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.

Ocular and neural genes jointly regulate the visuospatial working memory in ADHD children.

OBJECTIVE: Working memory (WM) deficits have frequently been linked to attention deficit hyperactivity disorder (ADHD). Despite previous studies suggested its high heritability, its genetic basis, especially in ADHD, remains unclear. The current study aimed to comprehensively explore the genetic basis of visual-spatial working memory (VSWM) in ADHD using wide-ranging genetic analyses. METHODS: The current study recruited a cohort consisted of 802 ADHD individuals, all met DSM-IV ADHD diagnostic criteria. VSWM was assessed by Rey-Osterrieth complex figure test (RCFT), which is a widely used psychological test include four memory indexes: detail delayed (DD), structure delayed (SD), structure immediate (SI), detail immediate (DI). Genetic analyses were conducted at the single nucleotide polymorphism (SNP), gene, pathway, polygenic and protein network levels. Polygenic Risk Scores (PRS) were based on summary statistics of various psychiatric disorders, including ADHD, autism spectrum disorder (ASD), major depressive disorder (MDD), schizophrenia (SCZ), obsessive compulsive disorders (OCD), and substance use disorder (SUD). RESULTS: Analyses at the single-marker level did not yield significant results (5E-08). However, the potential signals with P values less than E-05 and their mapped genes suggested the regulation of VSWM involved both ocular and neural system related genes, moreover, ADHD-related genes were also involved. The gene-based analysis found RAB11FIP1, whose encoded protein modulates several neurodevelopment processes and visual system, as significantly associated with DD scores (P = 1.96E-06, Padj = 0.036). Candidate pathway enrichment analyses (N = 53) found that forebrain neuron fate commitment significantly enriched in DD (P = 4.78E-04, Padj = 0.025), and dopamine transport enriched in SD (P = 5.90E-04, Padj = 0.031). We also observed a significant negative relationship between DD scores and ADHD PRS scores (P = 0.0025, Empirical P = 0.048). CONCLUSIONS: Our results emphasized the joint contribution of ocular and neural genes in regulating VSWM. The study reveals a shared genetic basis between ADHD and VSWM, with GWAS indicating the involvement of ADHD-related genes in VSWM. Additionally, the PRS analysis identifies a significant relationship between ADHD-PRS and DD scores. Overall, our findings shed light on the genetic basis of VSWM deficits in ADHD, and may have important implications for future research and clinical practice.

Shared and Unique Effects of Long-Term Administration of Methylphenidate and Atomoxetine on Degree Centrality in Medication-Naïve Children With Attention-Deficit/Hyperactive Disorder.

BACKGROUND: Although methylphenidate (MPH) and atomoxetine (ATX) can improve clinical symptoms and functional impairments in attention deficit/hyperactive disorder (ADHD), the underlying psychopharmacological mechanisms have not been clearly elucidated. Therefore, we aimed to explore the shared and unique neurologic basis of these 2 medications in alleviating the clinical symptoms and functional impairments observed in ADHD. METHODS: Sixty-seven ADHD and 44 age-matched children with typical development were included and underwent resting-state functional magnetic resonance imaging scans at baseline. Then patients were assigned to MPH, ATX, or untreated subgroups, based on the patients' and their parents' choice, for a 12-week follow-up and underwent a second functional magnetic resonance imaging scan. The treatment effect on degree centrality (DC) was identified and correlated with clinical symptoms and functional impairments in the ADHD group. RESULTS: Both MPH and ATX normalized the DC value in extensive brain regions mainly involving fronto-cingulo-parieto-cerebellum circuits. However, ATX showed limited significant effects on the cerebellum compared with ADHD at baseline. The improvements in clinical symptoms were correlated with increased DC in the right inferior temporal gyrus in both MPH and ATX subgroups but showed opposite effects. The alleviation of functional impairments in the school/learning domain negatively correlated with decreased DC in the bilateral cerebellum after MPH treatment, and the family functional domain positively correlated with decreased DC in the cerebellum and negatively correlated with decreased DC in the postcentral gyrus after ATX treatment. CONCLUSIONS: Both MPH and ATX can normalize abnormal brain functions that mainly involve the fronto-cingulo-parieto-cerebellum circuit in ADHD. Furthermore, the 2 medications showed shared and unique effects on brain functions to alleviate clinical symptoms and functional impairment.

