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

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder influenced by both genetic and environmental factors, remains poorly understood regarding how its polygenic risk score (PRS) impacts functional networks and symptomology. This study capitalized on data from 11,430 children in the Adolescent Brain Cognitive Development study to explore the interplay between PRS_ADHD, brain function, and behavioral problems, along with their interactive effects. The results showed that children with a higher PRS_ADHD exhibited more severe attention deficits and rule-breaking problems, and experienced sleep disturbances, particularly in initiating and maintaining sleep. We also identified the central executive network, default mode network, and sensory-motor network as the functional networks most associated with PRS and symptoms in ADHD cases, with potential mediating roles. Particularly, the impact of PRS_ADHD was enhanced in children experiencing heightened sleep disturbances, emphasizing the need for early intervention in sleep issues to potentially mitigate subsequent ADHD symptoms.
Humans ; Attention Deficit Disorder with Hyperactivity/physiopathology* ; Male ; Female ; Sleep Wake Disorders/physiopathology* ; Adolescent ; Child ; Brain/diagnostic imaging* ; Multifactorial Inheritance ; Genetic Predisposition to Disease

OBJECTIVE: To characterize the traits of neuropsychological functioning deficits in patients with attention-deficit/ hyperactivity disorder (ADHD) with comorbid disruptive, impulse-control, and conduct disorders (DICCD). METHODS: Twenty out-patients with ADHD, 20 with ADHD with comorbid DICCD, and 20 with DICCD, all aged 6-16 years, were enrolled in this study, with 20 healthy subjects matched for age, gender and IQ serving as the healthy controls. The patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Revision (DSM-5). All the subjects were assessed with Golden Stroop test and emotional Stroop test to evaluate their response inhibition and emotional responding. RESULTS: In Golden Stroop test, the interference scores (IGs) of errors and reaction time both differed significantly among the groups ( < 0.05), and were the highest in patients with ADHD only. In emotional Stroop test, the mean reaction time (MRT) showed significant differences among the groups ( < 0.05); the MRT of positive- congruent trials in ADHD with comorbid DICCD group was shorter than that in ADHD group but longer than that in group DICCD; the MRT in the 3 case groups were all longer than that in the control group. The MRT of both positive-incongruent trials and negative-congruent trials in ADHD with comorbid DICCD group and DICCD group was shorter than that in ADHD group but longer than that in the control group. The MRT of negative- incongruent trials in DICCD group was shorter than that in ADHD group and ADHD with comorbid DICCD group but longer than that in the control group. CONCLUSIONS The response inhibition deficit and abnormal emotional responding are the core symptoms of ADHD. Bias emotional stimuli may render response inhibitory dysfunction in patients with DICCD with callous-unemotional traits of emotional responding disorder, especially in dealing with negative emotional trials, while the comorbidity of ADHD and DICCD tends to have the emotional response trait of DICCD.
Adolescent ; Attention Deficit Disorder with Hyperactivity ; diagnosis ; physiopathology ; Attention Deficit and Disruptive Behavior Disorders ; diagnosis ; physiopathology ; Case-Control Studies ; Child ; Comorbidity ; Diagnostic and Statistical Manual of Mental Disorders ; Emotions ; Humans ; Reaction Time ; Stroop Test

