Attention Deficit Hyperactivity Disorder Probands Research Articles

Risk of traumatic brain injury among patients with ADHD and their unaffected siblings.

As the relationship between attention deficit hyperactivity disorder (ADHD) and traumatic brain injury (TBI) is gaining increasing attention, the TBI risk in patients with ADHD, unaffected siblings of ADHD probands, and non-ADHD controls remains unclear. Overall, 18,645 patients with ADHD, 18,880 unaffected siblings of ADHD probands, and 188,800 age-/sex-matched controls were followed up from enrollment to the end of 2011. The cases of TBI and TBI requiring hospitalization were identified during follow-up. Patients with ADHD (hazard ratio [HR]: 1.57) and unaffected siblings (HR: 1.20) had an increased risk of any TBI compared with non-ADHD controls. Surprisingly, the likelihood of developing TBI requiring hospitalization during follow-up was higher in the unaffected siblings group (HR: 1.21) than in the control group, whereas it was lower in the ADHD probands group (HR: 0.86). Patients with ADHD and unaffected siblings of ADHD probands were more likely to develop any TBI during follow-up than controls. Unaffected siblings of patients with ADHD exhibited the highest risk of subsequent TBI requiring hospitalization compared with patients with ADHD and healthy controls. Therefore, TBI risk in patients with ADHD and their unaffected siblings would require further investigation. ADHD diagnosis and ADHD trait are associated with risk of traumatic brain injury (TBI). Both patients with ADHD and their unaffected siblings were more likely to develop TBI during the follow-up compared with the control group. TBI requiring hospitalization occurred more in the sibling group than in the proband group. TBI risk should be closely monitored among unaffected siblings of patients with ADHD.

Insomnia Polygenic Component on Attention Deficit-Hyperactivity Disorder: Exploring this Association Using Genomic Data from Brazilian Families

Abstract Introduction Insomnia is highly prevalent among individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the biological mechanisms shared between both conditions is still elusive. We aimed to investigate whether insomnia's genomic component is able to predict ADHD in childhood and adolescence. Methods A Brazilian sample of 259 ADHD probands and their biological parents were included in the study. Their genomic DNA genotypes were used to construct the polygenic risk score for insomnia (Insomnia PRS), using the largest GWAS summary statistics as a discovery sample. The association was tested using logistic regression, under a case-pseudocontrol design. Results Insomnia PRS was nominally associated with ADHD (OR = 1.228, p = 0.022), showing that the alleles that increase the risk for insomnia also increase the risk for ADHD. Discussion Our results suggest that genetic factors associated with insomnia may play a role in the ADHD genetic etiology, with both phenotypes likely to have a shared genetic mechanism.

Glutamate receptor genetic variants affected peripheral glutamatergic transmission and treatment induced improvement of Indian ADHD probands

Attention deficit hyperactivity disorder (ADHD), a childhood-onset neurobehavioral disorder, often perturbs scholastic achievement and peer-relationship. The pivotal role of glutamate (Glu) in learning and memory indicated an influence of Glu in ADHD, leading to the exploration of Glu in different brain regions of ADHD subjects. We for the first time analyzed GluR genetic variations, Glu levels, as well as expression of Glu receptors (GluR) in the peripheral blood of eastern Indian ADHD probands to find out the relevance of Glu in ADHD prognosis. After obtaining informed written consent for participation, peripheral blood was collected for analyzing the genetic variants, Glu level, and expression of target genes. Since ADHD probands are often treated with methylphenidate or atomoxetine for providing symptomatic remediation, we have also tested post-therapeutic improvement in the ADHD trait scores in the presence of different GluR genotypes. Two variants, GRM7 rs3749380 “T” and GRIA1 rs2195450 “C”, exhibited associations with ADHD (P ≤ 0.05). A few GluR genetic variants showed significant association with higher trait severity, low IQ, lower plasma Glu level, down-regulated GluR mRNA expression, and poor response to medications. This indicates that down-regulated glutamatergic system may have an effect on ADHD etiology and treatment efficacy warranting further in-depth investigation.

