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Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.
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Transtorno do Espectro Autista , Transtorno Autístico , Adulto , Masculino , Humanos , Ocitocina , Transtorno Autístico/tratamento farmacológico , Citocinas , Interleucina-7 , Interleucina-9/uso terapêutico , Método Duplo-Cego , Transtorno do Espectro Autista/tratamento farmacológico , Administração Intranasal , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
AIM: Autism spectrum disorder (ASD) is associated with abnormal lipid metabolism, such as a high total ratio of omega-6 to omega-3 in polyunsaturated fatty acids (PUFAs). PUFAs are metabolized to epoxy fatty acids by cytochrome P450 (CYP); then, dihydroxy fatty acid is produced by soluble epoxide hydrolase. This study examined the association between PUFA metabolites in the cord blood and ASD symptoms and adaptive functioning in children. METHODS: This prospective cohort study utilized cord blood to quantify PUFA metabolites of the CYP pathway. The Autism Diagnostic Observation Schedule (ADOS-2) and Vineland Adaptive Behaviors Scales, Second Edition (VABS-II) were used to assess subsequent ASD symptoms and adaptive functioning in children at 6 years. The analysis included 200 children and their mothers. RESULTS: Arachidonic acid-derived diols, 11,12-diHETrE was found to impact ASD symptom severity on the ADOS-2-calibrated severity scores and impairment in the socialization domain as assessed by the VABS-II (P = 0.0003; P = 0.004, respectively). High levels of 11,12-diHETrE impact social affect in ASD symptoms (P = 0.002), while low levels of 8,9-diHETrE impact repetitive/restrictive behavior (P = 0.003). Notably, there was specificity in the association between diHETrE and ASD symptoms, especially in girls. CONCLUSION: These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth. Given that the role of diol metabolites in neurodevelopment in vivo is completely uncharacterized, the results of this study provide important insight into the role of diHETrE and ASD pathophysiology.
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The social motivation hypothesis of autism proposes that social communication symptoms in autism-spectrum disorder (ASD) stem from atypical social attention and reward networks, where dopamine acts as a crucial mediator. However, despite evidence indicating that individuals with ASD show atypical activation in extrastriatal regions while processing reward and social stimuli, no previous studies have measured extrastriatal dopamine D2/3 receptor (D2/3R) availability in ASD. Here, we investigated extrastriatal D2/3R availability in individuals with ASD and its association with ASD social communication symptoms using positron emission tomography (PET). Moreover, we employed a whole-brain multivariate pattern analysis of resting-state functional magnetic resonance imaging (fMRI) to identify regions where functional connectivity atypically correlates with D2/3R availability depending on ASD diagnosis. Twenty-two psychotropic-free males with ASD and 24 age- and intelligence quotient-matched typically developing males underwent [11C]FLB457 PET, fMRI, and clinical symptom assessment. Participants with ASD showed lower D2/3R availability throughout the D2/3R-rich extrastriatal regions of the dopaminergic pathways. Among these, the posterior region of the thalamus, which primarily comprises the pulvinar, displayed the largest effect size for the lower D2/3R availability, which correlated with a higher score on the Social Affect domain of the Autism Diagnostic Observation Schedule-2 in participants with ASD. Moreover, lower D2/3R availability was correlated with lower functional connectivity of the thalamus-superior temporal sulcus and cerebellum-medial occipital cortex, specifically in individuals with ASD. The current findings provide novel molecular evidence for the social motivation theory of autism and offer a novel therapeutic target.
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Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno Autístico/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Comunicação , Dopamina , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Vias Neurais , Tomografia por Emissão de PósitronsRESUMO
Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.