BACKGROUND: There have been inconsistent findings reported on maternal passive smoking during pregnancy and child risk of ADHD. In this study, ADHD symptoms at pre-school age children in association with prenatal passive and active tobacco smoke exposure determined by maternal plasma cotinine levels in the third trimester were investigated. METHODS: This was a follow-up study of the birth cohort: the Hokkaido Study on Environment and Children's Health. Children whose parents answered Strengths and Difficulties Questionnaire (SDQ) to identify child ADHD symptoms (hyperactivity/inattention and conduct problems) and total difficulties at age 5 years with available maternal plasma cotinine level at the third trimester were included (n = 3216). Cotinine levels were categorized into 4 groups; ≦ 0.21 ng/ml (non-smoker), 0.22-0.51 ng/ml (low-passive smoker), 0.52-11.48 ng/ml (high-passive smoker), and ≧ 11.49 ng/ml (active smoker). RESULTS: Maternal cotinine levels of active smokers were significantly associated with an increased risk of total difficulties (OR = 1.67) and maternal low- and high-passive smoking also increased the risk (OR = 1.11, 1.25, respectively) without statistical significance. Similarly, maternal cotinine levels of active smokers were associated with an increased risk of hyperactivity/inattention (OR = 1.49). Maternal low- and high-passive smoking and active smoking increased the risk of hyperactivity/inattention (OR = 1.45, 1.43, and OR = 1.59, respectively) only in boys. CONCLUSION Our findings suggested that maternal active smoking during pregnancy may contribute to the increased risk of child total difficulties and hyperactivity/inattention at pre-school age. Pregnant women should be encouraged to quit smoking and avoid exposure to tobacco smoke.
Adult ; Attention Deficit Disorder with Hyperactivity ; epidemiology ; etiology ; physiopathology ; psychology ; Child, Preschool ; Cotinine ; blood ; Female ; Follow-Up Studies ; Humans ; Japan ; epidemiology ; Male ; Maternal Exposure ; adverse effects ; Mothers ; Pregnancy ; Pregnancy Trimester, Third ; Prenatal Exposure Delayed Effects ; epidemiology ; etiology ; Risk ; Sex Factors ; Tobacco Smoking ; adverse effects ; epidemiology

Background:Previous studies have found that schoolchildren with attention-deficit/hyperactivity disorder (ADHD) showed difficulties in neuropsychological function. This study aimed to assess neuropsychological function in Chinese preschoolers with ADHD using broad neuropsychological measures and rating scales and to test whether the pattern and severity of neuropsychological weakness differed among ADHD presentations in preschool children.

Methods:The 226 preschoolers (163 with ADHD and 63 controls) with the age of 4-5 years were included and assessed using the Behavior Rating Scale of Executive Function-Preschool Version (BRIEF-P) and a series of tests to investigate neuropsychological function.

ResultsPreschoolers with ADHD showed higher scores in all domains of the BRIEF-P (inhibition: 30.64 ± 5.78 vs.20.69 ± 3.86, P < 0.001; shift: 13.40 ± 3.03 vs.12.41 ± 2.79, P = 0.039; emotional control:15.10 ± 3.53 vs.12.20 ± 2.46, P < 0.001; working memory: 28.41 ± 4.99 vs.20.95 ± 4.60, P < 0.001; plan/organize: 17.04 ± 3.30 vs.13.29 ± 2.40, P < 0.001) and lower scores of Statue (23.18 ± 7.84 vs.28.27 ± 3.18, P = 0.001), Word Generation (15.22 ± 6.52 vs.19.53 ± 7.69, P = 0.025), Comprehension of Instructions (14.00 ± 4.44 vs.17.02 ± 3.39, P = 0.016), Visuomotor Precision (P < 0.050), Toy delay (P = 0.048), and Matrices tasks (P = 0.011), compared with normal control. In terms of the differences among ADHD subtypes, all ADHD presentations had higher scores in several domains of the BRIEF-P (P < 0.001), and the ADHD-combined symptoms (ADHD-C) group had the poorest ratings on inhibition and the ability to Plan/Organize. For neuropsychological measures, the results suggested that the ADHD-C group had poorer performances than the ADHD-predominantly inattentive symptoms (ADHD-I) group on Statue tasks (F = 7.34, η = 0.12, P < 0.001). Furthermore, the ADHD-hyperactive/impulsive symptoms group had significantly poorer performances compared to the ADHD-C group in the Block Construction task (F = 4.89, η = 0.067, P = 0.003). However, no significant group differences were found between the ADHD-I group and normal control.

