Search

Accelerated synaptic pruning and weakening of short-range functional connectivity are characteristic of adolescent brain development. Based on these structural microscopic and system-level functional changes, it was hypothesized that regional homogeneity (ReHo) may decrease with age in the developing brain, and a differential association between ReHo and cognitive performance was expected to depend on age. ReHo maps of typically developing participants were provided by the Attention-Deficit/Hyperactivity Disorder (ADHD)-200 Preprocessed repository. Intelligence quotient was evaluated using the Wechsler Intelligence Scale for Chinese Children-Revised and Wechsler Abbreviated Scale of Intelligence at Peking University and New York University, respectively. Correlations between ReHo and age were examined, along with the interaction effects of ReHo and age on intelligence quotient (IQ), in 121 typically developing youth aged 8-14 years. Of the 400 ROIs tested, ReHo in 105 brain regions was significantly correlated with age (p < 0.05, false discovery rate-corrected), among which 102 showed that ReHo decreased with age. In addition, ReHo in 18 brain regions was negatively correlated with age at Bonferroni-corrected thresholds (p < 0.05), and most associations were observed in the prefrontal cortex. The interaction analyses suggested that higher ReHo was associated with higher IQ in children, whereas this association was attenuated or reversed in adolescents (p < 0.05, uncorrected). ReHo decreased with age in the developing brain and was differentially associated with intelligence in children and adolescents., Competing Interests: Declaration of interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Few studies have empirically tested the relationships between anatomically defined thalamic nuclei and functionally defined cortical networks, and little is known about their implications in attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate the functional connectivity of the thalamus in youth with ADHD, using both anatomically and functionally defined thalamic seed regions., Methods: Resting-state functional MRIs obtained from the publicly available ADHD-200 database were analyzed. Thalamic seed regions were defined functionally and anatomically based on Yeo's 7 resting-state-network parcellation atlas and the AAL3 atlas, respectively. Functional connectivity maps of the thalamus were extracted, and thalamocortical functional connectivity was compared between youth with and without ADHD., Results: Using the functionally defined seeds, significant group differences in thalamocortical functional connectivity and significant negative correlations between thalamocortical connectivity and ADHD symptom severity were observed within the boundaries of corresponding large-scale networks. However, in the analysis using the anatomically defined thalamic seeds, significant group differences in connectivity and significant positive correlations were observed outside the expected boundaries of major anatomic projections. The thalamocortical connectivity originating from the lateral geniculate nuclei of the thalamus was significantly correlated with age in youth with ADHD., Limitations: The small sample size and smaller proportion of girls were limiting factors., Conclusion: Thalamocortical functional connectivity based on the intrinsic network architecture of the brain appears to be clinically relevant in ADHD. The positive association between thalamocortical functional connectivity and ADHD symptom severity may represent a compensatory process recruiting an alternative neural network., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Disruptions of the cortico-striato-thalamo-cortical circuit has been implicated in both attention-deficit/hyperactivity disorder and substance use disorder. Given the high prevalence of cannabis use among patients with attention-deficit/hyperactivity disorder, we set out to investigate the relationship between the two in the thalamus. We analyzed resting-state functional magnetic resonance imaging data obtained from the Addiction Connectome Preprocessed Initiative Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder database. Functional connectivity maps were extracted to compare thalamic connectivity among adults who had been diagnosed with attention-deficit/hyperactivity disorder during childhood according to whether or not they used cannabis. The study participants included 18 cannabis users and 15 cannabis non-users with childhood attention-deficit/hyperactivity disorder. Our results revealed that adults with attention-deficit/hyperactivity disorder who used cannabis (n = 18) had significantly decreased functional connectivity between the thalamus and parietal regions, which was particularly prominent in the inferior parietal areas, in comparison with those who did not use cannabis (n = 15). Left thalamic functional connectivity with the inferior parietal and middle frontal areas and right thalamic functional connectivity with the inferior parietal and superior frontal areas were increased in non-users of cannabis with attention-deficit/hyperactivity disorder compared with a local normative comparison group (n = 7). In conclusion, adults with a childhood history of attention-deficit/hyperactivity disorder who do not use cannabis often have relatively stronger thalamoparietal and thalamofrontal connectivity, which may help reduce the risk of cannabis use., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Lee, Hong. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To examine the association between variants of N-methyl-D-aspartate (NMDA) receptor subunit-encoding genes ( GRIN2A and GRIN2B ) and continuous performance test (CPT) variables in ADHD and healthy controls. Method: In all, 253 ADHD patients and 98 controls were recruited. The diagnosis, genotype, and diagnosis-genotype interaction effects for the CPT variables were examined. Results: Significant diagnosis effects were detected for all CPT variables. There were significant genotype and interaction effects on response time variability (RTV) by the GRIN2B variant. The C/C subgroup had higher RTV than the C/T + T/T subgroup in ADHD, but not in controls. There were significant genotype effects on omission errors by the GRIN2A variant. The G/G subgroup had more omission errors than the G/A + A/A subgroup in ADHD patients, but not in controls. Conclusion: These results suggest that the genetic variants of GRIN2B and GRIN2A confer an increased susceptibility to attentional impairment in ADHD patients.

