Hsiang-Yuan Lin

Regional brain volume differences between males with and without autism spectrum disorder are highly age-dependent

BackgroundNeuroanatomical differences between individuals with and without autism spectrum disorder (ASD) were inconsistent in the literature. Such heterogeneity may substantially originate from age-differential effects.MethodsVoxel-based morphometry was applied in 86 males with ASD and 90 typically developing control (TDC) males (aged 7 to 29 years). Three steps of statistical modeling (model 1, multiple regression with age as a covariate; model 2, multiple regression further considering diagnosis-by-age interaction; model 3, age-stratified analyses) were performed to dissect the moderating effects of age on diagnostic group differences in neuroanatomy.ResultsAcross ages, males with and without ASD did not differ significantly in total gray matter (GM) or white matter (WM) volumes. For both groups, total GM volumes decreased and WM volumes increased with age. For regional volume, comparing with the model only held the age constant (model 1), the main effect of group altered when diagnosis-by-age interaction effects were considered (model 2). Here, participants with ASD had significantly greater relative regional GM volumes than TDC in the right inferior orbitofrontal cortex and bilateral thalamus; for WM, participants with ASD were larger than TDC in the bilateral splenium of corpus callosum and right anterior corona radiata. Importantly, significant diagnosis-by-age interactions were identified at the bilateral anterior prefrontal cortex, bilateral cuneus, bilateral caudate, and the left cerebellum Crus I for GM and left forceps minor for WM. Finally, age-stratified analyses (model 3) showed distinct patterns in GM and WM volumetric alterations in ASD among subsamples of children, adolescents, and adults.ConclusionsOur findings suggest that the heterogeneous reports on the atypical neuroanatomy of ASD may substantially originate from age variation in the study samples. Age variation and its methodological and biological implications have to be carefully delineated in future studies of the neurobiology of ASD.

Intra-individual reaction time variability based on ex-Gaussian distribution as a potential endophenotype for attention-deficit/hyperactivity disorder

Intra‐individual variability in reaction time (IIV‐RT), defined by standard deviation of RT (RTSD), is considered as an endophenotype for attention‐deficit/hyperactivity disorder (ADHD). Ex‐Gaussian distributions of RT, rather than RTSD, could better characterize moment‐to‐moment fluctuations in neuropsychological performance. However, data of response variability based on ex‐Gaussian parameters as an endophenotypic candidate for ADHD are lacking.

An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE The efficacy of both methylphenidate and atomoxetine has been established in placebo-controlled trials. The present study aimed to directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms among children with attention-deficit/hyperactivity disorder (ADHD). METHODS The study sample included 160 drug-naïve children and adolescents 7-16 years of age, with DSM-IV-defined ADHD, randomly assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate) (n=80) and atomoxetine (n=80) in a 24 week, open-label, head-to-head clinical trial. The primary efficacy measure was the score of the ADHD Rating Scale-IV Parents Version: Investigator Administered and Scored (ADHD-RS-IV). The secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and Chinese Swanson, Nolan, and Pelham IV scale (SNAP-IV), based on the ratings of investigators, parents, teachers, and subjects. RESULTS At week 24, mean changes in ADHD-RS-IV Inattention scores were 13.58 points (Cohens d, -3.08) for OROS-methylphenidate and 12.65 points (Cohens d, -3.05) for atomoxetine; and mean changes in ADHD-RS-IV Hyperactivity-Impulsivity scores were 10.16 points (Cohens d, -1.75) for OROS-methylphenidate and 10.68 points (Cohens d, -1.87) for atomoxetine. In terms of parent-, teacher-, and self-ratings on behavioral symptoms, both of the two treatment groups significantly decreased on the SNAP-IV scores at the end-point, with effect sizes ranging from 0.9 to 0.96 on the Inattention subscale and from 0.61 to 0.8 on the Hyperactivity/Impulsivity subscale for OROS-methylphenidate; and from 0.51 to 0.88 on the Inattention subscale and from 0.29 to 0.57 on the Hyperactivity/Impulsivity subscale for atomoxetine. No statistically significant differences between treatment groups were observed on the outcome measures. Vomiting, somnolence, and dizziness were reported more often for atomoxetine than for OROS-methylphenidate, whereas insomnia was reported more often for OROS-methylphenidate than for atomoxetine. CONCLUSIONS After 24 weeks of treatment, OROS-methylphenidate and atomoxetine had comparable efficacy in reducing core ADHD symptoms in drug-naïve children and adolescents with ADHD.