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Transtorno do Espectro Autista , Transtorno Autístico , Administração Intranasal , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/tratamento farmacológico , Disponibilidade Biológica , Método Duplo-Cego , Feminino , Humanos , Masculino , Sprays Nasais , Ocitocina , Coelhos , Resultado do TratamentoRESUMO
AIM: Little is known about early manifestations of autism spectrum disorders (ASD) in females, including those who may be overlooked by the current diagnostic criteria. We longitudinally explored sex differences in the trajectories of cognitive and motor functions and adaptive behaviors in children with different levels of autistic traits. METHODS: The participants were 824 children from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), Japan, who were classified into three autistic trait groups-low, moderate, and high-based on the Social Responsiveness Scale-Second Edition. Cognitive and motor functions were measured at seven time-points from 0.5 to 3.5 years of age using the Mullen Scales of Early Learning. Adaptive behaviors were measured at five time-points from 2.7 to 9 years of age using the Vineland Adaptive Behavior Scales-Second Edition. Trajectories were depicted using latent growth curve modeling. RESULTS: Sex-specific trajectories were observed in the high-autistic-trait group, with only males showing a temporary decline in expressive language around the age of 2 years and a slight improvement thereafter. They also showed a slight improvement around 3 years in the adaptive behavior communication domain but a gradual downward trend later. Females in the high-autistic-trait group showed no distinct manifestation before the age of 3 years but showed a downward trend after 3.5 years in the adaptive behavior communication domain. CONCLUSION: Females and males with higher autistic traits than their same-sex peers, independent of clinical diagnosis, may have different phenotypes in certain neurodevelopmental domains during infancy and early childhood.
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Transtorno do Espectro Autista , Transtorno Autístico , Criança , Pré-Escolar , Humanos , Masculino , Feminino , Caracteres Sexuais , Transtorno do Espectro Autista/genética , Desenvolvimento Infantil , MãesRESUMO
BACKGROUND: Mastering language involves the development of expressive and receptive skills among children. While it has been speculated that early temperament plays a role in the acquisition of language, the actual mechanism has not yet been explored. We investigated whether temperament at 18 months predicted expressive or receptive language skills at 40 months. METHODS: A representative sample of 901 children and their mothers who were enrolled and followed-up longitudinally in the Hamamatsu Birth Cohort for Mothers and Children study was included in the analysis. Child temperament was measured at 18 months using the Japanese version of the Early Childhood Behavior Questionnaire. Expressive and receptive language skills were measured at 40 months using the Mullen Scales of Early Learning. RESULTS: The multiple regression analysis, adjusting for potential confounders, suggested that higher motor activation (fidgeting) at 18 months was associated with lower expressive and receptive language skills at 40 months. Higher perceptual sensitivity was associated with higher expressive and receptive language skills at 40 months. CONCLUSIONS: Specific temperament at 18 months of age predicted the development of the child's expressive and receptive language skills at 40 months.
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Idioma , Temperamento , Criança , Pré-Escolar , Cognição , Feminino , Humanos , Desenvolvimento da Linguagem , MãesRESUMO
BACKGROUND: Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. METHODS: We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as <2000 g, 2000-2499 g, and ≥2500 g. Polygenic risk score for ADHD was generated using the summary data of a large-scale genome-wide association study. The Rating Scale IV (ADHD-RS) assessed ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Following previous studies, sex, birth order of the child, gestational age at birth, mother's age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during pregnancy smoking status, alcohol consumption during pregnancy, father's age, education, and annual family income were considered as covariates. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, while adjusting for potential covariates. The interaction term between birth weight categories and binary polygenic risk was added to the model. RESULTS: Birth weight of 2000-2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07-2.27) and hyperactivity (RR 1.87, 95% CI 1.14-3.06). CONCLUSIONS: Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Peso ao Nascer , Criança , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Japão/epidemiologia , GravidezRESUMO
OBJECTIVES: Motor planning is the cognitive process of planning necessary steps for achieving a purposeful movement and is specifically reflected through object manipulation. This study aimed to investigate whether fine motor skills, a surrogate of the motor planning ability of object manipulation, in early childhood are associated with later social skills, in a general-population birth cohort. METHODS: A total of 913 children, participating in the Hamamatsu Birth Cohort for Mothers and Children, were enrolled. Social skills were measured using the Vineland Adaptive Behavior Scales-II, Socialization domain, at age 6 years. Fine motor skills were measured using the Mullen Scales of Early Learning at 14, 24, and 32 months. The associations between fine motor skills at ages 14, 24, and 32 months and social skills at age 6 years were tested separately through multivariable linear regression after adjusting for covariates, including gross motor and language skills at the contemporaneous age, autistic symptoms at age 6 years, and demographic factors. RESULTS: Fine motor skills at 24 and 32 months were significantly associated with social skills at age 6 years (at 24 months: nonstandardized regression coefficient = 1.38 [95% CI, 0.50-2.26], p = 0.002; at 32 months: 1.47 [0.56-2.38], p = 0.001). CONCLUSION: Fine motor skills in early childhood predicted social skills at age 6 years, indicating an association between the complex motor planning ability of object manipulation and later social skills. Children who demonstrate fine motor delay at as early an age as 2 years should be closely monitored by child professionals.