Objective: Sleep problems is the most common side effect of methylphenidate (MPH) treatment in ADHD youth and carry potential to negatively impact long-term self-regulatory functioning. This study aimed to examine whether applying machine learning approaches to pre-treatment demographic, clinical questionnaire, environmental, neuropsychological, genetic, and neuroimaging features can predict sleep side effects following MPH administration., Method: The present study included 83 ADHD subjects as a training dataset. The participants were enrolled in an 8-week, open-label trial of MPH. The Barkley Stimulant Side Effects Rating Scale was used to determine the presence/absence of sleep problems at the 2nd week of treatment. Prediction of sleep side effects were performed with step-wise addition of variables measured at baseline: demographics (age, gender, IQ, height/weight) and clinical variables (ADHD Rating Scale-IV (ADHD-RS) and Disruptive Behavior Disorder rating scale) at stage 1, neuropsychological test (continuous performance test (CPT), Stroop color word test) and genetic/environmental variables (dopamine and norepinephrine receptor gene (DAT1, DRD4, ADRA2A, and SLC6A2) polymorphisms, blood lead, and urine cotinine level) at stage 2, and structural connectivities of frontostriatal circuits at stage 3. Three different machine learning algorithms ((Logistic Ridge Regression (LR), support vector machine (SVM), J48) were used for data analysis. Robustness of classifier model was validated in the independent dataset of 36 ADHD subjects., Results: Classification accuracy of LR was 95.5% (area under receiver operating characteristic curve (AUC) 0.99), followed by SVM (91.0%, AUC 0.85) and J48 (90.0%, AUC 0.87) at stage 3 for predicting sleep problems. The inattention symptoms of ADHD-RS, CPT response time variability, the DAT1, ADRA2A DraI, and SLC6A2 A-3081T polymorphisms, and the structural connectivities between frontal and striatal brain regions were identified as the most differentiating subset of features. Validation analysis achieved accuracy of 86.1% (AUC 0.92) at stage 3 with J48., Conclusions: Our results provide preliminary support to the combination of multimodal classifier, in particular, neuroimaging features, as an informative method that can assist in predicting MPH side effects in ADHD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: We investigated the possible association between two NMDA subunit gene polymorphisms (GRIN2B rs2284411 and GRIN2A rs2229193) and treatment response to methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD)., Methods: A total of 75 ADHD patients aged 6-17 years underwent 6 months of MPH administration. Treatment response was defined by changes in scores of the ADHD-IV Rating Scale (ADHD-RS), clinician-rated Clinical Global Impression-Improvement (CGI-I), and Continuous Performance Test (CPT). The association of the GRIN2B and GRIN2A polymorphisms with treatment response was analyzed using logistic regression analyses., Results: The GRIN2B rs2284411 C/C genotype showed significantly better treatment response as assessed by ADHD-RS inattention ( p=0.009) and CGI-I scores ( p=0.009), and there was a nominally significant association in regard to ADHD-RS hyperactivity-impulsivity ( p=0.028) and total ( p=0.023) scores, after adjusting for age, sex, IQ, baseline Clinical Global Impression-Severity (CGI-S) score, baseline ADHD-RS total score, and final MPH dose. The GRIN2B C/C genotype also showed greater improvement at the CPT response time variability ( p<0.001). The GRIN2A G/G genotype was associated with a greater improvement in commission errors of the CPT compared to the G/A genotype ( p=0.001)., Conclusions: The results suggest that the GRIN2B rs2284411 genotype may be an important predictor of MPH response in ADHD.

