The underlying neuropsychological and neural correlates of the impaired Chinese reading skills in children with attention deficit hyperactivity disorder.

Impaired basic academic skills (e.g., word recognition) are common in children with Attention Deficit Hyperactivity Disorder (ADHD). The underlying neuropsychological and neural correlates of impaired Chinese reading skills in children with ADHD have not been substantially explored. Three hundred and two children with ADHD (all medication-naïve) and 105 healthy controls underwent the Chinese language skill assessment, and 175 also underwent fMRI scans (84 ADHD and 91 controls). Between-group and mediation analyses were applied to explore the interrelationships of the diagnosis of ADHD, cognitive dysfunction, and impaired reading skills. Five ADHD-related brain functional networks, including the default mode network (DMN) and the dorsal attention network (DAN), were built using predefined regions of interest. Voxel-based group-wise comparisons were performed. The ADHD group performed worse than the control group in word-level reading ability tests, with lower scores in Chinese character recognition (CR) and word chains (WS) (all P < 0.05). With full-scale IQ and sustained attention in the mediation model, the direct effect of ADHD status on the CR score became insignificant (P = 0.066). The underlying neural correlates for the orthographic knowledge (OT) and CR differed between the ADHD and the control group. The ADHD group tended to recruit more DMN regions to maintain their reading performance, while the control group seemed to utilize more DAN regions. Children with ADHD generally presented impaired word-level reading skills, which might be caused by impaired sustained attention and lower IQ. According to the brain functional results, we infer that ADHD children might utilize a different strategy to maintain their orthographic knowledge and character recognition performance.

Identifying subgroups of attention-deficit/hyperactivity disorder from the psychopathological and neuropsychological profiles.

The Research Domain Criteria (RDoC) advocates the dimensional approach in characterizing mental disorders. We followed RDoC to characterize children with ADHD using profiling based on the cognitive and psychopathological domains. We aimed to identify and validate ADHD subtypes with different clinical characteristics and functional impairments. We recruited 362 drug-naïve children with ADHD and 103 typically developing controls. The cluster analysis was used to identify subgroups based on the Child Behaviour Checklist (CBCL) and the Behaviour Rating Inventory of Executive Function (BRIEF). The subgroups' clinical characteristics and functional impairments were assessed using the WEISS Functional Impairment Rating Scale-Parent Report (WFIRS-P) and the Conners Parent Symptom Questionnaire (PSQ). The cluster analysis yielded four subgroups: (1) ADHD with severe impairment in psychopathology and executive functions (EF), (2) ADHD with mild executive dysfunctions and normal-level psychopathology, (3) ADHD with severe externalizing problems and (4) ADHD with severe executive dysfunctions. These subgroups showed different clinical characteristics and degrees of functional impairment. The EF impairment group displayed more serious learning problems and worse life skills than the externalizing group. The two groups with externalizing problems (i.e. the severe impairment group and the externalizing group) both exhibited higher rates of the combined subtype of ADHD and higher rates of comorbid ODD. Different subtypes of ADHD displayed different profiles of internalizing and externalizing problems and levels of executive dysfunctions. In particular, the subtype with severe impairment in EF exhibited more learning problems and worse life skills, suggesting EF is a critical target for intervention in children with ADHD.

