Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual developmental disorder (IDD), are highly prevalent and lack effective treatments, posing significant health challenges. These disorders are frequently comorbid with disruptions in sleep rhythms, and sleep-related indicators are often used to assess disease severity and treatment efficacy. Recent evidence has highlighted the crucial roles of circadian rhythm disturbances and circadian clock gene mutations in the pathogenesis of NDDs. This review focuses on the mechanisms by which circadian rhythm disruptions and circadian clock gene mutations contribute to cognitive, behavioral, and emotional disorders associated with NDDs, particularly through the dysregulation of dopamine system. Additionally, we discussed the potential of targeting the circadian system as novel therapeutic strategies for the treatment of NDDs.
Humans ; Neurodevelopmental Disorders/genetics* ; Attention Deficit Disorder with Hyperactivity/genetics* ; Circadian Rhythm/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation ; Intellectual Disability/genetics* ; Circadian Clocks/physiology* ; Dopamine/metabolism*

This study investigated the effects of Rehmanniae Radix Praeparata on striatal neuronal apoptosis in rats with attention deficit hyperactivity disorder(ADHD) based on the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X protein(Bax)/caspase-3 signaling pathway. Twenty-four 3-week-old male spontaneously hypertensive rats(SHR) were randomly divided into a model group, a methylphenidate group(2 mg·kg~(-1)·d~(-1)), and a Rehmanniae Radix Praeparata group(2.4 mg·kg~(-1)·d~(-1)). Age-matched male Wistar Kyoto(WKY) rats were used as the normal control group, with 8 rats in each group. The rats were administered by gavage for 28 days. Body weight and food intake were recorded for each group. The open field test and elevated plus maze test were used to assess hyperactivity and impulsive behaviors. Nissl staining was used to detect changes in striatal neurons and Nissl bodies. Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) fluorescence staining was used to detect striatal cell apoptosis. Western blot was employed to detect the expression levels of Bcl-2, Bax, and caspase-3 proteins in the striatum. The results showed that compared with the model group, Rehmanniae Radix Praeparata significantly reduced the total movement distance, average movement speed, and central area residence time in the open field test, and significantly reduced the ratio of open arm entries, open arm stay time, and head dipping in the elevated plus maze test. Furthermore, it increased the number of Nissl bodies in striatal neurons, significantly downregulated the apoptosis index, significantly increased Bcl-2 protein expression and the Bcl-2/Bax ratio, and reduced Bax and caspase-3 protein expression. In conclusion, Rehmanniae Radix Praeparata can reduce hyperactivity and impulsive behaviors in ADHD rats. Its mechanism may be related to the regulation of the Bcl-2/Bax/caspase-3 signaling pathway in the striatum, enhancing the anti-apoptotic capacity of striatal neurons.
Animals ; Male ; Apoptosis/drug effects* ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Caspase 3/genetics* ; Proto-Oncogene Proteins c-bcl-2/genetics* ; bcl-2-Associated X Protein/genetics* ; Rehmannia/chemistry* ; Attention Deficit Disorder with Hyperactivity/physiopathology* ; Signal Transduction/drug effects* ; Neurons/cytology* ; Rats, Inbred SHR ; Rats, Inbred WKY ; Humans ; Corpus Striatum/cytology* ; Plant Extracts

OBJECTIVES: To investigate the relationship between the polygenic risks for various psychiatric disorders and clinical and neuropsychological characteristics in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Using a cross-sectional design, 285 children with ADHD and 107 healthy controls were assessed using the Child Behavior Checklist, the Behavior Rating Inventory of Executive Function for parents, the Wechsler Intelligence Scale for Children, Fourth Edition, and the Cambridge Neuropsychological Test Automated Battery. Blood samples were collected for genetic data. Polygenic risk scores (PRSs) for various psychiatric disorders were calculated using the PRSice-2 software. RESULTS: Compared with the healthy controls, the children with ADHD displayed significantly higher PRSs for ADHD, major depressive disorder, anxiety disorder, and obsessive-compulsive disorder (P<0.05). In terms of daily-life executive function, ADHD-related PRS was significantly correlated with the working memory factor; panic disorder-related PRS was significantly correlated with the initiation factor; bipolar disorder-related PRS was significantly correlated with the shift factor; schizophrenia-related PRS was significantly correlated with the inhibition, emotional control, initiation, working memory, planning, organization, and monitoring factors (P<0.05). The PRS related to anxiety disorders was negatively correlated with total IQ and processing speed index (P<0.05). The PRS related to obsessive-compulsive disorder was negatively correlated with the processing speed index and positively correlated with the stop-signal reaction time index of the stop-signal task (P<0.05). CONCLUSIONS PRSs for various psychiatric disorders are closely correlated with the behavioral and cognitive characteristics in children with ADHD, which provides more insights into the heterogeneity of ADHD.
Humans ; Attention Deficit Disorder with Hyperactivity/genetics* ; Child ; Male ; Female ; Cross-Sectional Studies ; Neuropsychological Tests ; Multifactorial Inheritance ; Adolescent ; Mental Disorders/etiology* ; Executive Function ; Genetic Risk Score