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Destreza Motora , Habilidades Sociais , Pré-Escolar , Criança , Feminino , Humanos , Cognição , Aprendizagem , MãesRESUMO
Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder clinically characterized by abnormalities in eye contact during social exchanges. We aimed to clarify whether the amount of gaze fixation, measured at the age of 6 years using Gazefinder, which is an established eye-tracking device, is associated with ASD symptoms and functioning. Methods: The current study included 742 participants from the Hamamatsu Birth Cohort Study. Autistic symptoms were evaluated according to the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the functioning of the participating children in real life was assessed using the Japanese version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). The Gazefinder system was used for gaze fixation rates; two areas of interest (eyes and mouth) were defined in a talking movie clip, and eye gaze positions were calculated through corneal reflection techniques. Results: The participants had an average age of 6.06 ± 0.14 years (males: 384; 52%). According to ADOS, 617 (83%) children were assessed as having none/mild ASD and 51 (7%) as severe. The average VABS-II scores were approximately 100 (standard deviation = 12). A higher gaze fixation rate on the eyes was associated with a significantly lower likelihood of the child being assigned to the severe ADOS group after controlling for covariates (odds ratio [OR], 0.02; 95% confidence interval [CI], 0.002-0.38). The gaze fixation rate on the mouth was not associated with ASD symptoms. A higher gaze fixation rate on the mouth was associated with a significantly lower likelihood of the child being assigned to the low score group in VABS-II socialization after controlling for covariates (OR, 0.18; 95% CI, 0.04-0.85). The gaze fixation rate on the eyes was not associated with functioning. Conclusion: We found that children with low gaze fixation rates on the eyes were likely to have more ASD symptoms, and children with low gaze fixation rates on the mouth were likely to demonstrate poorer functioning in socialization. Hence, preschool children could be independently assessed in the general population for clinically relevant endophenotypes predictive of ASD symptoms and functional impairments.
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Whether longer screen time in infancy increases risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and ADHD has long been debated, but no causal relationship between the two remains has been established. Using ongoing longitudinal cohort data, we found that in children 24 to 40 months of age, the genetic risk of ASD was associated with longer screen time and that of ADHD with an increase in screen time over time. These data suggest that prolonged screen time may not be a cause of the genetic risk for NDD, but an early sign of NDDs.
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Transtornos do Neurodesenvolvimento , Tempo de Tela , Transtornos do Neurodesenvolvimento/genética , Humanos , Fatores de Risco , Masculino , Feminino , Pré-Escolar , Transtorno do Espectro Autista , Predisposição Genética para Doença , Estudos Longitudinais , Transtorno do Deficit de Atenção com HiperatividadeRESUMO
Importance: Whether the association between higher screen time in infancy and later suboptimal neurodevelopment can be mitigated by frequency of outdoor play is unknown. Objective: To investigate whether higher screen time at age 2 years is associated with neurodevelopmental outcomes at age 4 years and whether this association is mediated by frequency of outdoor play at age 2 years 8 months. Design, Setting, and Participants: Participants were a subsample of the Hamamatsu Birth Cohort Study for Mothers and Children (HBC Study, N = 1258). Children were born between December 2007 and March 2012 and followed up from 1 year 6 months to 4 years. The analysis was conducted from April 2021 to June 2022. Exposures: Screen time longer than 1 hour a day at age 2 years was coded as higher screen time. Main Outcomes and Measures: Standardized scores for communication, daily living skills, and socialization domains of the Vineland Adaptive Behavior Scale, second edition, at age 4 years were used (mean [SD], 100 [15]). The mediating factor was frequency of outdoor play at age 2 years 8 months, with 6 or 7 days per week coded as frequent outdoor play. Results: Of 885 participants, 445 children (50%) were female; mean (SD) screen time per day was 2.6 (2.0) hours. Causal mediation analyses revealed that higher screen time at age 2 years was associated with lower scores in communication at age 4 years (nonstandardized coefficient b = -2.32; 95% CI, -4.03 to -0.60), but the association was not mediated by frequency of outdoor play. Higher screen time was also associated with lower scores in daily living skills (b = -1.76; 95% CI, -3.21 to -0.31); 18% of this association was mediated by frequency of outdoor play. Frequency of outdoor play was associated with socialization (b = 2.73; 95% CI, 1.06 to 4.39), whereas higher screen time was not (b = -1.34; 95% CI, -3.05 to 0.36). Conclusions and Relevance: Higher screen time at age 2 years was directly associated with poorer communication at age 4 years. It was also associated with daily living skills, but frequency of outdoor play at age 2 years 8 months alleviated it, suggesting outdoor play mitigated the association between higher screen time and suboptimal neurodevelopment. Future research should specify the nature of the associations and intervention measures, enabling targeted interventions that reduce the potential risk in screen time.
