COMT genotype affects brain white matter pathways in attention-deficit/hyperactivity disorder.
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ABSTRACT:
SUBMITTER: Hong SB
PROVIDER: S-EPMC6869623 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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COMT genotype affects brain white matter pathways in attention-deficit/hyperactivity disorder.
Hong Soon-Beom SB Zalesky Andrew A Park Subin S Yang Young-Hui YH Park Min-Hyeon MH Kim BoAh B Song In-Chan IC Sohn Chul-Ho CH Shin Min-Sup MS Kim Bung-Nyun BN Cho Soo-Churl SC Kim Jae-Won JW
Human brain mapping 20140909 1
Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. This study aimed to derive a comprehensive, whole-brain characterization of large-scale axonal connectivity differences in attention-deficit/hyperactivity disorder (ADHD) associated with catechol-O-methyltransferase gene (COMT) Val158Met polymorphism. Using diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach, we characterized altered white ...[more]
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Project description:BackgroundThis study sought to identify attention-deficit/hyperactivity disorder (ADHD) abnormalities in relationships between brain white matter structure and individual differences in several types of impulsive behavior.MethodsAdolescents, n = 67 with ADHD combined subtype and n = 68 without ADHD, were given neuropsychological tests and underwent diffusion tensor imaging scans. Principal component analysis reduced test scores into factors representing different types of impulsive behavior. Tract-based spatial statistics quantified white matter integrity in relationship to components of impulsive behavior. ADHD versus non-ADHD differences in the strength and nature of linear relationships between regional white matter and three impulsivity components were examined using multiple regression.ResultsPrincipal component analysis found three separate impulsivity-related factors that were interpreted as motor response inhibition, impulsive choice, and delay aversion. Relationships between regional fractional anisotropy and response inhibition or impulsive choice did not differ between ADHD and non-ADHD groups. There was a significant interaction between diagnostic group and delay aversion test performance relationships with regional fractional anisotropy. For youths without ADHD, greater anisotropy in numerous tracts predicted better delay aversion test performance. In contrast, anisotropy in regions including the corpus callosum, corona radiata, internal capsule, and corticospinal tracts had either a negative or no relationship with delay aversion test performance in ADHD.ConclusionsThe results provide additional support that different proposed etiological pathways to ADHD have discretely different neurobiological features. Large disorganization of white matter microstructure appears to contribute to reward-based ADHD pathways rather than motor inhibition.
| S-EPMC6549508 | biostudies-literature
Project description:INTRODUCTION:In this article, the COMT gene val(158)met polymorphism and attention-deficit hyperactivity disorder (ADHD)-related differences in diffusion-tensor-imaging-measured white matter (WM) structure in children with ADHD and controls were investigated. PATIENTS AND METHODS:A total of 71 children diagnosed with ADHD and 24 controls aged 8-15 years were recruited. Using diffusion tensor imaging, COMT polymorphism and ADHD-related WM alterations were investigated, and any interaction effect between the COMT polymorphism and ADHD was also examined. The effects of age, sex, and estimated total IQ were controlled by multivariate analysis of covariance (MANCOVA). RESULTS:First, an interaction between the COMT val(158)met polymorphism and ADHD in the right (R) cingulum (cingulate gyrus) (CGC) was found. According to this, valine (val) homozygote ADHD-diagnosed children had significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the R-CGC than ADHD-diagnosed methionine (met) carriers, and val homozygote controls had higher FA and lower RD in the R-CGC than val homozygote ADHD patients. Second, met carriers had higher FA and axial diffusivity in the left (L)-uncinate fasciculus and lower RD in the L-posterior corona radiata and L-posterior thalamic radiation (include optic radiation) than the val homozygotes, independent of ADHD diagnosis. Third, children with ADHD had lower FA in the L-CGC and R-retrolenticular part of the internal capsule than the controls, independent of the COMT polymorphism. CONCLUSION:Significant differences reported here may be evidence that the COMT gene val(158)met polymorphism variants, as well as ADHD, could affect brain development. ADHD and the COMT polymorphism might be interactively affecting WM development in the R-CGC to alter the WM connectivity in children with val homozygote ADHD.
