participation in a BPT program can affect parenting practices and improve outcomes for ADHD children. BPT programs are effective in reducing negative parenting practices and improving outcomes for this population.

Behavioral changes and hyperglycemia in NODEF mice following bisphenol S exposure are affected by diets

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 μg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 μg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L–cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 μg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.

Chanwuyi Lifestyle Medicine Program Alleviates Immunological Deviation and Improves Behaviors in Autism

Given the association between deviated inflammatory chemokines, the pathogenesis of autism spectrum disorders (ASD), and our previous findings of the Chanwuyi Lifestyle Medicine Program regarding improved cognitive and behavioral problems in ASD, the present study aims to explore if this intervention can alter pro-inflammatory chemokines concentration. Thirty-two boys with ASD were assigned to the experimental group receiving the Chanwuyi Lifestyle Medicine Program for 7 months or the control group without a change in their lifestyle. The experimental group, but not the control group, demonstrated significantly reduced CCL2 and CXCL8, a trend of reduction in CCL5, and elevation of CXCL9. The experimental group also demonstrated significantly reduced social communication problems, repetitive/stereotypic behaviors, and hyperactive behaviors. The present findings support the potential efficacy and applicability of the Chanwuyi Lifestyle Medicine Program for reducing both behavioral problems and immunological dysfunction in ASD. Further studies are warranted to verify its treatment effect and its association with brain functions.

Duration of breast feeding and attention-deficit/hyperactivity disorder in United States preschool-aged children

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by difficulties sustaining attention and controlling hyperactivity and impulsive behavior. Population-based studies concerning the association between breast-feeding duration and ADHD among preschool-aged children in the United States (U.S.) have been sparse. AimsTo determine whether there is an association between the duration of breast feeding and ADHD in U.S. children aged 2–5 years. Methods and proceduresWe used nationally representative data from the 2016, 2017, and 2018 National Survey of Children’s Health (NSCH) to examine the association between breast-feeding duration and ADHD in U.S. preschool-aged children. Sample characteristics were compared using Rao-Scott chi-square test, and adjusted prevalence odds ratios and 95 % confidence intervals were estimated using unconditional logistic regression. Outcomes and resultsOf the 20,453 children eligible for our study, 1.5 % had received a diagnosis of ADHD and 77.5 % were reported to have been fed human milk as infants. Prevalence odds of ADHD were 57 % lower among children fed human milk for 6–12 months compared to children never fed human milk after controlling for potential confounders. Among children with durations of breast feeding lasting less than 6 months or lasting 12 months or longer, prevalence odds of ADHD were not significantly lower than the comparison group, children who were never fed human milk, after controlling for potential confounders. Conclusions and implicationsWe noted an inverse association between breast feeding durations of 6–12 months and parent-reported diagnosis of ADHD in preschool-aged children in the U.S. Future studies should use longitudinal designs to examine ADHD and duration of breast-feeding measures.

Assessment of Mental Health Problems of School Children Using Self Report Strengths and Difficulties Questionnaire

Introduction: Psychological disorders among children and adolescents are the least discussed health problems in pediatrics. There is limited data on the prevalence of mental health problems among adolescents in low-income countries like Nepal. This study intended to find the prevalence of mental health problems among school children in a secondary school in western Nepal. Methods: In this descriptive cross-sectional study, students of grades six to eleven of two private schools of a district in Nepal were randomly selected. The self-rated version of Goodman’s Strength and Difficulty Questionnaire were used to assess mental health problem in these adolescents. Outcomes were measured in a scale of zero to 10 for each of emotional, conduct, hyperactivity, peer problem and pro-social behavior. Difficulty scale and its impact on life were also measured. Results: Out of 902 students, 5% (n=49) had significant and 14% (n=127) had probable mental health problem. Peer problems was the commonest (25%) followed by emotional (15%) and conduct problem (15%) and hyperactivity and pro-social problems were seen in 7% each. Boys had more mental health problem than girls except emotional problem. Mental health problem was more common in lower grade or younger age students. Its impact on life were 0-7.4%. Abnormal internalizing and externalizing problems were reported in 20% and 11% respectively. Conclusion: Mental health problem was prevalent (5 to 25%) in secondary school children. Screening school children for the same would be beneficial for early diagnosis.

ADHD Symptomatology, Executive Function and Cognitive Performance Differences between Family Foster Care and Control Group in ADHD-Diagnosed Children.