Background: Low-level environmental exposure to lead has been associated with both reduced intelligence and symptoms of attention deficit/hyperactivity disorder (ADHD). However, few studies have estimated the association of lead and intelligence independent of ADHD, and it is not clear from previous studies whether lead is associated with both inattention and impulsivity ADHD symptoms., Objectives: We estimated mutually adjusted associations of environmental lead exposure with both intelligence and ADHD symptoms, and associations between lead and specific ADHD-related domains., Methods: Blood lead concentrations were measured in a general population of 1,001 children 8-11 years of age. We used multivariable linear regression models to estimate associations of blood lead concentrations with IQ scores, teacher and parent ratings of ADHD symptoms, and measures of inattention and impulsivity. Models were adjusted for demographic variables and other environmental exposures (blood levels of mercury and manganese, urinary concentrations of cotinine, phthalate metabolites, and bisphenol A)., Results: Associations of blood lead with lower IQ and higher impulsivity were robust to adjustment for a variety of covariates. When adjusted for demographic characteristics, other environmental exposures, and ADHD symptoms or IQ, a 10-fold increase in blood lead concentration was associated with lower Full-Scale IQ (-7.23; 95% CI: -13.39, -1.07) and higher parent- and teacher-rated hyperactivity/impulsivity scores (ADHD Rating Scale, 1.99; 95% CI: 0.17, 3.81 and 3.66; 95% CI: 1.18, 6.13, respectively) and commission errors (Continuous Performance Test, 12.27; 95% CI: -0.08, 24.62). Blood lead was not significantly associated with inattention in adjusted models., Conclusions: Low-level lead exposure was adversely associated with intelligence in school-age children independent of ADHD, and environmental lead exposure was selectively associated with impulsivity among the clinical features of ADHD.

Background: Brain frontostriatal circuits have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, effects of methylphenidate on circuit-level functional connectivity are as yet unclear. The aim of the present study was to comprehensively investigate the functional connectivity of major striatal subregions in children with ADHD, including subanalyses directed at mapping cognitive and treatment response characteristics., Methods: Using a comprehensive seeding strategy, we examined resting-state functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen in children and adolescents with ADHD and in age- and sex-matched healthy controls., Results: We enrolled 83 patients with ADHD and 22 controls in our study. Patients showed significantly reduced dorsal caudate functional connectivity with the superior and middle prefrontal cortices as well as reduced dorsal putamen connectivity with the parahippocampal cortex. These connectivity measures were correlated in opposite directions in patients and controls with attentional performance, as assessed using the Continuous Performance Test. Patients showing a good response to methylphenidate had significantly reduced ventral caudate/nucleus accumbens connectivity with the inferior frontal cortices compared with poor responders., Limitations: Possible confounding effects of age-related functional connectivity change were not excluded owing to the wide age range of participants., Conclusion: We observed a region-specific effect of methylphenidate on resting-state functional connectivity, suggesting the pretreatment level of ventral frontostriatal functional connectivity as a possible methylphenidate response biomarker of ADHD.

Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. This study aimed to derive a comprehensive, whole-brain characterization of large-scale axonal connectivity differences in attention-deficit/hyperactivity disorder (ADHD) associated with catechol-O-methyltransferase gene (COMT) Val158Met polymorphism. Using diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in youth with ADHD who were COMT Val-homozygous (N = 29) compared with those who were Met-carriers (N = 29). Additionally, we examined whether dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) polymorphisms were associated with white matter differences. Level of attention was assessed using the continuous performance test before and after an 8-week open-label trial of methylphenidate (MPH). A network of white matter connections linking 18 different brain regions was significantly weakened in youth with ADHD who were COMT Met-carriers compared to those who were Val-homozygous (P < 0.05, family-wise error-corrected). A measure of white matter integrity, fractional anisotropy, was correlated with impaired pretreatment performance in continuous performance test omission errors and response time variability, as well as with improvement in continuous performance test response time variability after MPH treatment. Altered white matter connectivity was exclusively based on COMT genotypes, and was not evident in DAT1 or DRD4. We demonstrated that white matter connectivity in youth with ADHD is associated with COMT Val158Met genotypes. The present findings suggest that different layers of dopamine-related genes and interindividual variability in the genetic polymorphisms should be taken into account when investigating the human connectome., (© 2014 Wiley Periodicals, Inc.)

Patients with attention-deficit/hyperactivity disorder (ADHD) appear to be more vulnerable to the development of other psychiatric disorders than the general population. The proposed neurotoxic mechanisms of manganese involve striatal dopamine neurotransmission, implicated in the pathophysiology of ADHD. We investigated whether the adverse impact of manganese is particularly pronounced in children with ADHD. Blood manganese concentration and diagnosis of ADHD were assessed in a general population of 890 children, aged 8-11 years. The main outcome measure was the Child Behavior Checklist (CBCL). A significant interaction was found between ADHD status and blood manganese level in predicting CBCL total problems score as well as anxiety/depression, social problems, delinquent behavior, aggressive behavior, internalizing problems, and externalizing problems. The directions of the interactions indicated that blood manganese level was more positively correlated with CBCL scores in ADHD children than in the healthy population. In ADHD children, only the fifth quintile of blood manganese concentration was significantly associated with the CBCL total problems score. ADHD children may be more vulnerable than the general school-age population to the neurotoxic effects of manganese exposure, which lead to an elevated risk of developing comorbid mental conditions., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background: Few studies have sought to identify, in a regionally unbiased way, the precise cortical and subcortical regions that are affected by white matter abnormalities in attention-deficit/hyperactivity disorder (ADHD). This study aimed to derive a comprehensive, whole-brain characterization of connectomic disturbances in ADHD., Methods: Using diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in 71 children and adolescents with ADHD compared with 26 healthy control subjects. White matter differences were further delineated between patients with (n = 40) and without (n = 26) the predominantly hyperactive/impulsive subtype of ADHD., Results: A significant network comprising 25 distinct fiber bundles linking 23 different brain regions spanning frontal, striatal, and cerebellar brain regions showed altered white matter structure in ADHD patients (p < .05, family-wise error-corrected). Moreover, fractional anisotropy in some of these fiber bundles correlated with attentional disturbances. Attention-deficit/hyperactivity disorder subtypes were differentiated by a right-lateralized network (p < .05, family-wise error-corrected) predominantly linking frontal, cingulate, and supplementary motor areas. Fractional anisotropy in this network was also correlated with continuous performance test scores., Conclusions: Using an unbiased, whole-brain, data-driven approach, we demonstrated abnormal white matter connectivity in ADHD. The correlations observed with measures of attentional performance underscore the functional importance of these connectomic disturbances for the clinical phenotype of ADHD. A distributed pattern of white matter microstructural integrity separately involving frontal, striatal, and cerebellar brain regions, rather than direct frontostriatal connectivity, appears to be disrupted in children and adolescents with ADHD., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This study compared children who experience attention-deficit/hyperactivity disorder (ADHD) symptoms but do not meet criteria (i.e., subthreshold ADHD) with those with the full syndrome and healthy controls. Presence of ADHD symptoms was determined in a nationwide community sample of 921 children, aged 8-11 years. The main outcome measures comprised attentional symptoms, comorbidity profiles, academic performance, and neurocognitive ability (i.e., ADHD Rating Scale, Child Behavior Checklist, Learning Disability Evaluation Scale, and Stroop Color-Word Test, respectively). Subthreshold ADHD was equally prevalent in boys and girls, and more prevalent in low-income families. Throughout all the outcome measurements, subthreshold ADHD was both a significantly milder condition than full syndrome ADHD and a significantly more severe condition than non-ADHD status. The findings were consistent across the total as well as the subtest scores, and after correction for multiple comparisons (p < 0.0017). Children with subthreshold ADHD were found to experience significant symptoms and functional impairments. The results of this study support the clinical relevance of subthreshold ADHD in a childhood population. Subthreshold diagnostic criteria for ADHD may be more sensitive in detecting ADHD symptoms in girls than the full syndrome criteria, and subthreshold clinical, cognitive, and behavioral symptoms of ADHD may occur in a subset of children who are possibly more sensitive to their environment. Further consideration about the diagnostic threshold for ADHD may particularly benefit girls and children in low-income families.