| S-EPMC4844431 | biostudies-literature
Project description:Attention-deficit/hyperactivity disorder has been identified to involve the impairment of large-scale functional networks within grey matter, and recent studies have suggested that white matter, which also encodes neural activity, can manifest intrinsic functional organization similar to that of grey matter. However, the alterations in white matter functional networks in attention-deficit/hyperactivity disorder remain unknown. We recruited a total of 99 children, including 66 drug-naive patients and 33 typically developing controls aged from 6 to 14, to characterize the alterations in functional networks within white matter in drug-naive children with attention-deficit/hyperactivity disorder. Using clustering analysis, resting-state functional MRI data in the white matter were parsed into different networks. Intrinsic activity within each network and connectivity between networks and the associations between network activity strength and clinical symptoms were assessed. We identified eight distinct white matter functional networks: the default mode network, the somatomotor network, the dorsal attention network, the ventral attention network, the visual network, the deep frontoparietal network, the deep frontal network and the inferior corticospinal-posterior cerebellum network. The default mode, somatomotor, dorsal attention and ventral attention networks showed lower spontaneous neural activity in patients. In particular, the default mode network and the somatomotor network largely showed higher connectivity with other networks, which correlated with more severe hyperactive behaviour, while the dorsal and ventral attention networks mainly had lower connectivity with other networks, which correlated with poor attention performance. In conclusion, there are two distinct patterns of white matter functional networks in children with attention-deficit/hyperactivity disorder, with one being the hyperactivity-related hot networks including default mode network and somatomotor network and the other being inattention-related cold networks including dorsal attention and ventral attention network. These results extended upon our understanding of brain functional networks in attention-deficit/hyperactivity disorder from the perspective of white matter dysfunction.
| S-EPMC7660033 | biostudies-literature
Project description:ImportanceClinical overlap between autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the underlying brain mechanisms remain unknown to date.ObjectiveTo examine associations between white matter organization and 2 commonly co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and dimensional approaches.Design, setting, and participantsThis investigation was a cross-sectional diffusion tensor imaging (DTI) study at an outpatient academic clinical and research center, the Department of Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants were children with ASD, children with ADHD, or typically developing children. Data collection was ongoing from December 2008 to October 2015.Main outcomes and measuresThe primary measure was voxelwise fractional anisotropy (FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy (MA).ResultsThis cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9 years), selected from a larger sample after quality assurance to be group matched on age and sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age, 8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and 50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD, and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of 4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum. Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05) with a significant association with parent ratings in the social responsiveness scale. Similar results were evident using an independent measure of ASD traits (ie, children communication checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716 voxels. All these findings were robust to algorithmic correction of motion artifacts with the DTIPrep software.Conclusions and relevanceDimensional analyses provided a more complete picture of associations between ASD traits and inattention and indexes of white matter organization, particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional relationships linking white matter structure to neurodevelopmental symptoms.
| S-EPMC5710226 | biostudies-literature
Project description:Previous voxel-based and regions-of-interest (ROI)-based diffusion tensor imaging (DTI) studies have found above-normal mean diffusivity (MD) and below-normal fractional anisotropy (FA) in subjects with attention-deficit/hyperactivity disorder (ADHD). However, findings remain mixed, and few studies have examined the contribution of ADHD familial liability to white matter microstructure.We used refined DTI tractography methods to examine MD, FA, axial diffusivity (AD), and radial diffusivity (RD) of the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major, forceps minor, superior longitudinal fasciculus, and uncinate fasciculus in children and adolescents with ADHD (n = 56), unaffected siblings of ADHD probands (n = 31), and healthy controls (n = 17).Subjects with ADHD showed significantly higher MD than controls in the anterior thalamic radiation, forceps minor, and superior longitudinal fasciculus. Unaffected siblings of subjects with ADHD displayed similar differences in MD as subjects with ADHD. Although none of the tested tracts showed a significant effect of FA, the tracts with elevated MD likewise displayed elevated AD both in subjects with ADHD and in unaffected siblings. Differences in RD between subjects with ADHD, unaffected siblings, and controls were not as widespread as differences in MD and AD.Our findings suggest that disruptions in white matter microstructure occur in several large white matter pathways in association with ADHD and indicate a familial liability for the disorder. Furthermore, MD may reflect these abnormalities more sensitively than FA.