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Comunicação , Mães , Humanos , Criança , Feminino , Pré-Escolar , Masculino , Estudos de Coortes , Tempo de TelaRESUMO
OBJECTIVE: Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction. METHODS: This case-control study used positron emission tomography (PET) with 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF), a radioligand that binds to the mitochondrial electron transport chain complex I, to examine the topographical distribution of mitochondrial dysfunction in living brains of individuals with ASD. Twenty-three adult males with high-functioning ASD, with no psychiatric comorbidities and free of psychotropic medication, and 24 typically developed males with no psychiatric diagnoses, matched with the ASD group on age, parental socioeconomic background, and IQ, underwent [18F]BCPP-EF PET measurements. Individuals with mitochondrial disease were excluded by clinical evaluation and blood tests for abnormalities in lactate and pyruvate levels. RESULTS: Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [18F]BCPP-EF availability specifically in the anterior cingulate cortex compared with typically developed participants. The regional specificity was revealed by a significant interaction between diagnosis and brain regions. Moreover, the lower [18F]BCPP-EF availability in the anterior cingulate cortex was significantly correlated with the more severe ASD core symptom of social communication deficits. CONCLUSIONS: This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.
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Transtorno do Espectro Autista , Transtorno Autístico , Encefalopatias , Masculino , Adulto , Humanos , Transtorno Autístico/diagnóstico por imagem , Transtorno do Espectro Autista/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Estudos de Casos e Controles , Piridinas/metabolismo , Tomografia por Emissão de Pósitrons , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Ácido Láctico/metabolismoRESUMO
Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (ß [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (ß [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (ß [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (ß [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; ß [SE], 0.664[0.152]; P < 0.001 for the high-risk group). Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD.
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The ability of humans to use rules for organizing action demands a high level of executive control. Situational complexity mediates rule selection, from the adoption of a given rule to the selection of complex rules to achieve an appropriate response. Several rules have been proposed to be superordinate to human behavior in a cognitive hierarchy and mediated by different brain regions. In the present study, using a novel rule-selection task based on pre-response evaluations that require several cognitive operations, we examined whether the task is mediated by a specific region of the prefrontal cortex using near-infrared spectroscopy. We showed that the selection of rules, including prior evaluation of a stimulus, activates broader areas of the prefrontal and premotor regions than response selection based on a given rule. The results are discussed in terms of hierarchical cognitive models, the functional specialization of multiple-cognitive operations in the prefrontal cortex, and their contribution to a novel cognitive task.
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Córtex Pré-Frontal , Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Córtex Pré-Frontal/diagnóstico por imagem , Função Executiva , EspecializaçãoRESUMO
It is unclear whether neurodevelopmental progress from infancy to early childhood remains stable. Moreover, little is known about the risk factors, if any, affecting neurodevelopmental descending transition patterns and the relationship between these patterns and later childhood adaptive behaviours. We used data of 875 children from the Hamamatsu Birth Cohort Study in Japan. Children's neurodevelopment at 18 and 32 months and adaptive behaviours at 40 months were evaluated. Perinatal factors and infant overweight status at 18 months were investigated to identify descending-transition-associated risk factors. In the latent transition analysis, ultimately, three classes were identified for each time-point, resulting in nine transition patterns; among them, 10.4% of children showed descending class shifts (normal to delayed class). Such decelerated growth was predicted by maternal pre-pregnancy overweight status (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.23, 5.02), low maternal educational history (OR 1.20; 95% CI 1.04, 1.36), and infant overweight status at 18 months (OR 5.89; 95% CI 1.26, 27.45). Children with descending transition showed poor functioning in adaptive behaviours at the age of 40 months. To prevent subsequent poor adaptive functioning, it may be necessary to consider that a certain percentage of children show decelerated growth.