Children in foster care have a high prevalence of attention deficit and hyperactivity disorder (ADHD) diagnosis, together with other difficulties in inattentive/hyperactive behaviors, executive and cognitive processes. Early exposure to adversity is a risk factor for developing ADHD via neurodevelopmental pathways. The goal of this research is (a) to study the cognitive and executive performance and inattentive/hyperactive behavior of ADHD-diagnosed children living in foster families in Spain, and (b) to analyze the role of placement variables in their performance. The sample was composed of 102 ADHD-diagnosed children aged 6- to 12-years-old, divided into two groups: 59 children living with non-relative foster families and 43 children not involved with protection services. Children’s executive function–inhibition, working memory, flexibility, attention, intellectual capacity, verbal comprehension, perceptive reasoning, working memory and processing speed were assessed using objective testing measures. At the same time, parents and teachers reported on children’s inattentive, hyperactive and impulsive behaviors. Children in foster care obtained lower scores in the general ability index than the control group after controlling the age at assessment. However, no differences were found in executive processes. Regarding placement factors, children with shorter exposure to adversities in their birth families and more time in foster care showed better executive performance. Professionals should consider the placement history of children in foster care and its influence on their symptomatology and cognitive capacities.

Attention deficit hyperactivity disorder (ADHD) symptoms, comorbid psychopathology, behaviour problems and gastrointestinal symptoms in children and adolescents with autism spectrum disorder.

The study aims to investigate attention deficit hyperactivity disorder (ADHD) symptoms, gastrointestinal (GI) symptoms, comorbid psychopathology and behaviour problems in children and adolescents with autism spectrum disorder (ASD). Parents of 147 children and adolescents with ASD aged 6-18 years completed the Conners 3 Parent-Short Form, Gastrointestinal Symptom Inventory, Behavior Problems Inventory-Short Form and Autism Spectrum Disorder-Comorbid for Children. Fifty-six per cent of children and adolescents had a comorbid diagnosis of ADHD, yet over 70% presented with clinically significant ADHD symptoms. Forty per cent of participants received a diagnosis of ADHD before ASD and 25.6% received a diagnosis of ASD first. Relationships were found between ADHD symptoms and comorbid psychopathology, GI symptoms, and behaviour problems. The outcomes suggest that ADHD is being underestimated as a comorbid disorder of ASD. This may have implications on treatment and interventions for children and adolescents who have a diagnosis of both ASD and ADHD.

Hyperactive behaviour in Angelman syndrome: the association with sleep problems and age of epilepsy onset

AbstractBackgroundSleep problems are common in many neurodevelopmental disorders, but little is known about how sleep is related to behavioural symptoms in Angelman syndrome (AS) or other genetic disorders. Hyperactive behaviour, sleep problems and epilepsy seem to be more common in AS than in other genetic conditions associated with severe intellectual disability. We hypothesised that both more sleep problems and earlier onset of epileptic seizures would predict more symptoms of hyperactivity. Hence, the aim of the project was to explore the association between hyperactive behaviour, sleep problems and age of epilepsy onset in individuals with AS.MethodAll known parents/guardians (n = 115) of individuals with AS in Norway were invited to participate in this descriptive correlational study. Fifty‐six individuals (49%) responded, and 42 people (25 male and 17 female; mean age 18.5 years, range 2–57 years) with genetically verified AS were included. Scores for ‘hyperactivity’ and ‘sleep problems’ were derived from questionnaire data. Information on epilepsy was obtained from medical records.Results‘Hyperactivity’ was positively correlated with ‘total sleep problems’ (r = 0.46, P = 0.002) and negatively correlated with ‘age of epilepsy onset’ (r = −0.47, P = 0.01). ‘Age of epilepsy onset’ was not correlated with ‘total sleep problems’. An overall multiple regression model with ‘hyperactivity’ as the dependent variable and ‘age of epilepsy onset’ and ‘total sleep problems’ as covariates was significant (R2 = 0.39, F = 8.16, P = 0.002). Hence, hyperactivity in AS could be predicted from both age of epilepsy onset and current sleep problems.ConclusionsSleep problems may increase hyperactivity symptoms in individuals with AS. The association between hyperactivity and sleep problems in AS indicates that both should be investigated together as part of routine clinical assessment and intervention for either area of difficulty. Younger age of epilepsy onset was associated with more hyperactivity in AS, which may be related to encephalopathic effects of seizures and epilepsy.

A Case of Definitive Therapy in Persistent Congenital Hyperthyroidism Secondary to an Activating Variant of the TSHR Gene