Conclusion:Based on the combined evaluation of performance-based neuropsychological tests and the BRIEF-P, preschoolers with ADHD show difficulties of neuropsychological function in many aspects.

Asian Continental Ancestry Group ; Attention Deficit Disorder with Hyperactivity ; physiopathology ; Behavior Rating Scale ; Child, Preschool ; Executive Function ; physiology ; Female ; Humans ; Male ; Neuropsychological Tests

The neurocircuitries that constitute the cortico-striato-thalamo-cortical (CSTC) circuit provide a framework for bridging gaps between neuroscience and executive function in attention deficit hyperactivity disorder (ADHD), but it has been difficult to identify the mechanisms for regulating emotional problems from the understanding of ADHD comorbidity with disruptive behavior disorders (DBD). Research based on "cool" and "hot" executive functional theory and the dual pathway models, which are thought of as applied response inhibition and delay aversion, respectively, within the neuropsychological view of ADHD, has shed light on emotional responding before and after decontextualized stimuli, while CSTC circuit-related domains have been suggested to explain the different emotional symptoms of ADHD with or without comorbid DBD. This review discusses the role of abnormal connections in each CSTC circuit, especially in the emotion circuit, which may be responsible for targeted executive dysfunction at the neuroscience level. Thus, the two major domains - abstract thinking (cool) and emotional trait (hot) - trigger the mechanism of onset of ADHD.
Animals ; Attention Deficit Disorder with Hyperactivity ; complications ; pathology ; psychology ; Attention Deficit and Disruptive Behavior Disorders ; complications ; pathology ; psychology ; Brain ; physiopathology ; Cerebral Cortex ; physiopathology ; Corpus Striatum ; physiopathology ; Emotions ; Humans ; Inhibition (Psychology) ; Neuropsychological Tests ; Thalamus ; physiopathology

OBJECTIVETo study the effect of baicalin on synaptosomal adenosine triphosphatase (ATPase) and lactate dehydrogenase (LDH) and its regulatory effect on the adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in rats with attention deficit hyperactivity disorder (ADHD).

METHODSA total of 40 SHR rats were randomly divided into five groups: ADHD model, methylphenidate hydrochloride treatment (0.07 mg/mL), and low-dose (3.33 mg/mL), medium-dose (6.67 mg/mL), and high-dose (10 mg/mL) baicalin treatment (n=8 each). Eight WKY rats were selected as normal control group. Percoll density gradient centrifugation was used to prepare brain synaptosomes and an electron microscope was used to observe their structure. Colorimetry was used to measure the activities of ATPase and LDH in synaptosomes. ELISA was used to measure the content of AC, cAMP, and PKA.

RESULTSCompared with the normal control group, the ADHD model group had a significant reduction in the ATPase activity, a significant increase in the LDH activity, and significant reductions in the content of AC, cAMP, and PKA (P<0.05). Compared with the ADHD model group, the methylphenidate hydrochloride group and the medium- and high-dose baicalin groups had a significant increase in the ATPase activity (P<0.05), a significant reduction in the LDH activity (P<0.05), and significant increases in the content of AC, cAMP, and PKA (P<0.05). Compared with the methylphenidate hydrochloride group, the high-dose baicalin group had significantly greater changes in these indices (P<0.05). Compared with the low-dose baicalin group, the high-dose baicalin group had a significant increase in the ATPase activity (P<0.05); the medium- and high-dose baicalin groups had a significant reduction in the LDH activity (P<0.05) and significant increases in the content of AC, cAMP, and PKA (P<0.05). Compared with the medium-dose baicalin group, the high-dose baicalin group had a significant increase in the ATPase activity (P<0.05).

CONCLUSIONSBoth methylphenidate hydrochloride and baicalin can improve synaptosomal ATPase and LDH activities in rats with ADHD. The effect of baicalin is dose-dependent, and high-dose baicalin has a significantly greater effect than methylphenidate hydrochloride. Baicalin exerts its therapeutic effect possibly by upregulating the AC/cAMP/PKA signaling pathway.