Efficacy and tolerability of antidepressant drugs in treatment of depression in children and adolescents: a network meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of antidepressants in treatment of depression disorder in children and adolescents by network meta-analysis. METHODS: Databases of PubMed, Cochrane Library, EMBASE, Web of Science, PsycINFO, CBM, CNKI and Wanfang Data were searched for randomized controlled trials (RCT) related to antidepressants in treatment of children and adolescents with depression from inception to December 2021. Quality assessment and data extraction from the included RCTs were performed. Statistical analyses of efficacy and tolerability were conducted with Stata 15.1 software. Surface under the cumulative ranking (SUCAR) was used to rank the value of the antidepressants. RESULTS: A total of 33 RCTs were included in 32 articles, involving 6949 patients. There are 13 antidepressants used in total, including amitriptyline, vilazodone, fluoxetine, selegiline, paroxetine, imipramine, desipramine, sertraline, nortriptyline, escitalopram, citalopram, venlafaxine and duloxetine. The results of network meta-analysis showed that the efficacy of duloxetine ( OR=1.95, 95% CI: 1.41-2.69), fluoxetine ( OR=1.73, 95% CI: 1.40-2.14), venlafaxine ( OR=1.37, 95% CI: 1.04-1.80) and escitalopram ( OR=1.48, 95% CI: 1.12-1.95) were significantly higher than that of placebos (all P<0.05); the probability cumulative ranks were duloxetine (87.0%), amitriptyline (83.3%), fluoxetine (79.0%), escitalopram (62.7%), etc. The results showed that the intolerability of patients receiving imipramine ( OR=0.15, 95% CI: 0.08-0.27), sertraline ( OR=0.33, 95% CI: 0.16-0.71), venlafaxine ( OR=0.35, 95% CI: 0.17-0.72), duloxetine ( OR=0.35, 95% CI: 0.17-0.73) and paroxetine ( OR=0.52, 95% CI: 0.30-0.88) were significantly higher than that of placebos (all P<0.05), and the probability cumulative ranks were imipramine (95.7%), sertraline (69.6%), venlafaxine (68.6%), duloxetine (68.2%), etc. Conclusion: Among 13 antidepressants, duloxetine, fluoxetine, escitalopram and venlafaxine are significantly better than placebo in terms of efficacy, but duloxetine and venlafaxine are less well tolerated.

Efficacy and acceptability of a second dose of ecological executive skills training for children with ADHD: a randomized controlled study and follow-up.

To explore the efficacy and acceptability of a second dose of the 12-session ecological executive skills training (EEST) 1 year after the initial training in children with ADHD. A total of 97 children (aged 6-12) with ADHD who finished the first dose for about 1 year were recruited in the current study. 70 children who agreed to participate the second dose were randomized to the second dose or waitlist group. Both groups were followed up 1 year after the second dose. Executive function, core symptoms were assessed at the time of pre-intervention first dose, pre-intervention second dose, post-intervention second dose and follow-up 1 year after second dose (phase 0-3). For the immediate efficacy, the improvements in the second dose group were greater than the waitlist group on planning by Stockings of Cambridge and delay aversion by Cambridge gambling task (P = 0.02-0.04, η2 = 0.07-0.08). The parent rating of symptoms assessed by ADHD-RS-IV of the second dose group were also greater than the waitlist group rated by self-report. For long term efficacy, Linear mixed model indicated that there was significant time effect for both groups between phase 3 and phase 1, phase 1 and phase 0 on Behavior Rating Scales of Executive Function and ADHD-RS-IV (F = 2.849-21.560, P = 0.001-0.048). The compliance rate was 94.3% for the second dose group and 49% for waitlist group. A second dose of EEST program might bring further efficacy of EF and core symptoms for children with ADHD and it was well accepted.

Predictors of outcome in early onset schizophrenia: a 10-year follow-up study.