Distinct Thalamic and Frontal Neuroanatomical Substrates in Children with Familial vs. Non-Familial Attention-Deficit/Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent, inheritable, and heterogeneous neurodevelopmental disorder. Children with a family history of ADHD are at elevated risk of having ADHD and persisting its symptoms into adulthood. The objective of this study was to investigate the influence of having or not having positive family risk factor in the neuroanatomy of the brain in children with ADHD. Cortical thickness-, surface area-, and volume-based measures were extracted and compared in a total of 606 participants, including 132, 165, and 309 in groups of familial ADHD (ADHD-F), non-familial ADHD (ADHD-NF), and typically developed children, respectively. Compared to controls, ADHD probands showed significantly reduced gray matter surface area in the left cuneus. Among the ADHD subgroups, ADHD-F showed significantly increased gray matter volume in the right thalamus and significantly thinner cortical thickness in the right pars orbitalis. Among ADHD-F, an increased volume of the right thalamus was significantly correlated with a reduced DSM-oriented t-score for ADHD problems. The findings of this study may suggest that a positive family history of ADHD is associated with the structural abnormalities in the thalamus and inferior frontal gyrus; these anatomical abnormalities may significantly contribute to the emergence of ADHD symptoms.

Direct and Indirect Effects in Trio Studies: You Don’t Know What You’re Missing

In the current issue of Biological Psychiatry, Martin et al. (1) analyzed genome-wide single nucleotide polymorphism array data of probands with attention-deficit/hyperactivity disorder (ADHD) and their parents to evaluate the potential contributions of direct (transmitted) and indirect (nontransmitted) genetic effects of polygenic liability for several neurodevelopmental and psychiatric disorders, as well as cognitive ability, in ADHD probands. The authors observed overtransmission of ADHD polygenic risk scores (PRSs) from parents to ADHD probands, as well as undertransmission of PRSs for cognitive ability and obsessive-compulsive disorder (OCD).

Kainate receptor subunit 1 (GRIK1) risk variants and GRIK1 deficiency were detected in the Indian ADHD probands

Executive dysfunctions caused by structural and functional abnormalities of the prefrontal cortex were reported in patients with Attention deficit hyperactivity disorder (ADHD). Owing to a higher expression of the glutamate ionotropic receptor kainate type subunit 1 (GluK1), encoded by the GRIK1 gene, in brain regions responsible for learning and memory, we hypothesized that GRIK1 might have a role in ADHD. GRIK1 variants rs363504 and rs363538, affecting the receptor function, were analyzed by case–control and family-based methods to identify the association with ADHD. The impact of these variants on ADHD-associated traits and pharmacological intervention were also analyzed. GRIK1 expression was quantified in the peripheral blood. The probands and their fathers had a higher frequency of rs363504 ‘CC’ and rs363538 ‘CA’ genotypes. Family-based investigation revealed maternal over transmission of rs363504 ‘C’ and rs363538 ‘A’ alleles to the probands. Quantitative trait analysis exhibited an association of rs363504 ‘TT’ and rs363538 ‘AA’ genotypes with higher hyperactivity scores of the probands. In the presence of rs363504 ‘TT’ and rs363538 ‘CC’ genotypes, MPH treatment improved hyperactivity and inattention, respectively. GRIK1 expression was significantly downregulated in the probands. We infer that GRIK1 affects ADHD etiology, warranting further in-depth investigation involving a larger cohort and more functional variants.

Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations.

Symptomatic remediation from attention deficit hyperactivity disorder (ADHD)-associated traits is achieved by treatment with methylphenidate (MPH)/atomoxetine (ATX). We have analyzed the association of functional CYP2D6 variations, rs1065852, rs3892097, rs1135840, and rs1058164, with ADHD in the Indian subjects. Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders. Trait scores were obtained from the Conner's Parents Rating Scale-Revised. After obtaining informed consent, blood was collected for DNA isolation, and genotyping was performed by PCR or TaqMan-based methods. Probands were treated with MPH or ATX based on age, symptoms, and drug availability. Treatment outcome was assessed using a structured questionnaire. Data obtained was analyzed to identify the association of CYP2D6 variations and the SLC6A3 rs28363170 with the treatment outcome. The frequency of rs1135840 "G" and rs1065852 "G" was higher in the male ADHD probands. Bias in parental transmission (p=0.007) and association with higher trait scores were observed for rs1065852 "A". Independent influence of rs1065852 on ADHD was also observed. Probands carrying rs1065852 'GG', rs1135840 'CG', and rs28363170 10R exhibited significant symptomatic improvement with MPH, while probands with rs1135840 'CC' and rs28363170 9R showed improvement after ATX treatment. ADHD probands having specific CYP2D6 genetic variations respond differentially to pharmaceutical intervention.

