Article

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: A cross-sectional mega-analysis

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Background: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. Methods: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156. Findings: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5). Interpretation: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. Funding: National Institutes of Health.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Finally, we estimated the heritability of the neural and behavioral markers and examined sex differences in the heritability estimates. The overall goal was to characterize structural brain alterations during an early and prodromal stage of ADHD, as with many of the ENIGMA studies of ADHD 19,54 , and to inform longitudinal research of later releases of the ABCD data. ...
... On the other hand, few extant VBM studies reported OFC GMV reduction in ADHD 27,52,103 . Children in the ABCD cohort were of 9 to 10 years of age, younger than the subject population reported in most of the earlier studies, which have suggested age-related changes in the volumetric correlates of ADHD 19,104 . For instance, machine learning demonstrated that although structural MRI data can significantly separate ADHD from control participants for both children and adults, prediction performance and effect sizes were better for the child than the adult samples 105 . ...
... Second, the correlations between ADHD scores and GMVs are relatively weak, which may reflect the non-clinical populations of the ABCD cohort. On the other hand, it is worth noting that the effect sizes were within the range reported of volumetric markers of ADHD cases 19 . Third, pubertal maturation may contribute to sex differences in brain development 149 . ...
Article
Full-text available
Previous research has demonstrated reduction in cortical and subcortical, including basal ganglia (BG), gray matter volumes (GMV) in individuals with attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition that is more prevalent in males than in females. However, the volumetric deficits vary across studies. Whether volumetric reductions are more significant in males than females; to what extent these neural markers are heritable and relate to cognitive dysfunction in ADHD remain unclear. To address these questions, we followed published routines and performed voxel-based morphometry analysis of a data set (n = 11,502; 5,464 girls, 9–10 years) curated from the Adolescent Brain Cognition Development project, a population-based study of typically developing children. Of the sample, 634 and 2,826 were identified as monozygotic twins and dizygotic twins/siblings, respectively. In linear regressions, a cluster in the hypothalamus showed larger GMV, and bilateral caudate and putamen, lateral orbitofrontal and occipital cortex showed smaller GMVs, in correlation with higher ADHD scores in girls and boys combined. When examined separately, boys relative to girls showed more widespread (including BG) and stronger associations between GMV deficits and ADHD scores. ADHD traits and the volumetric correlates demonstrated heritability estimates (a²) between 0.59 and 0.79, replicating prior findings of the genetic basis of ADHD. Further, ADHD traits and the volumetric correlates (except for the hypothalamus) were each negatively and positively correlated with N-back performance. Together, these findings confirm volumetric deficits in children with more prominent ADHD traits. Highly heritable in both girls and boys and potentially more significant in boys than in girls, the structural deficits underlie diminished capacity in working memory and potentially other cognitive deficits in ADHD.
... Considering that vision problems, including vision loss, blurred vision and strabismus, are influenced by environmental biological factors (e.g., pre-term birth [4] and/or systemic infections such as toxoplasmosis) [5,6], and given the established evidence on the involvement of these environmental risk factors in ADHD etiology [7], altered neurodevelopment may concurrently lead to the onset of vision disorders and symptoms of ADHD. Moreover, structures of the eye develop from the same embryological tissue as the brain [7,8] and ADHD is a neurodevelopmental disorder presenting with structural brain abnormalities [9]. Therefore, the development of ocular structures (including major structures of the eye and neural connections with brain structures involved in visual information processing and perception) might be affected by the same processes that cause ADHD [7,8,10]. ...
... This is further confounded by the close and intertwined relationship between perception and higher-level cognitive functions, and an incomplete understanding of the pathophysiology of ADHD. So far, the neurocognitive symptoms that define ADHD are largely conceived of as arising from structural and molecular abnormalities in the brain [9]. The brain and retina share embryological origins [7,8,10] and structural abnormalities of the eye have been detected in neuropsychiatric disorders with a genetic overlap with ADHD [87], including schizophrenia [88][89][90], bipolar disorder [91] and autism [92]. ...