Hyperconnectivity of the Right Posterior Temporo‐parietal Junction Predicts Social Difficulties in Boys with Autism Spectrum Disorder

The posterior right temporo‐parietal junction (pRTPJ) is a key brain region representing others mental status. Despite reports of atypical activation at pRTPJ during mentalizing in individuals with autism spectrum disorder (ASD), the intrinsic functional connectivity (iFC) of the pRTPJ remains under‐investigated. We examined whether boys with ASD show altered resting‐state iFC of the pRTPJ, and whether atypical iFC of the pRTPJ is associated with social deficits in ASD in a sample of 40 boys with high‐functioning ASD (aged 9–17 years, mean age, 12.38 ± 2.17; mean IQ, 105.60 ± 16.06) and 42 typically developing (TD) boys (aged 9–17 years, mean age, 11.64 ± 2.71; mean IQ, 111.29 ± 13.45). Both groups received resting‐state fMRI assessment after imaging data quality control for in‐scanner head motion and spatial coverage. Seed‐based approach was used to investigate iFC of the pRTPJ. TD and ASD boys demonstrated a resting‐state pRTPJ iFC pattern comparable to the known spatial involvement of the default‐mode network. Boys with ASD showed pRTPJ hyperconnectivity relative to TD boys in the right ventral occipito‐temporal cortex. This atypically increased iFC in the ASD group was positively correlated with social deficits assessed by the Chinese version of the Autism Diagnostic Interview‐Revised and the Social Responsive Scale. Our findings provide empirical support for functional “dysconnectivity,” that is, atypical functional integration among brain regions, as an integral component of the atypical neurobiology of ASD. Autism Res 2015, 8: 427–441.

Atomoxetine Treatment Strengthens an Anti-Correlated Relationship between Functional Brain Networks in Medication-Naïve Adults with Attention-Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Clinical Trial

Background: Although atomoxetine demonstrates efficacy in individuals with attention-deficit hyperactivity disorder, its treatment effects on brain resting-state functional connectivity remain unknown. Therefore, we aimed to investigate major brain functional networks in medication-naïve adults with attention-deficit hyperactivity disorder and the efficacy of atomoxetine treatment on resting-state functional connectivity. Methods: After collecting baseline resting-state functional MRI scans from 24 adults with attention-deficit hyperactivity disorder (aged 18–52 years) and 24 healthy controls (matched in demographic characteristics), the participants with attention-deficit hyperactivity disorder were randomly assigned to atomoxetine (n=12) and placebo (n=12) arms in an 8-week, double-blind, placebo-controlled trial. The primary outcome was functional connectivity assessed by a resting-state functional MRI. Seed-based functional connectivity was calculated and compared for the affective, attention, default, and cognitive control networks. Results: At baseline, we found atypical cross talk between the default, cognitive control, and dorsal attention networks and hypoconnectivity within the dorsal attention and default networks in adults with attention-deficit hyperactivity disorder. Our first-ever placebo-controlled clinical trial incorporating resting-state functional MRI showed that treatment with atomoxetine strengthened an anticorrelated relationship between the default and task-positive networks and modulated all major brain networks. The strengthened anticorrelations were associated with improving clinical symptoms in the atomoxetine-treated adults. Conclusions: Our results support the idea that atypical default mode network task-positive network interaction plays an important role in the pathophysiology of adult attention-deficit hyperactivity disorder. Strengthening this atypical relationship following atomoxetine treatment suggests an important pathway to treat attention-deficit hyperactivity disorder.

Differential effects of methylphenidate and atomoxetine on intrinsic brain activity in children with attention deficit hyperactivity disorder.

BACKGROUND Methylphenidate and atomoxetine are commonly prescribed for treating attention deficit hyperactivity disorder (ADHD). However, their therapeutic neural mechanisms remain unclear. METHOD After baseline evaluation including cognitive testing of the Cambridge Neuropsychological Test Automated Battery (CANTAB), drug-naive children with ADHD (n = 46), aged 7-17 years, were randomly assigned to a 12-week treatment with methylphenidate (n = 22) or atomoxetine (n = 24). Intrinsic brain activity, including the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo), was quantified via resting-state functional magnetic resonance imaging at baseline and week 12. RESULTS Reductions in inattentive symptoms were related to increased fALFF in the left superior temporal gyrus and left inferior parietal lobule for ADHD children treated with methylphenidate, and in the left lingual gyrus and left inferior occipital gyrus for ADHD children treated with atomoxetine. Hyperactivity/impulsivity symptom reductions were differentially related to increased fALFF in the methylphenidate group and to decreased fALFF in the atomoxetine group in bilateral precentral and postcentral gyri. Prediction analyses in the atomoxetine group revealed negative correlations between pre-treatment CANTAB simple reaction time and fALFF change in the left lingual gyrus and left inferior occipital gyrus, and positive correlations between pre-treatment CANTAB simple movement time and fALFF change in bilateral precentral and postcentral gyri and left precuneus, with a negative correlation between movement time and the fALFF change in the left lingual gyrus and the inferior occipital gyrus. CONCLUSIONS Our findings suggest differential neurophysiological mechanisms for the treatment effects of methylphenidate and atomoxetine in children with ADHD.