| S-EPMC3633105 | biostudies-literature
Project description:BackgroundMagnetic resonance imaging (MRI) is able to provide detailed insights into the structural organization of the brain, e.g., by means of mapping brain anatomy and white matter microstructure. Understanding interrelations between MRI modalities, rather than mapping modalities in isolation, will contribute to unraveling the complex neural mechanisms associated with neuropsychiatric disorders as deficits detected across modalities suggest common underlying mechanisms. Here, we conduct a multimodal analysis of structural MRI modalities in the context of attention-deficit/hyperactivity disorder (ADHD).MethodsGray matter volume, cortical thickness, surface areal expansion estimates, and white matter diffusion indices of 129 participants with ADHD and 204 participants without ADHD were entered into a linked independent component analysis. This data-driven analysis decomposes the data into multimodal independent components reflecting common inter-subject variation across imaging modalities.ResultsADHD severity was related to two multimodal components. The first component revealed smaller prefrontal volumes in participants with more symptoms, co-occurring with abnormal white matter indices in prefrontal cortex. The second component demonstrated decreased orbitofrontal volume as well as abnormalities in insula, occipital, and somato-sensory areas in participants with more ADHD symptoms.ConclusionsOur results replicate and extend previous unimodal structural MRI findings by demonstrating that prefrontal, parietal, and occipital areas, as well as fronto-striatal and fronto-limbic systems are implicated in ADHD. By including multiple modalities, sensitivity for between-participant effects is increased, as shared variance across modalities is modeled. The convergence of modality-specific findings in our results suggests that different aspects of brain structure share underlying pathophysiology and brings us closer to a biological characterization of ADHD.
| S-EPMC4893015 | biostudies-literature
Project description:Attention-deficit/hyperactivity disorder (ADHD) in childhood is characterized by gray and white matter abnormalities in several brain areas. Considerably less is known about white matter microstructure in adults with ADHD and its relation with clinical symptoms and cognitive performance. In 107 adult ADHD patients and 109 gender-, age- and IQ-matched controls, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) to investigate whole-skeleton changes of fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). Additionally, we studied the relation of FA and MD values with symptom severity and cognitive performance on tasks measuring working memory, attention, inhibition, and delay discounting. In comparison to controls, participants with ADHD showed reduced FA in corpus callosum, bilateral corona radiata, and thalamic radiation. Higher MD and RD were found in overlapping and even more widespread areas in both hemispheres, also encompassing internal and external capsule, sagittal stratum, fornix, and superior lateral fasciculus. Values of FA and MD were not associated with symptom severity. However, within some white matter clusters that distinguished patients from controls, worse inhibition performance was associated with reduced FA and more impulsive decision making was associated with increased MD. This study shows widespread differences in white matter integrity between adults with persistent ADHD and healthy individuals. Changes in RD suggest aberrant myelination as a pathophysiological factor in persistent ADHD. The microstructural differences in adult ADHD may contribute to poor inhibition and greater impulsivity but appear to be independent of disease severity.