Specific brain imaging alterations underlying autistic traits in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Autistic traits (ATs) are frequently reported in children with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aimed to examine ATs in children with ADHD from both behavioral and neuroimaging perspectives. METHODS: We used the Autism Spectrum Screening Questionnaire (ASSQ) to assess and define subjects with and without ATs. For behavioral analyses, 67 children with ADHD and ATs (ADHD + ATs), 105 children with ADHD but without ATs (ADHD - ATs), and 44 typically developing healthy controls without ATs (HC - ATs) were recruited. We collected resting-state functional magnetic resonance imaging (rs-fMRI) data and analyzed the mean amplitude of low-frequency fluctuation (mALFF) values (an approach used to depict different spontaneous brain activities) in a sub-sample. The imaging features that were shared between ATs and ADHD symptoms or that were unique to one or the other set of symptoms were illustrated as a way to explore the "brain-behavior" relationship. RESULTS: Compared to ADHD-ATs, the ADHD + ATs group showed more global impairment in all aspects of autistic symptoms and higher hyperactivity/impulsivity (HI). Partial-correlation analysis indicated that HI was significantly positively correlated with all aspects of ATs in ADHD. Imaging analyses indicated that mALFF values in the left middle occipital gyrus (MOG), left parietal lobe (PL)/precuneus, and left middle temporal gyrus (MTG) might be specifically related to ADHD, while those in the right MTG might be more closely associated with ATs. Furthermore, altered mALFF in the right PL/precuneus correlated with both ADHD and ATs, albeit in diverse directions. CONCLUSIONS: The co-occurrence of ATs in children with ADHD manifested as different behavioral characteristics and specific brain functional alterations. Assessing ATs in children with ADHD could help us understand the heterogeneity of ADHD, further explore its pathogenesis, and promote clinical interventions.

The clinical, neuropsychological, and brain functional characteristics of the ADHD restrictive inattentive presentation.

Objectives: There is an ongoing debate about the restrictive inattentive (RI) presentation of attention deficit hyperactivity disorder (ADHD). The current study aimed to systematically investigate the clinical, neuropsychological, and brain functional characteristics of children with ADHD restrictive inattentive presentation. Methods: A clinical sample of 789 children with or without ADHD participated in the current study and finished clinical interviews, questionnaires, and neuropsychological tests. Those individuals with a diagnosis of ADHD were further divided into three subgroups according to the presentation of inattentive and/or hyperactive/impulsive symptoms, the ADHD-RI, the ADHD-I (inattentive), and the ADHD-C (combined) groups. Between-group comparisons were carried out on each clinical and neuropsychological measure using ANCOVA, with age and sex as covariates. Bonferroni corrections were applied to correct for multiple comparisons. Two hundred twenty-seven of the subjects also went through resting-state functional magnetic resonance imaging scans. Five ADHD-related brain functional networks, including the default mode network (DMN), the dorsal attention network (DAN), the ventral attention network, the executive control network, and the salience network, were built using predefined regions of interest (ROIs). Voxel-based group-wise comparisons were performed. Results: Compared with healthy controls, all ADHD groups presented more clinical problems and weaker cognitive function. Among the ADHD groups, the ADHD-C group had the most clinical problems, especially delinquent and aggressive behaviors. Regarding cognitive function, the ADHD-RI group displayed the most impaired sustained attention, and the ADHD-C group had the worst response inhibition function. In terms of brain functional connectivity (FC), reduced FC in the DMN was identified in the ADHD-C and the ADHD-I groups but not the ADHD-RI group, compared to the healthy controls. Subjects with ADHD-I also presented decreased FC in the DAN in contrast to the control group. The ADHD-RI displayed marginally significantly lower FC in the salience network compared to the ADHD-I and the control groups. Conclusion: The ADHD-RI group is distinguishable from the ADHD-I and the ADHD-C groups. It is characterized by fewer externalizing behaviors, worse sustained attention, and better response inhibition function. The absence of abnormally high hyperactive/impulsive symptoms in ADHD-RI might be related to less impaired brain function in DMN, but potentially more impairment in the salience network.

Behavioral and brain functional characteristics of children with Attention-Deficit/Hyperactivity disorder and anxiety trait.