Article
Full-text available
Aim To conduct the first systematic review and meta-analysis assessing whether attention-deficit/hyperactivity disorder (ADHD) is associated with disorders of the eye, and/or altered measures of visual function. Method Based on a pre-registered protocol (PROSPERO: CRD42021256352), we searched PubMed, Web of Knowledge/Science, Ovid Medline, Embase and APA PsycINFO up to 16th November 2021, with no language/type of document restrictions. We included observational studies reporting at least one measure of vision in people of any age meeting DSM/ICD criteria for ADHD and in people without ADHD; or the prevalence of ADHD in people with and without vision disorders. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS). Random effects meta-analyses were used for data synthesis. Results We included 42 studies in the narrative synthesis and 35 studies in the meta-analyses (3,250,905 participants). We found meta-analytic evidence of increased risk of astigmatism (OR = 1.79 [CI: 1.50, 2.14]), hyperopia and hypermetropia (OR = 1.79 [CI: 1.66, 1.94]), strabismus (OR = 1.93 [CI: 1.75, 2.12]), unspecified vision problems (OR = 1.94 [CI: 1.38, 2.73]) and reduced near point of convergence (OR = 5.02 [CI: 1.78, 14.11]); increased lag (Hedge’s g = 0.63 [CI: 0.30, 0.96]) and variability (Hedge’s g = 0.40 [CI: 0.17, 0.64]) of the accommodative response; and increased self-reported vision problems (Hedge’s g = 0.63 [CI: 0.44, 0.82]) in people with ADHD compared to those without ADHD (with no significant heterogeneity). We also found meta-analytic evidence of no differences between people with and without ADHD on retinal nerve fiber layer thickness (Hedge’s g = −0.19 [CI: −0.41, 0.02]) and refractive error (Hedge’s g = 0.08 [CI: −0.26, 0.42]) (with no significant heterogeneity). Discussion ADHD is associated with some self-reported and objectively ascertained functional vision problems, but not with structural alterations of the eye. Further studies should clarify the causal relationship, if any, between ADHD and problems of vision. Trial registration PROSPERO registration: CRD42021256352.
... Importantly, brain structural findings in CNV carriers appear to overlap, to some extent, with patterns of brain alterations found in several major brain disorders including ADHD (Hoogman et al., 2017), ASD (van Rooij et al., 2018), SCZ (van Erp et al., 2016), bipolar disorder , major depressive disorder (Schmaal et al., 2016), and epilepsy (Whelan et al., 2018). However, several CNVs clearly have effect sizes far greater than those of the idiopathic diseases (Figures 4 and 5). ...
... These alterations overlapped with the subcortical effects observed in the largest neuroimaging study of SCZ (van Erp et al., 2016), including smaller overall ICV, amygdala, hippocampal, and thalamic volumes. Furthermore, when compared to other ENIGMA subcortical psychiatric studies using the same image processing pipelines, subcortical volume alterations in 22q11DSassociated psychosis were strongly correlated with case-control effects found in studies of major depressive disorder (Schmaal et al., 2016), bipolar disorder (Hibar et al., 2016) and obsessive compulsive disorder (OCD; Boedhoe et al., 2017), but not with subcortical patterns reported in studies of ASD (van Rooij et al., 2018) or ADHD(Hoogman et al., 2017). Overall, 22q11DS and 22q11DS-associated psychosis effect sizes were larger than those found in all other ENIGMA studies of idiopathic psychiatric disorders(Figure 4). ...
Article
Full-text available
The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
... A previous metaanalysis showed that compared to healthy controls, children and adults with ADHD had smaller volumes in the nucleus accumbens, amygdala, caudate nucleus, hippocampus and putamen. 11 Preschoolers with ADHD also displayed smaller thalamus volumes compared to healthy controls. 12 Previous findings for hippocampal volumes in people with ADHD have been contradictory. ...
... 12 Previous findings for hippocampal volumes in people with ADHD have been contradictory. For example, unlike the metaanalysis described above, 11 1 study showed increased hippocampal volumes in children and adolescents with ADHD compared to controls. 13 Previous research has shown that subregions of the hippocampus and amygdala were distinguished both anatomically and functionally, 14,15 and that they responded differently in psychiatric disorders. ...
Article
Background: Patients with attention-deficit/hyperactivity disorder (ADHD) show structural alterations in the subcortical and dopaminergic regions of the brain. Methylphenidate is a first-line treatment for ADHD, and it is known to affect the subcortical and dopaminergic systems. The degree of pretreatment structural alterations in patients with ADHD may be an important factor in predicting methylphenidate treatment outcomes. The present study examined whether pretreatment volumetric alterations in the subcortical and dopaminergic regions predicted treatment response in youth with ADHD. Methods: This study included 67 youth with ADHD and 25 healthy controls. Youth with ADHD received 8 weeks of methylphenidate treatment. They completed baseline (pretreatment) T 1-weighted structural MRI scans and underwent clinical assessments before and after methylphenidate treatment. The healthy controls also completed baseline structural MRI scans. We assessed volumetric alterations using relative volumes (volume of each region of interest/intracranial volume). Results: Among 67 youth with ADHD, 44 were treatment responders and 23 were nonresponders based on post-treatment scores on the Clinical Global Impression Scale-Improvement. Nonresponders had larger volumes in the bilateral amygdala and right thalamus than responders. Nonresponders also had larger volumes in amygdalar subregions (i.e., the bilateral lateral nucleus and right basal nucleus) and hippocampal subregions (i.e., the right hippocampal head and right molecular layer) relative to responders. Limitations: We did not collect post-treatment structural T 1-weighted images, so volumetric changes related to methylphenidate treatment in youth with ADHD were undetermined. Conclusion: These findings suggest that pretreatment volumetric alterations in subcortical regions may serve as biomarkers for predicting methylphenidate treatment response in youth with ADHD.