BACKGROUND: Younger age at onset is generally thought to be a predictor of poor outcome in Early Onset Schizophrenia (EOS), but there is a paucity of epidemiological data supporting this belief. This study aims to describe long-term outcomes and predictors of patient functioning in EOS, with a focus on the effect of age at onset. METHODS: We consecutively enrolled 118 EOS patients who were hospitalized in 2006. Mean age at baseline was 13.3 ± 2.3 years. Sixty-five subjects were successfully interviewed. Mean length of follow up was 10.4 ± 0.3 years. Baseline data were collected from inpatient medical records, while follow up was conducted primarily through telephone interviews of patient relatives. WHODAS 2.0 was used to measure global functioning at follow up. Outcomes included education, employment, marriage status, physical health, subsequent diagnoses and treatment, and patient functioning. Univariate and multivariate regression models were used to assess predictors of outcome, while propensity scores were used to adjust for confounding in analyzing the effect of age at onset on functional outcome. RESULTS: Of the 65 subjects where follow-up data were available, 3 were deceased at follow up. Five (8%) discontinued treatment. Diagnostic stability was 76%. Nearly a quarter (24%) were using clozapine at follow up. In male and female patients, 61 and 55% respectively were overweight, while 29 and 32% respectively were obese. Sixteen (26%) were economically self-sufficient, while 34 (55%) were unemployed. Thirteen (21%) patients had ever been married. The median WHODAS score was 15 (IQR 2 to 35), roughly corresponding to the 78th percentile on population norms. Extroverted personality (p = 0.01), suspicious personality (p = 0.02), and high level of education (p = 0.001) predicted better functioning. Age of onset was not associated with function in either the univariate model (p = 0.24), full model (p = 0.17) or the final risk factor model (p = 0.11), nor after using propensity scores to further adjust for confounders. CONCLUSION: The long-term functional outcome of EOS is more optimistic than generally believed. Age at disease onset does not predict long-term functional outcome in EOS populations.

Influence of More Than 5 Years of Continuous Exposure to Antipsychotics on Cerebral Functional Connectivity of Chronic Schizophrenia.

OBJECTIVE: To explore the effect of long-term antipsychotics use on the strength of functional connectivity (FC) in the brains of patients with chronic schizophrenia. METHOD: We collected resting-state functional magnetic resonance imaging from 15 patients with continuously treated chronic schizophrenia (TCS), 19 patients with minimally TCS (MTCS), and 20 healthy controls (HCs). Then, we evaluated and compared the whole-brain FC strength (FCS; including full-range, short-range, and long-range FCS) among patients with TCS, MTCS, and HCs. RESULTS: Patients with TCS and MTCS showed reduced full-/short-range FC compared with the HCs. No significant differences in the whole-brain FCS (including full-range, short-range, and long-range FCS) or clinical characteristics were identified between patients with TCS and MTCS. Additionally, the FCS in the right fusiform gyrus, right inferior temporal gyrus, and right inferior occipital gyrus negatively correlated with the duration of illness and positively correlated with onset age across all patients with chronic schizophrenia. CONCLUSIONS: Regardless of the long-term use of antipsychotics, patients with chronic schizophrenia show decreased FC compared with healthy individuals. For some patients with chronic schizophrenia, the influence of long-term and minimal/short-term antipsychotic exposure on resting-state FC was similar. The decreased full- and short-range FCS in the right fusiform gyrus, right inferior temporal gyrus, and right inferior occipital gyrus may be an ongoing pathological process that is not altered by antipsychotic interventions in patients with chronic schizophrenia. Large-sample, long-term follow-up studies are still needed for further exploration.

[Multi-dimensional exploration of the characteristics of emotional regulation in children with attention-deficit/hyperactivity disorder].

OBJECTIVE: To explore the characteristics of emotional regulation in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Two hundred and eighty-two children who were diagnosed as ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) were recruited from the child psychiatric clinic of Peking University Sixth Hospital/Institute of Mental Health from August 2012 to April 2014. And 260 normal children from the local primary schools were selected as the healthy control group. The emotional factors or items of Conners' Parent Rating Scale, Behavior Rating Inventory of Executive Function (BRIEF), Achenbach's Child Behavior Checklist (CBCL) and Rutter Children Behavior Questionnaire were used to assess the characteristics of emotional regulation multi-dimensionally. RESULTS: After controlling for the effects of age, sex and intelligence quotient (IQ), in Conner scale, the emotional lability (EL) scores of ADHD group were significantly higher than that of healthy control group [(4.3±2.6) vs (1.4±1.5), P<0.001]. In BRIEF scale, the emotional control (ECTRL) scores of ADHD group were significantly higher than that of control group [(16.1±4.4) vs (12.0±2.5), P<0.001]. In CBCL scale, the deficient emotional self-regulation (DESR) scores of ADHD group were significantly higher than that of control group [(26.8±11.0) vs (6.6±6.8), P<0.001]. In Rutter questionnaire, the emotional symptoms (ES) scores of ADHD group were significantly higher than that of control group [(2.7±2.0) vs (1.7±1.5), P<0.001]. Based on the receiver operating characteristics (ROC) curve, the area under the curve (AUC) of EL was 0.84 with 95% Confidence Intervals (CI) 0.81-0.87. The AUC of ECTRL was 0.81 with 95%CI 0.77-0.84. The AUC of DESR was 0.95 with 95%CI 0.93-0.97. The AUC of ES was 0.66 with 95%CI 0.61-0.70. CONCLUSIONS: The study multi-dimensionally indicated that children with ADHD displayed significant deficient emotional regulation.