Adenosine Triphosphatases ; metabolism ; Adenylyl Cyclases ; physiology ; Animals ; Attention Deficit Disorder with Hyperactivity ; drug therapy ; physiopathology ; Cyclic AMP ; physiology ; Cyclic AMP-Dependent Protein Kinases ; physiology ; Flavonoids ; pharmacology ; therapeutic use ; L-Lactate Dehydrogenase ; metabolism ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Signal Transduction ; drug effects ; Synaptosomes ; chemistry ; ultrastructure

BACKGROUNDAccumulating evidence indicates that attention deficit hyperactivity disorder (ADHD) is associated with core deficits in executive function (EF) which predicts poorer academic and occupational functioning. This makes early intervention targeting EF impairments important to prevent long-term negative outcomes. Cognitive training is a potential ADHD treatment target. The present study aimed to explore the efficacy, feasibility, and acceptability of a cognitive training program (targeting child's multiple EF components and involving parent support in daily life), as a nonpharmacological intervention for children with ADHD.

METHODSForty-four school -age children with ADHD and their parents participated in 12 sessions of EF training (last for 12 weeks) and 88 health controls (HC) were also recruited. Training effects were explored using both neuropsychological tests (Stroop color-word test, Rey-Osterrieth complex figure test, trail making test, tower of Hanoi, and false-belief task) and reports of daily life (ADHD rating scale-IV, Conners' parent rating scale, and behavior rating inventory of executive function [BRIEF]) by analysis of paired sample t-test and Wilcoxon signed-rank test. The differences on EF performances between children with ADHD after training and HC were explored using multivariate analysis.

RESULTSThe results (before vs. after EF training) showed that after intervention, the children with ADHD presented better performances of EF both in neuropsychological tests (word interference of Stroop: 36.1 ± 14.6 vs. 27.1 ± 11.1, t = 4.731, P < 0.001; shift time of TMT: 194.9 ± 115.4 vs. 124.8 ± 72.4, Z = -4.639, P < 0.001; false-belief task: χ2 = 6.932, P = 0.008) and reports of daily life (global executive composite of BRIEF: 148.9 ± 17.5 vs. 127.8 ± 17.5, t = 6.433, P < 0.001). The performances on EF tasks for children with ADHD after EF training could match with the level of HC children. The ADHD symptoms (ADHD rating scale total score: 32.4 ± 8.9 vs. 22.9 ± 8.2, t = 6.331, P < 0.001) and behavioral problems of the children as reported by parents also reduced significantly after the intervention. Participants reported that the EF training program was feasible to administer and acceptable.

CONCLUSIONSThe EF training program was feasible and acceptable to children with ADHD and parents. Although replication with a larger sample and an active control group are needed, EF training program with multiple EF focus and parent involving in real-life activities could be a potentially promising intervention associated with significant EF (near transfer) and ADHD symptoms improvement (far transfer).

Attention Deficit Disorder with Hyperactivity ; physiopathology ; Child ; Executive Function ; physiology ; Female ; Humans ; Male ; Neuropsychological Tests

BACKGROUNDThe cognitive function of children with either attention deficit hyperactivity disorder (ADHD) or learning disabilities (LDs) is known to be impaired. However, little is known about the cognitive function of children with comorbid ADHD and LD. The present study aimed to explore the cognitive function of children and adolescents with ADHD and learning difficulties in comparison with children with ADHD and healthy controls in different age groups in a large Chinese sample.

METHODSTotally, 1043 participants with ADHD and learning difficulties (the ADHD + learning difficulties group), 870 with pure ADHD (the pure ADHD group), and 496 healthy controls were recruited. To investigate the difference in cognitive impairment using a developmental approach, all participants were divided into three age groups (6-8, 9-11, and 12-14 years old). Measurements were the Chinese-Wechsler Intelligence Scale for Children, the Stroop Color-Word Test, the Trail-Making Test, and the Behavior Rating Inventory of Executive Function-Parents (BRIEF). Multivariate analysis of variance was used.

