Zhaomin Wu

Applying Imaging Genetics to ADHD: the Promises and the Challenges

Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent childhood psychiatric disorders. During the past decades, studies have focused on its genetic background and the abnormality of the brain structure and function. Recently, an advanced technique linking these two areas, namely, the imaging genetics emerged and kept growing. Imaging genetics primarily identifies genes that influence the brain variations. There are three main strategies of doing an imaging genetic study: using neuroimaging as endophenotypes to find the associated DNA variants, finding neuroimaging effects of risk genes, and hypothesis-free whole-brain voxelwise genome-wide association study. In this review, we begin with demonstrating the basic principles of imaging genetics precisely, with examples from other psychiatric conditions, and then go on to synthesize the existing imaging genetic studies in ADHD. Finally, we elaborate the challenges of applying imaging genetics to ADHD. We conclude that imaging genetics has somewhat showed its potential to provide a more precise understanding of how the genes shape the brain variations and further the clinical features of ADHD.

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.

Abnormalities of structural covariance networks in drug-naïve boys with attention deficit hyperactivity disorder.

The aim of this study is to investigate whether the anatomical organization of large-scale brain systems would change in ADHD patients compared to healthy controls. We utilized a structural covariance network (SCN) mapping approach to investigate large-scale networks in 30 drug-naïve ADHD boys and 30 gender- and age-matched controls. The regions showing significant between-group differences in gray matter (GM) volume were defined as seed regions of interest. Then, the SCNs derived from these seeds were statistically compared between ADHD and controls. Significant regional GM volume decreases (P<0.05, corrected) were observed in the right insula and the right orbito-frontal cortex (OFC) in ADHD relative to controls. Both SCNs derived from these two seeds showed more localized topology in ADHD group. Furthermore, significantly decreased structural connectivity were found between insula and right hippocampus, bilateral olfactory cortex, and between OFC and bilateral caudate nucleus (P<0.05, corrected) in ADHD group. Significantly increased association was observed between insula and left middle temporal gyrus (P<0.05, corrected) in ADHD group. Taken together, our results reveal abnormal regional brain anatomy as well as aberrant structural covariance networks in ADHD, supporting previous findings of dysfunction in distributed network organization in patients with ADHD.

The effects of cognitive-behavioral therapy on intrinsic functional brain networks in adults with attention-deficit/hyperactivity disorder.

Cognitive-behavioral therapy (CBT) is an efficacious psychological treatment for adults with attention-deficit/hyperactivity disorder (ADHD), but the neural processes underlying the benefits of CBT are not well understood. This study aims to unravel psychosocial mechanisms for treatment ADHD by exploring the effects of CBT on functional brain networks. Ten adults with ADHD were enrolled and resting-state functional magnetic resonance imaging scans were acquired before and after a 12-session CBT. Twelve age- and gender-matched healthy controls were also scanned. We constructed whole-brain functional connectivity networks using graph-theory approaches and further computed the changes of regional functional connectivity strength (rFCS) between pre- and post-CBT in ADHD for measuring the effects of CBT. The results showed that rFCS was increased in the fronto-parietal network and cerebellum, the brain regions that were most often affected by medication, in adults with ADHD following CBT. Furthermore, the enhanced functional coupling between bilateral superior parietal gyrus was positively correlated with the improvement of ADHD symptoms following CBT. Together, these findings provide evidence that CBT can selectively modulate the intrinsic network connectivity in the fronto-parietal network and cerebellum and suggest that the CBT may share common brain mechanism with the pharmacology in adults with ADHD.

Is Emotional Lability Distinct From "Angry/Irritable Mood," "Negative Affect," or Other Subdimensions of Oppositional Defiant Disorder in Children With ADHD?

Objective: Emotional lability (EL) and oppositional defiant disorder (ODD) frequently co-occur with ADHD. This study evaluates whether EL merely represents the negative “mood/affect” component of ODD or forms a distinct dimension. Method: EL and ODD data from 1,317 ADHD participants were analyzed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) for binary data. Results: Within ADHD, 39.4% children had ODD and 42.6% had EL. A sizable proportion expressed only either ODD or EL: 16.6% had ODD-only, 19.7% had EL-only, and 22.9% expressed both. In both EFA and CFA, EL forms a separate dimension from ODD items and the “mood/affect” subdimensions (whether classified by Diagnostic and Statistical Manual of Mental Disorders [5th ed.; DSM-5] or the Burke et al. models or the de novo ODD subdimensions derived from our data). This factorial structure remains invariant across gender. Conclusion: EL is distinct from ODD and its “mood/affect” subdimensions. In line with emerging evidence, our findings provide further evidence of factorial validity for EL as a separate construct from ODD.

Integrity of Amygdala Subregion-Based Functional Networks and Emotional Lability in Drug-Naïve Boys With ADHD

Objective: This study evaluated the functional networks of amygdala subregions (basolateral [BLA], centromedial [CMA], and superficial amygdala [SFA]) in ADHD and their association with emotional lability (EL) symptoms. Method: Resting-state functional connectivity (RSFC) of amygdala subregions and their correlations with EL scores were evaluated in 35 drug-naïve boys with ADHD and 30 age-matched healthy controls (HC). Results: Compared with HC, altered RSFC were detected differently for each amygdala subregion in ADHD: altered RSFC of BLA with the thalamus and vermis; aberrant RSFC of CMA with the superior temporal gyrus/pole and insula, precuneus and cerebellum; reduced RSFC of SFA with dorsal frontoparietal cortices. Within ADHD, higher EL scores were associated with reduced negative RSFC of SFA with the dorsolateral prefrontal cortex and inferior parietal lobe. Conclusion: Diffuse alterations of amygdala subregion-based networks are associated with ADHD, and the weaker SFA–frontoparietal networks might be involved in the hypothesized top–down effortful regulation of emotion.

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.

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.