Probabilistic diffusion tractography and graph theory analysis reveal abnormal white matter structural connectivity networks in drug-naive boys with attention deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD), which is characterized by core symptoms of inattention and hyperactivity/impulsivity, is one of the most common neurodevelopmental disorders of childhood. Neuroimaging studies have suggested that these behavioral disturbances are associated with abnormal functional connectivity among brain regions. However, the alterations in the structural connections that underlie these behavioral and functional deficits remain poorly understood. Here, we used diffusion magnetic resonance imaging and probabilistic tractography method to examine whole-brain white matter (WM) structural connectivity in 30 drug-naive boys with ADHD and 30 healthy controls. The WM networks of the human brain were constructed by estimating inter-regional connectivity probability. The topological properties of the resultant networks (e.g., small-world and network efficiency) were then analyzed using graph theoretical approaches. Nonparametric permutation tests were applied for between-group comparisons of these graphic metrics. We found that both the ADHD and control groups showed an efficient small-world organization in the whole-brain WM networks, suggesting a balance between structurally segregated and integrated connectivity patterns. However, relative to controls, patients with ADHD exhibited decreased global efficiency and increased shortest path length, with the most pronounced efficiency decreases in the left parietal, frontal, and occipital cortices. Intriguingly, the ADHD group showed decreased structural connectivity in the prefrontal-dominant circuitry and increased connectivity in the orbitofrontal-striatal circuitry, and these changes significantly correlated with the inattention and hyperactivity/impulsivity symptoms, respectively. The present study shows disrupted topological organization of large-scale WM networks in ADHD, extending our understanding of how structural disruptions of neuronal circuits underlie behavioral disturbances in patients with ADHD.

[Altered anatomical asymmetry in children with attention deficit/hyperactivity disorder: a pilot optimized voxel-based morphometric study].

OBJECTIVE: Mounting evidence suggests that attention deficit/hyperactivity disorder (ADHD) is related with abnormal anatomical asymmetry in some brain regions, such as basal ganglia.However, few cross-sectional studies have examined the abnormalities of anatomical asymmetry in whole brain of ADHD. Thus this cross-sectional study was to explore the anatomical asymmetry in whole brain of ADHD with optimized voxel-based morphometry (OVBM). METHODS: Twenty-five boys with ADHD and 27 age and gender-matched controls were recruited. All participants were right-handed. The grey matter concentration of each voxel was calculated with OVBM. A statistical evaluation of grey matter asymmetry was then conducted on normalized grey matter images and their flipped counterparts. RESULTS: One-sample t-test revealed that the whole-brain anatomical asymmetry pattern was similar in two groups. Through group comparisons, ADHD showed reversed left-greater-than-right asymmetry in superior and middle frontal gyri versus controls. CONCLUSION: Anatomical asymmetry of prefrontal cortex is abnormal in children with ADHD. And abnormal anatomical asymmetry may play an important role in the pathophysiology of ADHD.

[Memory characteristic in boys with attention deficit/hyperactivity disorder comorbid learning disability].