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Sobrepeso , Obesidade Infantil , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Razão de Chances , Sobrepeso/epidemiologia , Sobrepeso/etiologia , Obesidade Infantil/complicações , Gravidez , Fatores de RiscoRESUMO
BACKGROUND: Maternal postpartum depression (PPD) is a well-established risk factor for psychological problems in children; however, little is known about the sustained impact of persistent PPD patterns and severity on these problems in children. METHODS: Data were obtained from mothers (N = 714) and children (N = 768) from the Hamamatsu Birth Cohort for Mothers and Children. Maternal depression was measured using the Edinburgh Postpartum Depression Scale at 2, 4, 10 weeks and 10 months postpartum. Children's internalizing and externalizing problems were assessed using the Strengths and Difficulties Questionnaire at 6 years and 8-9 years old. Mothers were divided into 4 groups based on the trajectory of their PPD persistence: "No PPD," "Transient PPD," "Worsening PPD" and "Persistent PPD." Linear regression analysis was used to examine the association of PPD persistence and severity with children's internalizing and externalizing problems. RESULTS: "Persistent PPD" was significantly associated with children's internalizing problems at 6 years old (Coefficient [95%CI] = 2.74 [1.30-4.19], P < .001), but no association was found at 8-9 years old. No associations were found between PPD severity and children's internalizing and externalizing problems in either age category. LIMITATIONS: "Persistent PPD" and "Worsening PPD" groups had a relatively small sample size. The mothers' depression statuses were not ascertained simultaneously with the children's behavioral assessments. There was no information regarding the mothers' treatment for PPD. CONCLUSION: PPD persistence negatively affected children's internalizing problems but was not long-lasting. Future studies are needed to identify protective factors against PPD persistence in children's psychological problems.
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Transtornos do Comportamento Infantil , Depressão Pós-Parto , Criança , Transtornos do Comportamento Infantil/psicologia , Depressão , Depressão Pós-Parto/psicologia , Feminino , Humanos , Mães/psicologiaRESUMO
Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)-a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales-Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.
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Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated. Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory. Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (ß[SE], -1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (ß[SE], -2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (ß[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (ß[SE], -2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children. Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.
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INTRODUCTION: Accumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet. METHODS: This study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8-9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB). RESULTS: Umbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081-1.556, p = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206-2.055, p = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000-1.004, p = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000-1.004, p = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000-1.003, p = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant. DISCUSSION: The present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms.
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Atypical eye gaze is an established clinical sign in the diagnosis of autism spectrum disorder (ASD). We propose a computerized diagnostic algorithm for ASD, applicable to children and adolescents aged between 5 and 17 years using Gazefinder, a system where a set of devices to capture eye gaze patterns and stimulus movie clips are equipped in a personal computer with a monitor. We enrolled 222 individuals aged 5-17 years at seven research facilities in Japan. Among them, we extracted 39 individuals with ASD without any comorbid neurodevelopmental abnormalities (ASD group), 102 typically developing individuals (TD group), and an independent sample of 24 individuals (the second control group). All participants underwent psychoneurological and diagnostic assessments, including the Autism Diagnostic Observation Schedule, second edition, and an examination with Gazefinder (2 min). To enhance the predictive validity, a best-fit diagnostic algorithm of computationally selected attributes originally extracted from Gazefinder was proposed. The inputs were classified automatically into either ASD or TD groups, based on the attribute values. We cross-validated the algorithm using the leave-one-out method in the ASD and TD groups and tested the predictability in the second control group. The best-fit algorithm showed an area under curve (AUC) of 0.84, and the sensitivity, specificity, and accuracy were 74, 80, and 78%, respectively. The AUC for the cross-validation was 0.74 and that for validation in the second control group was 0.91. We confirmed that the diagnostic performance of the best-fit algorithm is comparable to the diagnostic assessment tools for ASD.