The current study aimed to explore the behavioral, daily-life executive functional, and brain functional connectivity patterns in children with attention-deficit/hyperactivity disorder (ADHD) and anxiety. A total of 246 children with non-comorbid ADHD and 91 healthy controls (HCs) participated in the current study, among whom 175 subjects went through resting-state functional magnetic resonance imaging (fMRI) scans. The ADHD participants were divided into two subgroups: ADHD with a high level of anxiety (ADHD + ANX) and ADHD with a low level of anxiety (ADHD-ANX). The Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF) were used to capture the behavioral and daily-life executive functional characteristics. Independent component analysis with dual regression models was applied to the fMRI data. All statistical models were estimated with age and sex as covariates. Compared with the ADHD-ANX group, the ADHD + ANX group showed more withdrawn, somatic, social, thought, attention, delinquent, and aggressive problems (all corrected p < 0.05). The ADHD + ANX group also displayed more impaired emotional control and working memory than the ADHD-ANX (all corrected p < 0.05). The ADHD-ANX group, but not the ADHD + ANX group, showed elevated functional connectivity within the default mode network compared with the HC group. The mean function connectivity within the default mode network significantly mediated the correlation between anxiety level and attention problems. In sum, anxiety in children with ADHD was associated with more social, emotional, and behavioral problems, more impaired daily-life executive function, and altered brain function. Our work provides important information on the heterogeneity of ADHD.

Association between oppositional defiant disorder and parenting style in children with attention deficit hyperactivity disorder. / æ³¨æ„ç¼ºé™·å¤šåŠ¨éšœç¢å„¿ç«¥å ±æ‚£å¯¹ç«‹è¿æŠ—æ€§éšœç¢ä¸Žçˆ¶æ¯å »è‚²æ–¹å¼çš„ç›¸å ³æ€§.

OBJECTIVES: To study the association between oppositional defiant disorder (ODD) and parenting style in children with attention deficit hyperactivity disorder (ADHD). METHODS: A case-control study was performed on 482 children with ADHD, among whom 322 did not have ODD (simple ADHD group) and 160 had ODD (ADHD+ODD group). General demographic data and the Parenting Style Scale assessment scores were collected from the two groups. A multivariate logistic regression analysis was used to identify the association between parenting style and ODD in children with ADHD. RESULTS: There was no significant difference in parenting style scores (including rejection factor, emotional warmth factor, overprotection factor, and preference factor) and general demographic data between the simple ADHD and ADHD+ODD groups (P>0.05). Among the children with the predominantly inattentive type of ADHD, the older the child or the lower the father's educational level, the higher the risk of ODD (P<0.05), while there was no significant association between parenting style and the development of ODD (P>0.05). CONCLUSIONS: Parenting style is not significantly associated with the development of ODD in children with ADHD. In clinical practice, it is necessary to eliminate the stereotype that the parents of children with ADHD and comorbid ODD have a poor parenting style and look for the causes of development of ODD from multiple perspectives, so as to provide reasonable intervention recommendations.

Neuropsychological characteristics of children with Attention-Deficit/Hyperactivity Disorder and Sluggish Cognitive Tempo.

OBJECTIVE: The present study aims to explore the neuropsychological features of children with Attention-Deficit/Hyperactivity Disorder (ADHD) and Sluggish Cognitive Tempo (SCT). METHODS: Fifty-eight children with ADHD+SCT, 480 children with ADHD-SCT, and 105 healthy controls (HC) were recruited. Neuropsychological tests and the Behavior Rating Inventory of Executive Function (BRIEF) were used. RESULTS: The ADHD+SCT group performed worse than the HC in processing speed (p = .005), set-shifting (p = .0003), interference control (p = .00014), and visual memory (p = .007), while the ADHD-SCT group performed worse than the HC in sustained attention measurements (all p < .0001). The ADHD+SCT group scored higher than the ADHD-SCT group in the following factors from BRIEF: plan/organize (p = .00083), working memory (p < .001), and shift (p = .0054). CONCLUSION: Our results indicated that SCT symptoms are associated with worse executive function in children with ADHD except for sustained attention.

ADHD-inattentive versus ADHD-Combined subtypes: A severity continuum or two distinct entities? A comprehensive analysis of clinical, cognitive and neuroimaging data.