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.
Adult ; Child ; Humans ; Adrenergic Uptake Inhibitors/therapeutic use* ; Atomoxetine Hydrochloride/therapeutic use* ; Attention Deficit Disorder with Hyperactivity/genetics* ; Cytochrome P-450 CYP2D6/therapeutic use* ; Drug Monitoring ; Genetic Testing ; Propylamines/therapeutic use* ; Treatment Outcome

Attention deficit hyperactivity disorder (ADHD) is a form of neuronal dysplasia featuring high hereditary (up to 76%). This paper reviews recent progress made in genetic research on the cognitive function in ADHD. Two aspects of cognitive function were explored from the perspective of genetics, including intelligence and executive function.
Attention Deficit Disorder with Hyperactivity ; genetics ; Cognition ; Executive Function ; Genetic Research ; Humans ; Intelligence

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.
Attention Deficit Disorder with Hyperactivity ; diagnostic imaging ; genetics ; pathology ; Brain ; diagnostic imaging ; Cerebellum ; diagnostic imaging ; Child ; Corpus Striatum ; diagnostic imaging ; Female ; Frontal Lobe ; diagnostic imaging ; Genotype ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Minisatellite Repeats ; genetics ; Neural Pathways ; diagnostic imaging ; Oxygen ; blood ; Receptors, Dopamine D4 ; genetics ; metabolism ; Rest

OBJECTIVETo explore common biological pathways for attention deficit hyperactivity disorder (ADHD) and low birth weight (LBW).

METHODSThei-Gsea4GwasV2 software was used to analyze the result of genome-wide association analysis (GWAS) for LBW (pathways were derived from Reactome), and nominally significant (P< 0.05, FDR< 0.25) pathways were tested for replication in ADHD.Significant pathways were analyzed with DAPPLE and Reatome FI software to identify genes involved in such pathways, with each cluster enriched with the gene ontology (GO). The Centiscape2.0 software was used to calculate the degree of genetic networks and the betweenness value to explore the core node (gene). Weighed gene co-expression network analysis (WGCNA) was then used to explore the co-expression of genes in these pathways.With gene expression data derived from BrainSpan, GO enrichment was carried out for each gene module.

RESULTSEleven significant biological pathways was identified in association with LBW, among which two (Selenoamino acid metabolism and Diseases associated with glycosaminoglycan metabolism) were replicated during subsequent ADHD analysis. Network analysis of 130 genes in these pathways revealed that some of the sub-networksare related with morphology of cerebellum, development of hippocampus, and plasticity of synaptic structure. Upon co-expression network analysis, 120 genes passed the quality control and were found to express in 3 gene modules. These modules are mainly related to the regulation of synaptic structure and activity regulation.

CONCLUSIONADHD and LBW share some biological regulation processes. Anomalies of such proces sesmay predispose to ADHD.