A three-pronged analysis confirms the association of the serotoninergic system with attention deficit hyperactivity disorder.

The serotonin transporter (SERT), encoded by the solute carrier family 6 number 4 (SLC6A4) gene, controls serotonin (5-HT) availability and is essential for the regulation of behavioral traits. Two SLC6A4 genetic variants, 5-HTTLPR and STin2, were widely investigated in patients with various neurobehavioral disorders, including attention deficit hyperactivity disorder (ADHD). We analyzed the association of the 5-HTTLPR (L/S) and STin2 (10/12) variants, plasma 5-HT, and 5-hydroxyindole acetic acid (5-HIAA), as well as SERT messenger RNA (mRNA) with ADHD in the eastern Indian subjects. Nuclear families with ADHD probands (n = 274) and ethnically matched controls (n = 367) were recruited following the Diagnostic and Statistical Manual of Mental Disorders. Behavioral traits, executive function, and intelligence quotient (IQ) of the probands were assessed using the Conner's Parent Rating Scale-Revised, Parental Account of Children's Symptoms (PACS), Barkley Deficit in Executive Functioning-Child and Adolescent Scale, and Wechsler Intelligence Scale for Children-III, respectively. After obtaining informed written consent, peripheral blood was collected to analyze genetic variants, plasma 5-HT, 5-HIAA, and SERT mRNA expression. ADHD probands showed a higher frequency of the 5-HTTLPR "L" allele and "L/L" genotype (P < 0.05), lower 5-HIAA level, and higher SERT mRNA expression. Scores for behavioral problems and hyperactivity were higher in the presence of the "S" allele and "S/S" genotype, while executive deficit was higher in the presence of the "L" allele. IQ score was lower in the presence of the STin2 "12" allele and L-12 haplotype. Data obtained indicate a significant association of the serotoninergic system with ADHD, warranting further in-depth investigation.

Differential effect of folate metabolic system genetic variants on attention deficit hyperactivity disorder severity

BackgroundAdequate folate level is vital for the synthesis of neurotransmitters, and hence, folate deficiency was related to neurobehavioral disorders like depression, Autism spectrum disorders, and Attention Deficit Hyperactivity Disorder (ADHD). Genetic variants involved in folate metabolism were also reported to affect ADHD traits. We have analyzed the contribution of FOLR1 rs2071010, FOLR2 rs2298444, TCN2 rs1801198, and SHMT1 rs1979277 in the etiology of Indian ADHD probands. MethodsEthnically matched controls (N = 286) and unrelated nuclear families with ADHD probands (N = 221) were recruited following the Diagnostic and Statistical Manual for Mental Disorders (DSM). Traits were assessed using the Conners' Parent Rating Scale-Revised, DSM, and Parental Account of Children's Symptoms criteria. Genetic variants were analyzed by PCR-based methods/TaqMan assay. Genetic association analyses were performed using the UNPHASED. Linkage disequilibrium was calculated using Haploview. Quantitative Trait Analysis was performed to identify the association between genetic variants and trait scores. ResultsParental bias in the transmission of rs1979277 “C” to the ADHD probands was detected. Maternally biased transmission of rs2298444 “G” was also observed. LD between rs2071010-rs2298444 was strong in the control population. Trait scores of the male ADHD probands were higher in the presence of rs2298444 “A” while the behavioral problem was less in the presence of rs1801198 “CC”. In the male probands, studied sites exhibited stronger independent effects, while in the female probands, additive effects between rs2298444-rs1801198 and rs2298444-rs1979277 were observed. ConclusionWe infer that ADHD severity is differentially influenced by genetic variants regulating folate metabolism.