| S-EPMC4515357 | biostudies-literature
Project description:Changes in cerebral cortical anatomy have been tied to the clinical course of attention deficit hyperactivity disorder (ADHD). We now ask if alterations in white matter tract microstructure are likewise linked with the adult outcome of childhood ADHD. Seventy-five young adults, 32 with ADHD persisting from childhood and 43 with symptom remission were contrasted against 74 never-affected comparison subjects. Using diffusion tensor imaging, we defined fractional anisotropy, a metric related to white matter microstructure, along with measures of diffusion perpendicular (radial) and parallel (axial) to the axon. Analyses were adjusted for head motion, age and sex, and controlled for multiple comparisons and medication history. Tract-based analyses showed that greater adult inattention, but not hyperactivity-impulsivity, was associated with significantly lower fractional anisotropy in the left uncinate (standardized β=-0.37, t=3.28, p=0.002) and inferior fronto-occipital fasciculi (standardized β=-0.37, t=3.29, p=0.002). The ADHD group with symptoms persisting into adulthood had significantly lower fractional anisotropy than the never-affected controls in these tracts, differences associated with medium to large effect sizes. By contrast, the ADHD group that remitted by adulthood did not differ significantly from controls. The anomalies were found in tracts that connect components of neural systems pertinent to ADHD, such as attention control (inferior fronto-occipital fasciculus) and emotion regulation and the processing of reward (the uncinate fasciculus). Change in radial rather than axial diffusivity was the primary driver of this effect, suggesting pathophysiological processes including altered myelination as future targets for pharmacological and behavioral interventions.
| S-EPMC4289964 | biostudies-literature
Project description:A developmental improvement of symptoms in attention-deficit/hyperactivity disorder (ADHD) is frequently reported, but the underlying neurobiological substrate has not been identified. The aim of this study was to determine whether white matter microstructure is related to developmental improvement of ADHD symptoms.A cross-sectional magnetic resonance imaging (MRI) analysis was embedded in a prospective follow-up of an adolescent cohort of ADHD and control subjects (NeuroIMAGE). Mean age at baseline was 11.9 years, mean interval of follow-up was 5.9 years. About 75.3% of the original cohort was retained successfully. Data of 101 participants with ADHD combined type at baseline and 40 healthy controls were analysed. ADHD symptoms were measured with semistructured, investigator-based interviews and Conners' questionnaires, on the basis of DSM-IV criteria. Fractional anisotropy (FA) and mean diffusivity (MD) indices of white matter microstructure were measured using whole brain diffusion tensor imaging at follow-up only. In a dimensional analysis FA and MD were related to change in ADHD symptoms. To link this analysis to DSM-IV diagnoses, a post hoc categorical group analysis was conducted comparing participants with persistent (n = 59) versus remittent (n = 42) ADHD and controls.Over time, participants with ADHD showed improvement mainly in hyperactive/impulsive symptoms. This improvement was associated with lower FA and higher MD values in the left corticospinal tract at follow-up. Findings of the dimensional and the categorical analysis strongly converged. Changes in inattentive symptoms over time were minimal and not related to white matter microstructure.The corticospinal tract is important in the control of voluntary movements, suggesting the importance of the motor system in the persistence of hyperactive/impulsive symptoms.
| S-EPMC4499023 | biostudies-literature
Project description:BackgroundAutism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have high rates of co-occurrence and share atypical behavioral characteristics, including sensory symptoms. The present diffusion tensor imaging (DTI) study was conducted to examine whether and how white matter alterations are observed in adult populations with developmental disorders (DD) and to determine how brain-sensory relationships are either shared between or distinct to ASD and ADHD.MethodsWe collected DTI data from adult population with DD (a primary diagnosis of ASD: n = 105, ADHD: n = 55) as well as age- and sex-matched typically developing (TD) participants (n = 58). Voxel-wise fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD) were analyzed using tract-based spatial statistics. The severities of sensory symptoms were assessed using the Adolescent/Adult Sensory Profile (AASP).ResultsCategorical analyses identified voxel clusters showing significant effects of DD on FA and RD in the posterior portion of the corpus callosum and its extension in the right hemisphere. Furthermore, regression analyses using the AASP scores revealed that slopes in relationships of FA or RD with the degree of sensory symptoms were parallel between the two DDs in large parts of the affected corpus callosum regions. A small but significant cluster did exist showing difference in association between an AASP subscale score and RD across ASD and ADHD.LimitationsWide age range of the participants may be oversimplified.ConclusionsThese results indicate that white matter alteration and their relationships to sensory symptoms are largely shared between ASD and ADHD, with localized abnormalities showing significant between-diagnosis differences within DD.
| S-EPMC7570037 | biostudies-literature