... Prior morphological analyses have shown that ADHD is associated with altered shape and volume of thalamic nuclei, whose connections within several cortical regions, particularly frontal areas, seem aberrant in children with ADHD (Svatkova et al., 2016;Xia et al., 2012). On the other hand, the role of thalamus in the etiology of the disorder is controversial, given that casecontrol volumetric differences in this area were not confirmed in a recent meta-analysis (Hoogman et al., 2017). The meta-analysis did provide evidence for a different influence of age on thalamic volumes between clinical and nonclinical samples. ...
... Reinforcing this finding, the TD group in our study displayed stronger anisotropic diffusivity along the ATR as compared to the ADHD group. This finding further highlights the role of the basal ganglia and their morphological and volumetric differences as potential predictors of the disorder (Aylward et al., 1996;Hoogman et al., 2017;Oldehinkel et al., 2016;Paclt et al., 2016;Qiu et al., 2009;Sethi et al., 2017;Von Rhein et al., 2016). ...
Article
Full-text available
While pharmacological treatment with methylphenidate (MPH) is a first line intervention for ADHD, its mechanisms of action have yet to be elucidated. We here seek to identify the white matter tracts that mediate MPH's effect on beta oscillations. We implemented a double-blind placebo-controlled crossover design, where boys diagnosed with ADHD underwent behavioral and MEG measurements during a spatial attention task while on and off MPH. The results were compared with an age/IQ-matched control group. Estimates of white matter tracts were obtained using diffusion tensor imaging (DTI). Via a stepwise model selection strategy, we identified the fiber tracts (regressors) significantly predicting values of the dependent variables of interest (i.e., oscillatory power, behavioral performance, and clinical symptoms): the anterior thalamic radiation (ATR), the superior longitudinal fasciculus ("parietal endings") (SLFp), and superior longitudinal fasciculus ("temporal endings") (SLFt). ADHD symptoms severity was associated with lower fractional anisotropy (FA) within the ATR. In addition, individuals with relatively higher FA in SLFp compared to SLFt, led to stronger behavioral effects of MPH in the form of faster and more accurate responses. Furthermore, the same parietotemporal FA gradient explained the effects of MPH on beta modulation: subjects with ADHD exhibiting higher FA in SLFp compared to SLFt also displayed greater effects of MPH on beta power during response preparation. Our data suggest that the behavioral deficits and aberrant oscillatory modulations observed in ADHD depend on a possibly detrimental structural connectivity imbalance within the SLF, caused by a diffusivity gradient in favor of parietal rather than temporal, fiber tracts.
... Further AD(H)D-specific features, such as genetic risk variants (Riglin et al., 2016;Demontis et al., 2019), biochemical variations (Elia et al., 2011), neuromorphological (Castellanos et al., 2002;Mostofsky et al., 2002;Nakao et al., 2011;Seither-Preisler et al., 2014;Serrallach et al., 2016;Hoogman et al., 2017Hoogman et al., , 2019Firouzabadi et al., 2021;Pereira-Sanchez and Castellanos, 2021) or neurofunctional differences (Kuperman et al., 1996;Seither-Preisler et al., 2014;Serrallach et al., 2016;McVoy et al., 2019;Müller et al., 2019) have been described. This evidence adds to the validity of AD(H)D, which is characterized by the key symptoms of hyperactivity, impulsivity, and/or inattention (American Psychiatric Association, 2013;World Health Organization, 2019), as a neurodevelopmental disorder. ...
... Further, to date, there is no consensus on how to deal with the heterogeneity of AD(H)D. There are studies distinguishing AD(H)D subtypes/presentations (Lee et al., 2008;Seither-Preisler et al., 2014;Serrallach et al., 2016;Groß et al., 2022) and studies considering AD(H)D as a single group (Mostofsky et al., 2002;Nakao et al., 2011;Hoogman et al., 2017Hoogman et al., , 2019. Differentiating subtypes/presentations in future studies, could help to shed more light on subtype/presentation specific characteristics. ...