Attention Deficit Disorder with Hyperactivity ; etiology ; genetics ; Gene Ontology ; Gene Regulatory Networks ; Genome-Wide Association Study ; Humans ; Infant, Low Birth Weight

OBJECTIVE: ObjectiveaaWe evaluated the distribution of alpha-2A adrenergic receptor (ADRA2A) and catechol-o-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) among ADHD subtypes and other homogeneous patient populations including treatment-resistant cases and patients with high symptom severity. METHODS: Methodsaa121 ADHD patients aged 6-18 years were included in the study. Diagnosis and subtypes designation were confirmed using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and symptoms were evaluated using the Conners' Parent (CPRS) and Teacher Rating Scales (CTRS). The response to methylphenidate was assessed objectively using the Clinical Global Impression-Severity Scale (CGI-S) and Global Assessment of Functioning Scale (GAS) as well as the Continuous Performance (CPT) and Trail Making tests (TMT-A, B). Patients were genotyped for ADRA2A (rs1800544) and COMT (rs4680) SNPs by PCR/RFLP and compared to a gender-matched control group. RESULTS: Although there was no association of COMT (rs4680) SNP with symptoms or diagnosis, the ADRA2A polymorphism, low socioeconomic status (SES), and comorbid psychiatric diagnosis were all associated with poor response to methylphenidate in logistic regression analysis. CONCLUSION: Clinicians may consider adjuvant strategies when these negative factors are present to increase the success of tailored ADHD treatments in the future.
Appointments and Schedules ; Attention Deficit Disorder with Hyperactivity* ; Catechol O-Methyltransferase ; Diagnosis ; Genetic Variation* ; Genetics ; Humans ; Logistic Models ; Mental Disorders ; Methylphenidate ; Mood Disorders ; Parents ; Phenotype ; Polymorphism, Single Nucleotide ; Receptors, Adrenergic, alpha-2 ; Schizophrenia ; Social Class ; Trail Making Test ; Weights and Measures

OBJECTIVETo investigate the risk factors for attention deficit hyperactivity disorder (ADHD) and to provide a basis for future prevention and treatment of this disease.

METHODSFollowing a systematic search for case-control studies on the risk factors for ADHD in China between 2000 and 2014, relevant family risk factors were extracted accordingly. The quality of selected studies was evaluated according to the NOS scale. A Meta analysis on the selected studies was conducted using Stata 12.0 software.

RESULTSA total of 16 studies were selected, involving 2 167 children with ADHD and 2 148 normal controls. Results of Meta analysis showed that good parenting (OR=0.32, 95% CI: 0.26-0.40), nuclear family (OR=0.56, 95% CI: 0.41-0.76), high education level of father (OR=0.56, 95% CI: 0.41-0.76), high education level of mother (OR=0.65, 95% CI: 0.47-0.89), and extroversion of mother (OR=0.33, 95% CI: 0.18-0.61) are favorable factors for ADHD. Poor parental relationship (OR=1.90, 95% CI: 1.17-3.06) and family history of ADHD (OR=5.86, 95% CI: 3.67-9.35) are risk factors for ADHD.

CONCLUSIONSGood parenting, nuclear family, high education level of parents, and mother with extroversion are protective factors for ADHD, whereas poor parental relationship and family history of ADHD are associated with an increased risk for ADHD.

Attention Deficit Disorder with Hyperactivity ; etiology ; genetics ; Family ; Humans ; Risk Factors

OBJECTIVETo examine the association between CLOCK gene T3111C polymorphism with attention deficit hyperactivity disorder (ADHD) and ADHD related sleep disturbances in children.

METHODSOne hundred and sixty-six unrelated children with ADHD diagnosed according to DSM-IV criteria and a control group of 150 normal children were enrolled in this study. Parents filled out the Sleep Disturbance Scale for Children (SDSC). Genotype and allele frequencies of T3111C of the CLOCK gene were examined by PCR-restriction fragment length polymorphisms (PCR-RFLP).

RESULTSThere were significant differences in the genotype and allele frequencies of T3111C of the CLOCK gene between the ADHD and control groups (P<0.05). C allele frequency in the ADHD group was significantly higher than in the control group (χ2=7.254, P=0.007, OR=1.740, 95%CI=1.160-2.612). The ADHD children with sleep disturbances were found to have higher C allele frequency than those without sleep disturbances (χ2=13.052, P<0.001, OR=2.766, 95%CI=1.573-4.865).

CONCLUSIONSThere is an association between CLOCK gene T3111C polymorphism and both ADHD and related sleep disturbances in children. The individuals with C allele are susceptible to ADHD as well as ADHD related sleep disturbances.

Adolescent ; Attention Deficit Disorder with Hyperactivity ; complications ; genetics ; CLOCK Proteins ; genetics ; Child ; Child, Preschool ; Female ; Humans ; Male ; Polymorphism, Genetic ; Sleep Wake Disorders ; etiology ; genetics