The current study aimed to explore the multimodal differences between the inattentive ADHD (ADHD-I) subtype and the combined ADHD (ADHD-C) subtype. A large sample of medication-naïve children with pure ADHD (i.e., without any comorbidity) (145 with ADHD-I, 132 with ADHD-C) and healthy controls (n = 98) were recruited. A battery of multiple scales and cognitive tests were utilized to assess the clinical and cognitive profiles of each individual. In addition, structural and diffusion magnetic resonance imaging (MRI) were acquired for 120 subjects with ADHD and 85 controls. Regional gray matter volume, white matter volume, and diffusion tensors, e.g., axial diffusivity (AD), were compared among the three groups in a whole-brain voxel-wise manner. Compared with healthy controls, both ADHD groups exhibited elevated levels of behavioral and emotional problems. The ADHD-C group had more behavioral problems and emotional liability, as well as less anxiety, than the ADHD-I group. The two ADHD groups were equally impaired in most cognitive domains, with the exception of sustained attention. Compared with healthy controls, the ADHD-C group showed a high gray matter volume (GMV) in the bilateral thalamus and a high white matter volume in the body of the corpus callosum, while the ADHD-I group presented an elevated GMV mainly in the left precentral gyrus and posterior cingulate cortex. Compared with participants with ADHD-C and healthy controls, subjects with ADHD-I showed increased AD in widespread brain regions. Our study has revealed a distinct, interconnected pattern of behavioral, cognitive, and brain structural characteristics in children with different ADHD subtypes.

Altered brain white matter microstructural asymmetry in children with ADHD.

OBJECTIVES: We aimed to examine brain white matter integrity in children with ADHD. METHODS: In a cohort of children with ADHD (n = 83) and healthy controls (n = 122), we used tract-based spatial statistics on Diffusion Tensor Imaging (DTI) data to obtain the mean fractional anisotropy (FA) in 40 bilateral regions of interest (ROIs). Lateralization Index (LI) was calculated. The difference in LI between groups and correlations between the LI of each ROI and ADHD symptom scores as well as cognitive function were examined. RESULTS: Children with ADHD had significantly greater LI at the posterior thalamic radiation (PTR) compared with healthy controls (mean LI in ADHD = 0.0096; in Control = 0.0044, p = 0.0143), and LI of the external capsule (EC) was significantly correlated with inattention symptoms in both groups (ß = -0.00059, p = 0.0181). LI of the PTR was significantly correlated with inhibitory function in healthy controls (ß = -0.0008510, p = 0.0248), but not in children with ADHD. CONCLUSION: We found increased brain white matter asymmetry (leftward) in children with ADHD compared with healthy controls at the posterior thalamic radiation. Leftward lateralization of FA values at the external capsule was negatively correlated with ADHD symptoms in both children with ADHD and healthy controls.

Linked anatomical and functional brain alterations in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: Neuroimaging studies have independently demonstrated brain anatomical and functional impairments in participants with ADHD. The aim of the current study was to explore the relationship between structural and functional brain alterations in ADHD through an integrated analysis of multimodal neuroimaging data. METHODS: We performed a multimodal analysis to integrate resting-state functional magnetic resonance imaging (MRI), structural MRI, and diffusion-weighted imaging data in a large, single-site sample of children with and without diagnosis for ADHD. The inferred subject contributions were fed into regression models to investigate the relationships between diagnosis, symptom severity, gender, and age. RESULTS: Compared with controls, children with ADHD diagnosis showed altered white matter microstructure in widespread white matter fiber tracts as well as greater gray matter volume (GMV) in bilateral frontal regions, smaller GMV in posterior regions, and altered functional connectivity (FC) in default mode and fronto-parietal networks. Age-related growth of GMV of bilateral occipital lobe, FC in frontal regions as well as age-related decline of GMV in medial regions seen in controls appeared reversed in children with ADHD. In the whole group, higher symptom severity was related to smaller GMV in widespread regions in bilateral frontal, parietal, and temporal lobes, as well as greater GMV in intracalcarine and temporal cortices. CONCLUSIONS: Through a multimodal analysis approach we show that structural and functional alterations in brain regions known to be altered in subjects with ADHD from unimodal studies are linked across modalities. The brain alterations were related to clinical features of ADHD, including disorder status, age, and symptom severity.

Verbal working memory-related functional connectivity alterations in boys with attention-deficit/hyperactivity disorder and the effects of methylphenidate.