Although there is some evidence supporting the existence of an association between prenatal maternal or postnatal child's urine phthalate metabolite concentrations and poor attentional performances, the interaction between urine phthalate metabolite levels and genetic variation for neuropsychological deficit of attention-deficit hyperactivity disorder (ADHD) has not been examined. The aim of this study was to determine whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. A cross-sectional examination of urine phthalate metabolite concentrations and the continuous performance test (CPT) were performed in 179 Korean children with ADHD recruited from department of psychiatry of university hospital. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, α-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. The results of this study suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Further prospective and epigenetic studies are needed to investigate causality and pathophysiological mechanisms.

Introduction: Given the shortage of pharmacogenetic studies on treatment response according to subtype of attention-deficit hyperactivity disorder (ADHD), we investigated the associations between the MspI and DraI polymorphisms of the alpha-2 A-adrenergic receptor gene (ADRA2A) and treatment response to methylphenidate according to subtype of ADHD., Methods: We enrolled 115 medication-naïve children with ADHD into an open label 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical -Global Impression (CGI), ADHD rating scale, and Continuous Performance Test (CPT) pre- and post-treatment., Results: There was no statistically significant association between the MspI or DraI genotypes and the relative frequency of CGI-improvement (CGI-I) 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those subjects with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status post-treatment (OR=4.45, p=0.045)., Discussion: The results of this study do not support the association between the the MspI or DraI genotypes and treatment response to methylphenidate in ADHD. However, our results -suggest that subtypes might influence pharmacogenetic results in ADHD.·available online at http://www.thieme-connect.de/ejournals/toc/pharmaco., (© Georg Thieme Verlag KG Stuttgart · New York.)

The authors examined the association between the MspI C/G and DraI C/T genotypes of the α2A-adrenergic receptor gene and white-matter connectivity and attentional performance before and after medication in 53 children with attention-deficit hyperactivity disorder. Subjects who carried the T allele at the DraI polymorphism showed fewer changes in the mean commission error scores after 8 weeks of medication and decreased fractional anisotropy (FA) values in the right middle frontal cortex than subjects without the T allele. Subjects with the C allele at the MspI polymorphism showed decreased FA values in the right postcentral gyrus than subjects without.

Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time variability is a viable endophenotype for ADHD and suggesting its utility as a surrogate end point for measuring stimulant response in pharmacogenetic studies.

Background: Although family education generally is recommended in the treatment of tic disorders, few studies have focused on the relationship between family environment and diagnosis of tic disorders., Methods: Presence of DSM-IV tic disorders was determined in a general population of 921 children in Korea from 2008 to 2009. Clinical risk factors were assessed, including comorbidity with attention-deficit/hyperactivity disorder; family-related factors such as the number of family members and primary caretaker of the child; and socioeconomic factors in the form of paternal education level and household yearly income. Multivariable logistic regression analyses were performed to estimate the association between a list of clinical, familial, and social variables and the odds of developing tic disorders., Results: At Bonferroni corrected thresholds, a higher risk of tic disorders was significantly associated with the number of changes in primary caretaker, whereas a lower risk was associated with increasing number of children in the family., Conclusions: Family-related environmental factors may play a role in the development or exacerbation of tic disorders. The results advocate the importance of family education when treating children with tic disorders, and further research is needed on the contextual risk factors of tic disorders.