OBJECTIVE: To explore the memory characteristic in boys with attention-deficit/hyperactivity disorder (ADHD) plus learning disability (LD). METHODS: A total of 97 ADHD boys with comorbid LD (ADHD+LD), 97 ADHD boys without comorbid LD (ADHD-LD) and 97 healthy controls (based on the criteria of DSM-IV) were recruited from the outpatient clinic of Peking University Sixth Hospital from December 2003 to September 2012. Individuals across three groups were matched by ages, intelligence quotient (IQ) and ADHD subtypes. The Wechsler Memory Scale (WMS) was used to access the characteristics of several memory domains. RESULTS: ADHD +LD group performed the worst and control group the best in memory quotient (MQ) (90 ± 15 vs 98 ± 14 & 104 ± 14) and long-term memory domain ((36.0 ± 10.2) vs (42.1 ± 7.8) & (45.6 ± 6.7) score, all P < 0.05) . ADHD+LD group scored significantly lower than the control group in short-term memory ( (53.0 ± 9.2) vs (58.0 ± 9.7) score, P < 0.05) and immediate memory domains ((10.0 ± 3.3) vs (11.3 ± 3.5) score, P < 0.05). However, ADHD+LD group scored slightly but not significantly lower than the ADHD-LD group ((54.9 ± 10.7),(10.8 ± 3.2) score, P > 0.05). In most subscales of WMS, ADHD+LD group scored significantly lower than both ADHD-LD and control group in current information and orientation, mental control (1→100) , mental control (100→1) and associate learning subscales ( (8.8 ± 3.1) vs (10.0 ± 3.0) & (9.9 ± 2.3) score, (8.7 ± 4.1) vs (10.0 ± 3.9) & (11.1 ± 3.6) score, (10.7 ± 3.9) vs (12.9 ± 2.8) & (13.7 ± 2.2) score, (9.8 ± 3.1) vs (10.8 ± 2.6) & (11.1 ± 2.1) score, all P < 0.05) . In mental control (accumulation) subscale, all pairwise comparisons were statistically significant (all P < 0.05) . In subscales of figure memory, visual reproduction and digit span, ADHD+LD scored significantly lower than the control group (all P < 0.05), but not the ADHD-LD group (all P > 0.05). CONCLUSIONS: Boys with ADHD comorbid LD show deficits in overall memory function and long-term memory while short-term memory is partially damaged. Impairment in immediate memory is not detected.

Altered Intrinsic Brain Spontaneous Activities in Children With Autism Spectrum Disorder Comorbid ADHD.

OBJECTIVE: The study involved 17 children with Autism Spectrum Disorder (ASD), 21 with ADHD, 30 with both (ASD + ADHD), and 28 typically developing children (TD). METHODS: The amplitude of low-frequency fluctuations (ALFF) was measured as a regional brain function index. Intrinsic functional connectivity (iFC) was also analyzed using the region of interest (ROI) identified in ALFF analysis. Statistical analysis was done via one-way ANCOVA, Gaussian random field (GRF) theory, and post-hoc pair-wise comparisons. RESULTS: The ASD + ADHD group showed increased ALFF in the left middle frontal gyrus (MFG.L) compared to the TD group. In terms of global brain function, the ASD group displayed underconnectivity in specific regions compared to the ASD + ADHD and TD groups. CONCLUSION: The findings contribute to understanding the neural mechanisms underlying ASD + ADHD.

The shared white matter developmental trajectory anomalies of attention-deficit/hyperactivity disorder and autism spectrum disorders: A meta-analysis of diffusion tensor imaging studies.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) show common brain area abnormalities, which may contribute to the high shared co-occurrence symptoms and comorbidity of the two disorders. However, neuroanatomic anomalies in neurodevelopmental disorders may change over the course of development, and the developmental variation of these two disorders is unclear. Our study conducted a systematic literature search of PubMed, Web of Science, and EMBASE databases to identify disorder-shared abnormalities of white matter (WM) from childhood to adulthood in ADHD and ASD. 28 ADHD and 23 ASD datasets were included in this meta-analysis and were analysed by AES-SDM to detect differences in fractional anisotropy in patients compared to typically developing individuals. Our main findings reveal the variable WM developmental trajectories in ADHD and ASD respectively, and the two disorders showed overlapping corpus callosum tract abnormalities in their development from children to adults. Furthermore, the overlapping abnormalities of the corpus callosum tract increased with age, which may be related to their gradually increasing shared symptoms and comorbidity in these two disorders.

RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder.