Specific dopaminergic genetic variants influence impulsivity, cognitive deficit, and disease severity of Indian ADHD probands.

Impulsivity (Imp), being one of the cardinal symptoms of Attention Deficit Hyperactivity Disorder (ADHD), often leads to inappropriate responses to stimuli. Since the dopaminergic system is the primary target for pharmaceutical intervention in ADHD, we investigated the association between ADHD-related Imp and functional gene variants of the dopamine transporter (SLC6A3) and catechol-O-methyltransferase involved in dopamine clearance. Indo-Caucasoid families with ADHD probands (N = 217) were recruited based on the Diagnostic and Statistical Manual of Mental Disorders (DSM). Imp of the probands was assessed using the Domain Specific Imp Scale for Children and DSM. Peripheral blood was collected after obtaining informed written consent for participation, genomic DNA was isolated, and target sites were genotyped by DNA sequencing. The association of genetic variants with Imp was examined by the Quantitative trait analysis (QTA) and Analysis of variance (ANOVA). Post-Hoc analysis following QTA and ANOVA showed significant associations of rs2254408, rs2981359, and rs2239393 with different domains of Imp (P < 0.05). Various haplotypic combinations also showed statistically significant associations with Imp (P < 0.05). Multifactor dimensionality reduction models revealed strong effects of the variants on Imp. ADHD probands harboring the risk alleles exhibited a deficit in performance during cognitive assessment. Longitudinal follow-up revealed a significant association of rs2254408 with trait persistence. The present study indicates the influence of the studied genetic variants on ADHD-associated imp, executive deficit, and disease persistence. Thus, these variants may be helpful as predictors for the success of individual therapeutic sessions during cognitive training.

Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample

SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus–Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs’ regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24–2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.

Is the temperamental trait of high persistence protective in siblings? - A comparative, exploratory study of healthy siblings, and attention deficit hyperactivity disorder probands.

Background:Study of temperament in first-degree relatives is an important line of inquiry to substantiate temperament as an etiological marker.Aim:This study aims to compare temperament in children with attention deficit hyperactivity disorder (ADHD) and their healthy siblings and to assess the association between ADHD symptoms and temperament dimensions in healthy siblings.Settings and Design:The study was carried out in the outpatient department of psychiatry in a tertiary care teaching hospital. A cross-sectional design with nonprobabilistic sampling technique was used for data collection.Materials and Methods:A hundred children (50 children with ADHD and 50 siblings-one for each child with ADHD) were assessed retrospectively on temperament measurement schedule (TMS) and conners parent rating scale-revised: short form (CPRS-R: S).Statistical Analysis:IBM SPSS Statistics for Windows, Version 20.0 was used for statistical analysis. Mean and standard deviation and frequency and percentage were computed for continuous and categorical variables, respectively. Student’s t-test was computed to compare means of the two groups and regression analysis was computed to see for the variance in ADHD subscale scores explained by temperament scores on TMS.Results:Siblings scored highest on the intensity of reaction and lowest on threshold of responsiveness. Compared to probands, siblings scored significantly higher on persistence and lower on activity level, even after controlling for gender. Persistence trait had a significant negative correlation with and explained 7.4% to 21% of variance of all CPRS-R: S subscales. Persistence and distractibility together explained 23.2% of inattention scores.Conclusion:Higher persistence in siblings appears to offer protection to these at-risk individuals who do not have ADHD; favoring the dual pathway model of ADHD.

Adhesion G protein-coupled receptor L3 gene variants: Statistically significant association observed in the male Indo-caucasoid Attention deficit hyperactivity disorder probands.