RESULTSThe results showed that after controlling for the effect of ADHD symptoms, the ADHD + learning difficulties group was still significantly worse than the pure ADHD group, which was, in turn, worse than the control group on full intelligence quotient (98.66 ± 13.87 vs. 105.17 ± 14.36 vs. 112.93 ± 13.87, P < 0.001). The same relationship was also evident for shift function (shifting time of the Trail-Making Test, 122.50 [62.00, 194.25] s vs. 122.00 [73.00, 201.50] s vs. 66.00 [45.00, 108.00] s, P< 0.001) and everyday life executive function (BRIEF total score, 145.71 ± 19.35 vs. 138.96 ± 18.00 vs. 122.71 ± 20.45, P < 0.001) after controlling for the effect of the severity of ADHD symptoms, intelligence quotient, age, and gender. As for the age groups, the differences among groups became nonsignificant in the 12-14 years old group for inhibition (meaning interference of the Stroop Color-Word Test, 18.00 [13.00, 25.00] s vs. 17.00 [15.00, 26.00] s vs. 17.00 [10.50, 20.00] s , P = 0.704) and shift function (shifting time of the Trail-Making Test, 62.00 [43.00, 97.00] s vs. 53.00 [38.00, 81.00] s vs. 101.00 [88.00, 114.00] s, P = 0.778).

CONCLUSIONSChildren and adolescents with ADHD and learning difficulties have more severe cognitive impairment than pure ADHD patients even after controlling for the effect of ADHD symptoms. However, the differences in impairment in inhibition and shift function are no longer significant when these individuals were 12-14 years old.

Adolescent ; Attention Deficit Disorder with Hyperactivity ; physiopathology ; Child ; Cognition ; physiology ; Cross-Sectional Studies ; Executive Function ; physiology ; Female ; Humans ; Intelligence Tests ; Learning Disorders ; physiopathology ; Male

OBJECTIVETo investigate the cognitive characteristics in early school-age children with attention deficit hyperactivity disorder (ADHD) using event-related potential (ERP) and Achenbach Child Behavior Checklist (CBCL), as well as the correlation between ERP and behavioral problems.

METHODSA total of 22 children aged 6-7 years with ADHD and 19 healthy children matched by age were enrolled. Continue Performance Test-AX (CPT-AX) was performed for ERP test. The amplitude and latency of N2 and P3 of Go and Nogo were compared. The CBCL was completed by the parents, and the correlation between behavioral factors and ERP was analyzed.

RESULTSThe ADHD group had a significantly higher number of ERP omissions than the normal control group (10±8 vs 5±4; P<0.05), while the reaction time and number of commission errors showed no significant differences between the two groups (P>0.05). The ADHD group showed a significantly lower Go-N2 amplitude than the normal control group (-8±5 μV vs -10±4 μV; P<0.05). In the ADHD group, the detection rates of hyperactivity, attack, and discipline violation were 27%, 27% and 9% respectively. The scores on attack and discipline violation subscales were negatively correlated with the Go-N2 amplitude of ERP (r=-0.43 and -0.48 respectively; P<0.05), while the score on hyperactivity subscale was positively correlated with the latency of Go-P3 (r=0.50, P<0.05).

CONCLUSIONSThe early school-age children with ADHD show the tendency to the impairment of attention/executive function, but the inhibition function defect has not been noted. In early school-age children with ADHD, the behavioral problems such as hyperactivity, attack, and discipline violation are associated with ERP.

Attention Deficit Disorder with Hyperactivity ; physiopathology ; psychology ; Child ; Child Behavior Disorders ; etiology ; Evoked Potentials ; physiology ; Humans