OBJECTIVE: Few studies have investigated verbal working memory-related functional connectivity patterns in participants with attention-deficit/hyperactivity disorder (ADHD). Thus, we aimed to compare working memory-related functional connectivity patterns in healthy children and those with ADHD, and study effects of methylphenidate (MPH). METHOD: Twenty-two boys with ADHD were scanned twice, under either MPH (single dose, 10 mg) or placebo, in a randomised, cross-over, counterbalanced placebo-controlled design. Thirty healthy boys were scanned once. We used fMRI during a numerical n-back task to examine functional connectivity patterns in case-control and MPH-placebo comparisons, using independent component analysis. RESULTS: There was no significant difference in behavioural performance between children with ADHD, treated with MPH or placebo, and healthy controls. Compared with controls, participants with ADHD under placebo showed increased functional connectivity within fronto-parietal and auditory networks, and decreased functional connectivity within the executive control network. MPH normalized the altered functional connectivity pattern and significantly enhanced functional connectivity within the executive control network, though in non-overlapping areas. CONCLUSION: Our study contributes to the identification of the neural substrates of working memory. Single dose of MPH normalized the altered brain functional connectivity network, but had no enhancing effect on (non-impaired) behavioural performance.

White Matter Microstructural Alterations in Children with ADHD: Categorical and Dimensional Perspectives.

Studies of brain alterations in children with attention-deficit/hyperactivity disorder (ADHD) have shown heterogeneous results. The aims of the current study were to investigate white matter microstructure in children using both categorical and dimensional definitions of ADHD and to determine the functional consequences of observed alterations. In a large single-site sample of children (aged 8-15 years) with ADHD (n=83) and healthy controls (n=122), we used tract-based spatial statistics on diffusion tensor imaging data to investigate whole-skeleton differences of fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, RD), and mode of anisotropy related to ADHD status (categorical) and symptom severity (dimensional). For categorical differences observed, we analyzed their association with cognitive functioning in working memory and inhibition. Compared with healthy controls, children with ADHD showed decreased FA and increased RD in widespread, overlapping brain regions, mainly in corpus callosum (CC) and major tracts in the left hemisphere. Decreased FA was associated with inhibition performance in the participants with ADHD. Using dimensional definitions, greater hyperactivity/impulsivity symptom severity was associated with higher FA also in widespread regions, mainly in CC and major tracts in the right hemisphere. Our study showed white matter alterations to be related to ADHD status and symptom severity in patients. The coexistence of decreased FA and increased RD in the absence of alterations in MD or AD might indicate altered myelination as a pathophysiological factor in ADHD.

Cognitive Function of Children and Adolescents with Attention Deficit Hyperactivity Disorder and Learning Difficulties: A Developmental Perspective.

BACKGROUND: The 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. METHODS: Totally, 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. RESULTS: The 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). CONCLUSIONS: Children 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.

Interactions between MAOA and SYP polymorphisms were associated with symptoms of attention-deficit/hyperactivity disorder in Chinese Han subjects.

As candidate genes of attention--deficit/hyperactivity disorder (ADHD), monoamine oxidase A (MAOA), and synaptophysin (SYP) are both on the X chromosome, and have been suggested to be associated with the predominantly inattentive subtype (ADHD-I). The present study is to investigate the potential gene-gene interaction (G × G) between rs5905859 of MAOA and rs5906754 of SYP for ADHD in Chinese Han subjects. For family-based association study, 177 female trios were included. For case-control study, 1,462 probands and 807 normal controls were recruited. The ADHD Rating Scale-IV (ADHD-RS-IV) was used to evaluate ADHD symptoms. Pedigree-based generalized multifactor dimensionality reduction (PGMDR) for female ADHD trios indicated significant gene interaction effect of rs5905859 and rs5906754. Generalized multifactor dimensionality reduction (GMDR) indicated potential gene-gene interplay on ADHD RS-IV scores in female ADHD-I. No associations were observed in male subjects in case-control analysis. In conclusion, our findings suggested that the interaction of MAOA and SYP may be involved in the genetic mechanism of ADHD-I subtype and predict ADHD symptoms.