Background: We examined the cross-sectional relationship between environmental tobacco smoke exposure, continuous performance test (CPT) measures, and attention deficit hyperactivity disorder (ADHD) or learning disability symptoms in school-aged children., Method: In total, 989 children (526 boys, mean age 9.1 ± 0.7 years), recruited from five South Korean cities participated in this study. We used urine cotinine as a biomarker for environmental tobacco smoke exposure, and obtained the children's scores on a CPT. Parents completed the Korean versions of the ADHD rating scale-IV (ADHD-RS) and learning disability evaluation scale (LDES). Using generalized linear mixed model (GLMM), we assessed the associations between urine cotinine concentrations, neuropsychological variables, and symptoms of ADHD and learning disabilities. Additionally, we conducted structural equation models to explore the effects' pathways., Results: After adjusting for a range of relevant covariates, GLMM showed urinary cotinine levels were significantly and positively associated with CPT scores on omission errors, commission errors, response time, and response time variability, and with parent- and teacher-rated ADHD-RS scores. In addition, urine cotinine levels were negatively associated with LDES scores on spelling and mathematical calculations. The structural equation model revealed that CPT variables mediated the association between urine cotinine levels and parental reports of symptoms of ADHD and learning disabilities., Conclusions: Our data indicate that environmental exposure to tobacco smoke is associated with ADHD and learning disabilities in children, and that impairments in attention and inhibitory control probably mediate the effect.

Objective: We aimed to investigate the independent and interaction effects of dopamine transporter gene (DAT1), dopamine D4 receptor gene (DRD4), alpha-2A adrenergic receptor gene (ADRA2A), and norepinephrine transporter gene (NET1), with regard to treatment response to methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD)., Methods: The participants of the study were 103 children and adolescents (ages 9.1±2.1 years) diagnosed as having ADHD according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria. They were enrolled in an 8-week, open-label trial of MPH. The good responder group was defined as subjects having an ≥50% decrease in the ADHD Rating Scale-IV (ADHD-RS) total score from the baseline, and at the same time a Clinical Global Impressions-Improvement Scale (CGI-I) score of 1 or 2, both at the 8th week of MPH treatment. Multivariate stepwise logistic regression was performed to examine the independent and interaction effects of genotypes on the dichotomized MPH treatment response., Results: Significant interaction effects on MPH response were detected between the genotypes of the DRD4 variable number of tandem repeat (VNTR) polymorphisms and those of either the ADRA2A DraI or the NET1 -3081(A/T) polymorphisms; significant interaction effects were also detected between the genotypes of the ADRA2A DraI polymorphisms and those of either the NET1 G1287A or the NET1 -3081(A/T) polymorphisms (Nagelkerke R(2)=0.40). No significant independent effect of a genotype was detected according to the stepwise logistic regression results., Conclusion: The results suggest that genes involved in the dopaminergic and noradrenergic systems might interact to form important predictors of short-term response to MPH.

Background: Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 gene and attentional performance before and after medication in children with ADHD., Methods: Fifty-three medication-naïve children with ADHD were genotyped and evaluated using the continuous performance test (CPT). After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2., Results: There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p = 0.006) than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T) showed a greater decrease in the mean commission error scores (p = 0.003) than those with the A/A genotypes., Conclusions: Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.