Atomoxetine could improve intra-individual variability in drug-naïve adults with attention-deficit/hyperactivity disorder comparably with methylphenidate: A head-to-head randomized clinical trial:

Objective: Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD. Methods: An 8–10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10–20 mg per dose) and atomoxetine once daily (n=26) (0.5–1.2 mg/kg/day). IIV-RT, derived from the Conners’ continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days). Results: We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors. Conclusion: Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation.

Shared atypical brain anatomy and intrinsic functional architecture in male youth with autism spectrum disorder and their unaffected brothers.

BACKGROUND Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males. METHOD The 94 participants (aged 9-19 years) - 20 male youth with ASD, 20 unaffected brothers and 54 TD males - received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference. RESULTS We found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers. CONCLUSIONS Atypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.

Neural correlates of impaired self-regulation in male youths with autism spectrum disorder: A voxel-based morphometry study

&NA; Although recent studies revealed impaired self‐regulation (dysregulation) in autism spectrum disorder (ASD), neural correlates of dysregulation and its impacts on autistic neuroanatomy remain unclear. Voxel‐based morphometry was applied on structural MRI images in 81 ASD and 61 typically developing (TD) boys aged 7–17 years. Dysregulation was defined by the sum of T‐scores of Attention, Aggression, and Anxiety/Depression subscales in the Child Behavior Checklist > 180. There were 53 and 28 boys in the ASD + Dysregulation and ASD‐Dysregulation groups, respectively. First, we compared regional gray matter (GM) volume for ASD and TD. Second, we investigated regional GM volumetric differences among the ASD + Dysregulation, ASD‐Dysregulation and TD groups. Lastly, shared and distinct neurostructural correlates of dysregulation were investigated in the ASD and TD groups. The ASD‐TD difference on neuroanatomy no longer existed after controlling the dysregulation severity. ASD + Dysregulation had larger regional GM volumes in the right fusiform gyrus, and smaller GM volumes in the anterior prefrontal cortex than ASD‐Dysregulation and TD, respectively. ASD + Dysregulation had smaller GM volumes in the left lateral occipital/superior parietal cortex than TD boys. No GM difference was identified between ASD‐Dysregulation and TD. ASD and TD had a shared association between GM volumes in the orbitofrontal cortex and dysregulation levels. Our findings suggest that atypical neuroanatomy associated with ASD might partially reflect a disproportionate level of impaired self‐regulation. Categorical and dimensional considerations of dysregulation should be implemented in future ASD studies. HighlightsNeural correlates of dysregulation in ASD remain unclear.ASD with and without dysregulation exhibits different regional GM volumes.Dysregulation might partially contribute to atypical neuroanatomy associated with ASD.OFC/VMPFC GM volumes are negatively associated with dysregulation levels.

Relationship between parenting stress and informant discrepancies on symptoms of ADHD/ODD and internalizing behaviors in preschool children

Parent and teacher ratings of child behaviors are often discrepant, and these discrepancies may be correlated with parenting stress. The present study explored whether various parenting stress factors are associated with discrepancies between parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder (ODD) as well as internalizing symptoms in preschool children. We recruited 299 Taiwanese preschool children (aged 4–6 years) from the community or via clinical referrals. A structural equation modeling was used to analyze the relationships among three factors derived from the Parenting Stress Index-Short Form and informant discrepancies on symptoms of inattention, hyperactivity/impulsivity, ODD, and internalizing behaviors. Scores reported by parents were higher for each of the symptoms examined than those reported by teachers, and the degree of agreement between informants ranged from low to moderate. The parental distress factor of parenting stress was associated only with parent ratings, whereas other factors of parenting stress—parent-child dysfunctional interaction and parents’ stress resulted from their child’s temperament—were correlated with both parent and teacher ratings. Only parental distress factor predicted informant discrepancies for all behavioral symptoms assessed. Our findings suggest that parental distress should be considered when parent rating scores show significant discrepancies from that of teacher rating scores.