Background: Many psychiatric disorders share a working memory (WM) impairment phenotype, yet the genetic causes remain unclear. Here, we generated genetic profiles of WM deficits using attention-deficit/hyperactivity disorder samples and validated the results in zebrafish models. Methods: We used 2 relatively large attention-deficit/hyperactivity disorder cohorts, 799 and 776 cases, respectively. WM impairment was assessed using the Rey Complex Figure Test. First, association analyses were conducted at single-variant, gene-based, and gene-set levels. Deeper insights into the biological mechanism were gained from further functional exploration by bioinformatic analyses and zebrafish models. Results: Genomic analyses identified and replicated a locus with rs75885813 as the index single nucleotide polymorphism showing significant association with WM defects but not with attention-deficit/hyperactivity disorder. Functional feature exploration found that these single nucleotide polymorphisms may regulate the expression level of RBFOX1 through chromatin interaction. Further pathway enrichment analysis of potential associated single nucleotide polymorphisms revealed the involvement of posttranscription regulation that affects messenger RNA stability and/or alternative splicing. Zebrafish with functionally knocked down or genome-edited rbfox1 exhibited WM impairment but no hyperactivity. Transcriptome profiling of rbfox1-defective zebrafish indicated that alternative exon usages of snap25a might partially lead to reduced WM learning of larval zebrafish. Conclusions: The locus with rs75885813 in RBFOX1 was identified as associated with WM. Rbfox1 regulates synaptic and long-term potentiation-related gene snap25a to adjust WM at the posttranscriptional level.

Cerebral blood flow characteristics of drug-naïve attention-deficit/hyperactivity disorder with social impairment: Evidence for region-symptom specificity.

Background: Social deficits are among the most important functional impairments in attention-deficit/hyperactivity disorder (ADHD). However, the relationship between social impairment and ADHD core symptoms as well as the underlying cerebral blood flow (CBF) characteristics remain unclear. Methods: A total of 62 ADHD subjects with social deficits (ADHD + SD), 100 ADHD subjects without social deficits (ADHD-SD) and 81 age-matched typically developing controls (TDC) were enrolled. We first examined the correlation between the Social Responsiveness Scale (SRS-1) and ADHD core symptoms (inattention, hyperactivity, and impulsion) and then explored categorical and dimensional ADHD-related regional CBF by arterial spin labeling (ASL). For the categorical analysis, a voxel-based comparison of CBF maps between the ADHD + SD, ADHD-SD, and TDC groups was performed. For the dimensional analysis, the whole-brain voxel-wise correlation between CBF and ADHD symptoms (inattention, hyperactivity/impulsivity, and total scores) was evaluated in three groups. Finally, correlations between the SRS-1 and ADHD-related regional CBF were investigated. We applied Gaussian random field (GRF) for the correction of multiple comparisons in imaging results (voxel-level P < 0.01, and cluster-level P < 0.05). Results: The clinical characteristics analysis showed that social deficits positively correlated with ADHD core symptoms, especially in social communication and autistic mannerisms domains. In the categorical analysis, we found that CBF in the left middle/inferior temporal gyrus in ADHD groups was higher than TDCs and was negatively correlated with the social motivation scores. Moreover, in dimensional analysis, we found that CBF in the left middle frontal gyrus was negatively correlated with the inattention scores, SRS total scores and autistic mannerisms scores in ADHD + SD subjects. Conclusion: The present study shows that inattention, hyperactivity, and impulsivity may be responsible for the occurrence of social deficits in ADHD, with autistic traits being another significant contributing factor. Additionally, CBF in the left middle/inferior temporal gyrus and the left middle frontal gyrus might represent the corresponding physiological mechanisms underlying social deficits in ADHD.

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.

Comparative study of OROS-MPH and atomoxetine on executive function improvement in ADHD: a randomized controlled trial.

This study aimed to compare the effects of osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine (ATX) on executive function in children and adolescents with attention deficit hyperactivity disorder (ADHD) by a randomized controlled trial. Subjects who met DSM-IV ADHD criteria were randomized to receive either OROS-MPH or ATX treatment. The doses were titrated to achieve optimal response and then maintained for 4-6 wk. A battery of executive function tests and the Behavior Rating Inventory of Executive Function (BRIEF) were administered to subjects who completed the dose titration (OROS-MPH, n=85; ATX, n=57) at the pre- and post-treatment periods. Forty-six children without ADHD were recruited as controls. Both OROS-MPH and ATX significantly improved scores in the Rey Complex Figure Test (RCFT), digit span, and Stroop color-word task. The scores in RCFT and the reverse digit span were not significantly different from the control group at post-treatment assessment (OROS-MPH=ATX=control, p>0.05), whereas the word interference time of the Stroop test was still more than that of the control group (OROS-MPH=ATX>control, p>0.05). OROS-MPH also significantly improved the total correct response in the verbal fluency test to normal level, and the shifting time in the trail-making test to subnormal level. The current findings suggest both OROS-MPH and ATX improved executive function generally in children and adolescents with ADHD, and could return working memory back to normative performance level.