Primary symptoms of Attention Deficit Hyperactivity Disorder (ADHD) are age inappropriate inattention, hyperactivity and impulsivity. Caucasoid individuals showed increased susceptibility to ADHD and disruptive behaviour in presence of Adhesion G-protein-coupled receptor L3 (ADGRL3) gene variants. We investigated ADGRL3 rs1868790, rs6551665, rs2345039 in Indo-Caucasoid families with ADHD probands (N = 249) and controls (N = 350). Behavioural traits, executive function, and IQ of probands were measured through Conner's Parent Rating Scale-Revised, Parental Account of Children's Symptoms, Barkley Deficit in Executive Functioning-Child & Adolescent Scale, and Wechsler Intelligence Scale for Children-III respectively. After obtaining informed written consent, peripheral blood was collected for genomic DNA isolation and target sites were analyzed by PCR based methods or TaqMan assay. Case-control analysis showed higher frequency of rs2345039 'C' allele, 'CC' genotype and A-A-C haplotype in the ADHD probands, principally due to higher occurrence of the 'C' allele and A-A-C haplotype in the male probands (P < 0.05). Mother of the probands also showed higher occurrence of the 'C' allele and "CC" genotype (P < 0.01). Executive function was better in presence of rs2345039 "GG" (P = 0.04) while IQ score was higher in presence of rs6551665 "AA" (P = 0.06). Linkage disequilibrium between rs6551665 and rs2345039 was stronger in the ADHD cases, chiefly in the male probands. Multifactor dimensionality reduction analysis showed strong interaction between rs6551665 and rs2345039 in the male probands while in the female probands rs1868790 and rs6551665 revealed non-linear interaction. Based on these observations, we infer that ADGRL3 may have a role in the aetiology of ADHD in this population warranting further in depth investigation.

Task-generic and task-specific connectivity modulations in the ADHD brain: an integrated analysis across multiple tasks

Attention-deficit/hyperactivity disorder (ADHD) is associated with altered functioning in multiple cognitive domains and neural networks. This paper offers an overarching biological perspective across these. We applied a novel strategy that extracts functional connectivity modulations in the brain across one (Psingle), two (Pmix) or three (Pall) cognitive tasks and compared the pattern of modulations between participants with ADHD (n-89), unaffected siblings (n = 93) and controls (n = 84; total N = 266; age range = 8–27 years). Participants with ADHD had significantly fewer Pall connections (modulated regardless of task), but significantly more task-specific (Psingle) connectivity modulations than the other groups. The amplitude of these Psingle modulations was significantly higher in ADHD. Unaffected siblings showed a similar degree of Pall connectivity modulation as controls but a similar degree of Psingle connectivity modulation as ADHD probands. Pall connections were strongly reproducible at the individual level in controls, but showed marked heterogeneity in both participants with ADHD and unaffected siblings. The pattern of reduced task-generic and increased task-specific connectivity modulations in ADHD may be interpreted as reflecting a less efficient functional brain architecture due to a reduction in the ability to generalise processing pathways across multiple cognitive domains. The higher amplitude of unique task-specific connectivity modulations in ADHD may index a more “effortful” coping strategy. Unaffected siblings displayed a task connectivity profile in between that of controls and ADHD probands, supporting an endophenotype view. Our approach provides a new perspective on the core neural underpinnings of ADHD.

Anatomical substrates of symptom remission and persistence in young adults with childhood attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder that emerges in childhood and persists into adulthood in a sizeable portion of afflicted individuals. The persistence of ADHD symptoms elevates the risk of adverse outcomes that result in substantial individual and societal burden. The objective of this study was to delineate neuroanatomical substrates associated with the diversity of adult outcomes of childhood ADHD, which may have considerable value for development of novel interventions that target mechanisms associated with recovery. Structural MRI and diffusion tensor imaging data from 32 young adults who were diagnosed with ADHD combined-type during childhood and 35 group-matched controls were analyzed. Adults with childhood ADHD were divided into 16 remitters and 16 persisters based on DSM-IV criteria. Compared to the controls, ADHD probands showed significantly reduced gray matter (GM) volume in right putamen and white matter (WM) volume in left parieto-insular fiber tracts. Within the ADHD probands, the remitters, as compared to persisters, showed significantly greater volume of right hippocampo-frontal and right parieto-insular WM fiber tracts, and those connecting caudate with the frontal, parietal, occipital, temporal, and insular cortices. Among ADHD probands, increased fractional anisotropy value of left caudate-parietal tract was significantly correlated with reduced hyperactive/impulsive symptoms. These findings suggest that optimal structural development in the WM tracts that connect caudate with cortical areas, especially in the caudate-parietal path, may play an important role in symptom remission in young adults with childhood ADHD.