Background: Sporadic congenital non-autoimmune hyperthyroidism (SCNAH) causes permanent hyperthyroidism secondary to activating mutations in the TSHR gene. SCNAH usually presents during infancy and can be difficult to treat with antithyroid drugs or subtotal thyroidectomy.1 When adequate therapy is delayed, irreversible sequela such as craniosynostosis, growth failure, and cognitive delays may develop. Definitive therapy for children with SCNAH is recommended with no consensus on timing or type of intervention. Our case highlights the importance of early total thyroidectomy to optimize clinical outcomes in patients with SCNAH.Clinical case: A now 3-year-old male was born small for gestational age (SGA) at 34 weeks gestation with biochemical and clinical signs of hyperthyroidism in the neonatal period. On day of life 6, his TSH was 0.02 mcU/mL (reference range 0.34-5.6 mcU/mL) and free thyroxine (T4) was 5.42 ng/dL (reference range 0.58-1.64 ng/dL). Methimazole (MMI) 0.3 mg/kg/day was started at that time, and the dose was titrated over 6 weeks of life to 0.8 mg/kg/day due to continued elevation of free T4 levels. Negative thyroid autoantibodies and normal maternal thyroid studies prompted genetic testing at 3 months of age. This testing revealed a heterozygous variant in the TSHR gene [c.842G->A (p.G116R)] that was determined to be pathologic. Despite frequent MMI dose changes and confirmation of medication adherence, high-dose MMI was not effective in consistently normalizing his TSH and free T4 levels in the first two years of life. Concerns for poor growth and hyperactive behavior were also present. A “block and replace” strategy was not feasible since the patient remained hyperthyroid even at MMI doses up to 0.8 mg/kg/day. Despite normal insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels, poor linear growth persisted with a height Z-score of -3.61 by age 3 years. While he was SGA at birth, his recurrent hyperthyroidism impeded catch-up growth potential, so treatment with growth hormone (rhGH) was initiated. His height Z-score improved to -2.39 after 9 months on rhGH dosed at 0.18 mg/kg/week. Due to the difficulty in consistently managing him medically with MMI, he underwent total thyroidectomy at age three.Conclusion: There is currently no consensus on the timing of definitive therapy for children with SCNAH. This case highlights the importance of considering total thyroidectomy at an early age to avoid long-term sequela of persistent hyperthyroidism.1. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322:125–34.

Neurodegeneration and Reduced Muscle Innervation in a Mouse Model Lacking the SPECC1L C‐terminal Actin‐Binding Domain

SPECC1L cytoskeletal protein is known to associate with microtubules via its second coiled coil domain and with actin filaments via a C-terminal calponin homology domain (CHD). Autosomal dominant point mutations in SPECC1L cluster in these two domains and result in a range of defects, including craniofacial malformations, omphalocele, as well as intellectual disability and autism. To study SPECC1L function, we generated many mouse alleles, including one with truncation of the C-terminal 510 amino acids that also removes CHD (ΔC510). Homozygous ΔC510 mutants are perinatal lethal while heterozygotes (hets) are viable and fertile. We noticed that some ΔC510 hets showed hyperactive behavior in their cages. A systematic actimeter-based analysis showed that these hyperactive ΔC510 hets travelled more distance and showed more stereotypies than non-hyperactive hets and wildtype. Interestingly, all hyperactive ΔC510 hets were females. Additional analyses with ΔC510 hets identified significant differences in marble burying and aspects of social chamber interaction, as well as poor performance on grip strength and inverted screen tests. The latter two measurements assessing muscle strength were significantly reduced in male ΔC510 hets. While SPECC1L is broadly expressed, its expression was strongest in cerebellar Purkinje cells and in nerves innervating the muscle. A detailed analysis of ΔC510 het cerebellums showed a significant loss of Purkinje cells. However, female ΔC510 hets showed a significant decrease in posterior lobes, which are associated with motor function and hyperactivity, while male ΔC510 hets showed a greater loss in anterior lobes associated with muscle strength and hypotonia. We also identified a significant decrease in the number of fully innervated neuromuscular junctions (NMJs) distally in both ΔC510 het adults and in E18.5 embryos, indicating abnormal NMJ development. At the molecular level, we identified that both wildtype and ΔC510proteins strongly associated with neurofilaments. In ΔC510 hets, the truncated SPECC1L and neurofilaments are abnormally expressed in the cerebellar molecular layer at presynaptic terminals. We propose that SPECC1L is required for normal localization of neurofilaments, and that loss of actin binding leads to abnormal presynaptic localization resulting in both Purkinje cell degeneration and poor NMJ innervation. Our results present novel neuronal function of SPECC1L and provide mechanistic insights into the underpinnings of the neuronal deficits observed in patients with SPECC1L mutations.

주의력 결핍 과잉행동장애(ADHD) 아동의 운동 중재 효과에 대한 메타분석

Purpose: The purpose of this study is to meta-analyze the effect of exercise intervention for ADHD children.<BR> Method: Meta-analysis was conducted on 21 papers selected through the literature review process. Analysis was performed using the CMA 3.0 program. Heterogeneity tests were performed using the Q test and I² statistic. Subgroup analysis and meta-regression analysis were also performed.<BR> Results: First, the overall effect size of the exercise intervention paper for children with ADHD was found to be the medium effect size (ES=.706). Second, exercise intervention had a medium effect size on major symptoms of ADHD (hyperactivity & problem behavior, attention, suppression of response, and performance function). Third, it was found that outdoor exercise had a higher effect on symptoms than indoor exercise. Fourth, a large effect size was found in the frequency of exercise participation per week (2 times, 5 times) and exercise participation time per session (40-50 minutes).<BR> Conclusion: The results of this study are significant in providing an academic basis for the positive effects of continuous exercise participation in ADHD children.