The noradrenergic system modulates attention and arousal. Dysregulation of the noradrenergic system may be involved in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). This study intended to examine the differences in methylphenidate (MPH) treatment response and pre- and post-treatment cerebral perfusion associated with the G1287A and -3081(A/T) polymorphisms of the norepinephrine transporter (NET) gene in ADHD children. Thirty-seven drug-naïve ADHD children (8.9±1.8 years old, M=32, F=5) were genotyped. Next, baseline single-photon emission computed tomography (SPECT) and clinical assessments were carried out for ADHD subjects. After 8 weeks of MPH treatment, SPECT and clinical assessment were repeated. There were no differences in baseline clinical assessments or cerebral perfusion based on genotype. However, after treatment, ADHD children with the G/G genotype at the G1287A polymorphism showed more improvement in symptoms than children without the G/G genotype as evaluated by the Clinical Global Impressions-Improvement scale (p=0.022). Furthermore, ADHD children with the G/G genotype at the G1287A polymorphism showed hyperperfusion in the right inferior temporal gyrus (p<0.001, uncorrected) and middle temporal gyrus (p=0.001, uncorrected) compared to children without the G/G genotype. Although the results of this study should be interpreted cautiously, they suggest that polymorphisms of the NET gene may contribute to an intermediate phenotype. Further studies should clearly elucidate the relationship between treatment response and functional connectivity in the brain according to this genetic polymorphism., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Research on psychostimulants, analysis of animal models and genetic association studies all suggest that the brain-derived neurotrophic factor gene (BDNF) may be a good candidate for pharmacogenetic studies of attention deficit hyperactivity disorder (ADHD). Yet to date there have been no pharmacogenetic studies of BDNF in ADHD. A total of 102 drug-naive ADHD children (8.7±2.1 yr) were treated with osmotic release oral system-methylphenidate (OROS-MPH) for 12 wk, and four kinds of response criteria were applied, based first, on a combined threshold of the ADHD Rating Scale - IV (ARS) and the Clinical Global Impression - Improvement scale (CGI-I); second, on scores of 1 or 2 vs. 3-7 on the CGI - Severity scale; third, on a >50% reduction in ARS scores; and fourth, on satisfaction of all of the aforementioned criteria. The Val⁶⁶Met polymorphism of BDNF and six single nucleotide polymorphisms from the SLC6A2, ADRA2A and NTF-3 genes were tested for association with each criterion. Relative to other genotypes, homozygosity for the Val allele of the BDNF Val⁶⁶Met polymorphism was associated with a greater relative frequency of good response under all four response criteria (after controlling for baseline ARS score, age, gender, final dose (mg/kg) of OROS-MPH at 12 wk, and level of academic functioning). This association was significant at the uncorrected level for the first and third response criteria (p=0.013 and p=0.018, respectively) and significant at a Bonferroni-corrected level for the second and fourth response criteria (p=0.0002, p=0.0003, respectively). Our findings support an association between homozygosity for the Val allele of BDNF and better response to OROS-MPH in Korean ADHD children as assessed by four different response criteria.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD., Methods: This study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment., Results: We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment., Conclusion: Our findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.

Background: Neurobiologic studies have suggested that dysregulation of central noradrenergic systems may be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD), and it has been hypothesized that genetic changes in the norepinephrine pathways might contribute to dysfunction of the prefrontal cortex circuits in ADHD. We previously reported decreased cerebral blood flow in the right lateral prefrontal cortex and both orbitofrontal cortices in children with ADHD. Genetic investigations have shown that the alpha-2A-adrenergic receptor gene (ADRA2A) is associated with ADHD. Our aim was to examine whether the presence of a risk allele of the ADRA2A MspI polymorphism is associated with differences in regional cerebral blood flow in boys with ADHD., Methods: We recruited 21 Korean boys with ADHD (mean age 9.9, standard deviation [SD] 2.7 yr) and 11 age- and sex-matched controls (mean age 10.6 [SD 2.1] yr). Each participant underwent technetium-99m-hexamethylpropylene amine oxime ((99m)Tc-HMPAO) single-photon emission computed tomography. We performed image analyses with voxe-wise t statistics using SPM2., Results: We found regional hypoperfusion in the prefrontal regions, including the right orbitofrontal and right medial gyri, and the bilateral putamen and cerebellum in boys with ADHD relative to controls (p < 0.0005, uncorrected for multiple comparisons). Boys with ADHD who carried the C allele (n = 13) at the ADRA2A MspI polymorphism had reduced perfusion in the bilateral orbitofrontal regions compared with those without the C allele (n = 8) (p < 0.0005, uncorrected for multiple comparisons)., Limitations: This study was limited by the small sample size, and we did not obtain genetic data from the controls., Conclusion: Our findings suggest that regional differences in cerebral perfusion in the orbitofrontal cortex represent an intermediate neuroimaging phenotype associated with the ADRA2A MspI polymorphism; these data support the validity of the noradrenergic hypothesis regarding the pathophysiology of ADHD.