Abnormal functional connectivity between the anterior cingulate and the default mode network in drug-naïve boys with attention deficit hyperactivity disorder.

A previous study indicated that adults with attention deficit hyperactivity disorder (ADHD) had a decreased anti-correlation between the dorsal anterior cingulate cortex (dACC) and the default mode network (DMN). In this study, we investigated whether children with ADHD also show a decreased anti-correlation between the dACC and the DMN. We also explored the developmental characteristics of the resting-state functional connectivity (RSFC) of the dACC with the DMN in children with ADHD. Resting-state functional magnetic resonance imaging scans were obtained from a 3T scanner in 19 drug-naïve boys with ADHD and 23 controls. Compared with normal controls, the dACC in boys with ADHD showed a significantly decreased negative RSFC with the DMN, including the dorsomedial prefrontal cortex and the posterior cingulate cortex. The RSFC strength between the dACC and the posterior cingulate cortex showed a significantly negative correlation with age in normal controls, but not in boys with ADHD. This decreased anti-correlation may suggest an abnormal balance or interaction between attentional and intrinsic thoughts. Our age-related analysis suggested an abnormal development pattern of the dACC-DMN interaction in ADHD.

Functional abnormality in the sensorimotor system attributed to NRXN1 variants in boys with attention deficit hyperactivity disorder.

Impaired sensorimotor circuits have been suggested in Attention-deficit/hyperactivity disorder (ADHD). NRXN1, highly expressed in cortex and cerebellum, was one of the candidate risk genes for ADHD, while its effects on sensorimotor circuits are unclear. In this content, we aimed to investigate the differential brain effects as functions of the cumulative genetic effects of NRXN1 variants in ADHD and healthy controls (HCs), identifying a potential pathway mapping from NRXN1, sensorimotor circuits, to ADHD. Magnetic resonance imaging, blood samples and clinical assessments were acquired from 53 male ADHD and 46 sex-matched HCs simultaneously. The effects of the cumulative genetic effects of NRXN1 variants valued by poly-variant risk score (PRS), on brain function was measured by resting-state functional connectivity (rs-FC) of cerebrocerebellar circuits. Mediation analyses were conducted to evaluate the association between NRXN1, functional abnormality, and ADHD diagnosis, as well as ADHD symptoms. The results were validated by bootstrapping and 10,000 times permutation tests. The rs-FC analyses demonstrated significant mediation models for ADHD diagnosis, and emphasized the involvement of cerebellum, middle cingulate gyrus and temporal gyrus, which are crucial parts of sensorimotor circuits. The current study suggested NRXN1 conferred risk for ADHD by regulating the function of sensorimotor circuits.

Identify aberrant white matter microstructure in ASD, ADHD and other neurodevelopmental disorders: A meta-analysis of diffusion tensor imaging studies.

BACKGROUND: Neurodevelopmental disorders (NDDs) usually present overlapping symptoms. Abnormal white matter (WM) microstructure has been found in these disorders. Identification of common and unique neural abnormalities across NDDs could provide further insight into the underlying pathophysiological mechanisms. METHODS: We performed a voxel-based meta-analysis of whole-brain diffusion tensor imaging (DTI) studies in autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) and other NDDs. A systematic literature search was conducted through March 2020 to identify studies that compared measures of WM microstructure between patients with NDDs and neurotypical controls. Peak voxel coordinates were meta-analyzed via anisotropic effect size-signed differential mapping (AES-SDM) as well as activation likelihood estimation (ALE). RESULTS: Our final sample included a total of 4137 subjects from 66 studies across five NDDs. Fractional anisotropy (FA) reductions were found in the splenium of the CC in ADHD, and the genu and splenium of CC in ASD. And mean diffusivity (MD) increases were shown in posterior thalamic radiation in ASD. No consistent abnormalities were detected in specific learning disorder, motor disorder or communication disorder. Significant differences between child/adolescent and adult patients were found within the CC across NDDs, reflective of aberrant neurodevelopmental processes in NDDs. CONCLUSIONS: The current study demonstrated atypical WM patterns in ASD, ADHD and other NDDs. Microstructural abnormalities in the splenium of the CC were possibly shared among ASD and ADHD.