Multimodal neuroimaging-based prediction of adult outcomes in childhood-onset ADHD using ensemble learning techniques.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and heterogeneous neurodevelopmental disorder, which is diagnosed using subjective symptom reports. Machine learning classifiers have been utilized to assist in the development of neuroimaging-based biomarkers for objective diagnosis of ADHD. However, existing basic model-based studies in ADHD report suboptimal classification performances and inconclusive results, mainly due to the limited flexibility for each type of basic classifier to appropriately handle multi-dimensional source features with varying properties. This study applied ensemble learning techniques (ELTs), a meta-algorithm that combine several basic machine learning models into one predictive model in order to decrease variance, bias, or improve predictions, in multimodal neuroimaging data collected from 72 young adults, including 36 probands (18 remitters and 18 persisters of childhood ADHD) and 36 group-matched controls. All currently available optimization strategies for ELTs (i.e., voting, bagging, boosting and stacking techniques) were tested in a pool of semifinal classification results generated by seven basic classifiers. The high-dimensional neuroimaging features for classification included regional cortical gray matter (GM) thickness and surface area, GM volume of subcortical structures, volume and fractional anisotropy of major white matter fiber tracts, pair-wise regional connectivity and global/nodal topological properties of the functional brain network for cue-evoked attention process. As a result, the bagging-based ELT with the base model of support vector machine achieved the best results, with significant improvement of the area under the receiver of operating characteristic curve (0.89 for ADHD vs. controls and 0.9 for ADHD persisters vs. remitters). Features of nodal efficiency in right inferior frontal gyrus, right middle frontal (MFG)-inferior parietal (IPL) functional connectivity, and right amygdala volume significantly contributed to accurate discrimination between ADHD probands and controls; higher nodal efficiency of right MFG greatly contributed to inattentive and hyperactive/impulsive symptom remission, while higher right MFG-IPL functional connectivity strongly linked to symptom persistence in adults with childhood ADHD. Considering their improved robustness than the commonly implemented basic classifiers, findings suggest that ELTs may have the potential to identify more reliable neurobiological markers for neurodevelopmental disorders.

P.047 Circulating exosomal microRNAs in bipolar disorder

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder that emerges in childhood and persists into adulthood in a sizeable portion of afflicted individuals. The persistence of ADHD symptoms elevates the risk of adverse outcomes that result in substantial individual and societal burden. The objective of this study was to delineate neuroanatomical substrates associated with the diversity of adult outcomes of childhood ADHD, which may have considerable value for development of novel interventions that target mechanisms associated with recovery. Structural MRI and diffusion tensor imaging data from 32 young adults who were diagnosed with ADHD combined-type during childhood and 35 group-matched controls were analyzed. Adults with childhood ADHD were divided into 16 remitters and 16 persisters based on DSM-IV criteria. Compared to the controls, ADHD probands showed significantly reduced gray matter (GM) volume in right putamen and white matter (WM) volume in left parieto-insular fiber tracts. Within the ADHD probands, the remitters, as compared to persisters, showed significantly greater volume of right hippocampo-frontal and right parieto-insular WM fiber tracts, and those connecting caudate with the frontal, parietal, occipital, temporal, and insular cortices. Among ADHD probands, increased fractional anisotropy value of left caudate-parietal tract was significantly correlated with reduced hyperactive/impulsive symptoms. These findings suggest that optimal structural development in the WM tracts that connect caudate with cortical areas, especially in the caudate-parietal path, may play an important role in symptom remission in young adults with childhood ADHD.

Increased Functional Segregation Related to the Salience Network in Unaffected Siblings of Youths With Attention-Deficit/Hyperactivity Disorder

Although there are frequent reports of shared neurofunctional and neurostructural alterations among probands with attention-deficit/hyperactivity disorder (ADHD) and their unaffected siblings, there is little knowledge regarding whether abnormalities in the resting-state functional connectivity of ADHD probands is also expressed in unaffected siblings, or whether this unaffected (but at-risk) cohort manifests distinct patterns. We used a multivariate connectome-wide association study examining intrinsic functional connectivity with resting-state functional magnetic resonance imaging (MRI) in a sample (aged 8-17 years) of medication-naive ADHD probands (n= 56), their unaffected siblings (n= 55), and typically developing (TD) youths (n= 106). ADHD probands showed, relative to TD youths, increased connectivity between the default-mode network (DMN) and task-positive networks. Relative to ADHD and TD groups, respectively, unaffected siblings showed increased connectivity within the salience network and reduced connectivity between the DMN and salience network. No shared alterations in functional connectivity among ADHD probands and their unaffected siblings were identified. These findings were largely confirmed by complementary pairwise connectomic comparisons. However, the main connectivity differences between ADHD and unaffected siblings were not replicated in a tightly age- and sex-matched subsample (20 proband-sibling pairs and 60 TD youths). Our findings suggest that increased functional segregation related to the attention networks, especially the salience (ventral attention) system, may be a potential feature of at-risk siblings who remain unaffected by ADHD expression. Further replications are needed in other larger and sex-matched samples. Structural and Functional Connectivity of Frontostriatal and Frontoparietal Networks as Endophenotypes of ADHD; https://clinicaltrials.gov/; NCT01682915.

Shared alterations in resting-state brain connectivity in adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental condition that often persists into adulthood with extensive negative consequences on quality of life. Despite emerging evidence indicating the genetic basis of ADHD, investigations into the familial expression of latent neurocognitive traits remain limited. In a group of adult ADHD probands (n = 20), their unaffected first-degree relatives (n = 20) and typically developing control participants (n = 20), we assessed endophenotypic alterations in the default mode network (DMN) connectivity during resting-state functional magnetic resonance imaging in relation to cognitive performance and clinical symptoms. In an external validation step, we also examined the dimensional nature of this neurocognitive trait in a sample of unrelated healthy young adults (n = 100) from the Human Connectome Project (HCP). The results illustrated reduced anti-correlations between the posterior cingulate cortex/precuneus and right middle frontal gyrus that was shared between adult ADHD probands and their first-degree relatives, but not with healthy controls. The observed connectivity alterations were linked to higher ADHD symptoms that was mediated by performance in a sustained attention task. Moreover, this brain-based neurocognitive trait dimensionally explained ADHD symptom variability in the HCP sample. Alterations in the default mode connectivity may represent a dimensional endophenotype of ADHD, hence a significant aspect of the neuropathophysiology of this disorder. As such, brain network organisation can potentially be employed as an important neurocognitive trait to enhance statistical power of genetic studies in ADHD and as a surrogate efficacy endpoint in the development of novel pharmaceuticals.

Risk of Atopic Diseases among Siblings of Patients with Attention-Deficit Hyperactivity Disorder: A Nationwide Population-Based Cohort Study

Background: Increasing evidence suggests a positive association between attention-deficit hyperactivity disorder (ADHD) and atopic diseases. However, the risk of atopic diseases in unaffected siblings of patients with ADHD has not been investigated. Objective: To investigate the risk of developing atopic diseases among unaffected siblings of ADHD probands. Methods: Using data from the Taiwan National Health Insurance Research Database, 20,170 unaffected siblings of patients with ADHD born between 1980 and 2000 and 80,680 age-, birth time-, and residence-matchedcontrols were included in this study. Diagnoses of atopic diseases, including asthma, atopic dermatitis, allergic rhinitis, and allergic conjunctivitis, were ascertained from 1996 or the birth time until the end of 2011. Results: Breslow-Cox proportional hazard regression analyses with adjustment for demographic data showed that compared with the controls, unaffected siblings of patients with ADHD had a higher risk of developing asthma (relative risk [RR], 1.19; 95% confidence interval [CI], 1.15–1.24), atopic dermatitis (RR, 1.10; 95% CI, 1.04–1.16), allergic rhinitis (RR, 1.17; 95% CI, 1.14–1.21), allergic conjunctivitis (RR, 1.13; 95% CI, 1.09–1.17), and any of these atopic diseases (RR, 1.13; 95% CI, 1.10–1.15). Conclusion: The unaffected siblings of ADHD probands were more likely to develop atopic diseases compared with the controls, suggesting shared risk factors for both diseases.