Article
Full-text available
Attention deficit (hyperactivity) disorder (AD(H)D) is one of the most common neurodevelopmental disorders in children with up to 60% probability of prevailing into adulthood. AD(H)D has far-fetching negative impacts on various areas of life. Until today, no observer-independent diagnostic biomarker is available for AD(H)D, however recent research found evidence that AD(H)D is reflected in auditory dysfunctions. Furthermore, the official diagnostic classification systems, being mainly the ICD-10 in Europe and the DSM-5 in the United States, are not entirely consistent. The neuro-auditory profiles of 82 adults (27 ADHD, 30 ADD, 25 controls) were measured via structural magnetic resonance imaging (MRI) and magnetoencephalography (MEG) to determine gray matter volumes and activity of auditory subareas [Heschl's gyrus (HG) and planum temporale (PT)]. All three groups (ADHD, ADD, and controls) revealed distinct neuro-auditory profiles. In the left hemisphere, both ADHD and ADD showed reduced gray matter volumes of the left HG, resulting in diminished left HG/PT ratios. In the right hemisphere, subjects with ADHD were characterized by lower right HG/PT ratios and ADD by a similar right HG/PT ratio compared to controls. Controls and ADD had well-balanced hemispheric response patterns, ADHD a left-right asynchrony. With this study, we present the structural and functional differences in the auditory cortex of adult patients with AD(H)D.
... In a recent meta-analysis of gray matter (GM), children with ADHD showed a decreased GM volume in the right globus pallidus, putamen, and bilateral caudate (6). Moreover, based on the ENIGMA-ADHD sample, the volumes of accumbens, amygdala, caudate, hippocampus, and putamen were found to be smaller in children with ADHD (7). So far, the majority of previous sMRI studies have applied univariate analysis methods, which provide local information but fail to demonstrate the interregional covarying relationship of GM volumes among different brain regions (8). ...
... These regions demonstrated a significant reduction of GM volume in ADHD relative to TDC. These findings are in line with our hypotheses and similar brain areas and GM volume changes have been reported in previous studies (6,7,(28)(29)(30)(31)(32)(33). Moreover, the basal ganglia are a key component of the dopaminergic mesolimbic system (34,35) and play a crucial role in goal-directed behaviors, motivation and reward processing, and motor control, all of which are known to be deficient in ADHD (10,36,37). ...
Article
Full-text available
Background Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset neurodevelopmental disorders; however, the underlying neural mechanisms for the inattention symptom remain elusive for children with ADHD. At present, the majority of studies have analyzed the structural MRI (sMRI) with the univariate method, which fails to demonstrate the interregional covarying relationship of gray matter (GM) volumes among brain regions. The scaled subprofile model of principal component analysis (SSM-PCA) is a multivariate method, which can detect more robust brain-behavioral phenotype association compared to the univariate analysis method. This study aims to identify the GM network associated with attention in children with ADHD by applying SSM-PCA to the sMRI.Methods The sMRI of 209 children with ADHD and 209 typically developing controls (TDCs) aged 7–14 years from the ADHD-200 dataset was used for anatomical computation, and the GM volume in each brain region was acquired. Then, SSM-PCA was applied to the GM volumes of all the subjects to capture the GM network of children with ADHD (i.e., ADHD-related pattern). The relationship between the expression of ADHD-related pattern and inattention symptom was further investigated. Finally, the influence of sample size on the analysis of this study was explored.ResultsThe ADHD-related pattern mainly included putamen, pallium, caudate, thalamus, right accumbens, superior/middle/inferior frontal cortex, superior occipital cortex, superior parietal cortex, and left middle occipital cortex. In addition, the expression of the ADHD-related pattern was related to inattention scores measured by the Conners’ Parent Rating Scale long version (CPRS-LV; r = 0.25, p = 0.0004) and the DuPaul ADHD Rating Scale IV (ADHD-RS; r = 0.18, p = 0.03). Finally, we found that when the sample size was 252, the results of ADHD-related pattern were relatively reliable. Similarly, the sample size needed to be 162 when exploring the relationship between ADHD-related pattern and behavioral indicator measured by CPRS-LV.Conclusion We captured a GM network associated with attention in children with ADHD, which is different from that in adolescents and adults with ADHD. Our findings may shed light on the diverse neural mechanisms of inattention and provide treatment targets for children with ADHD.
... The basal ganglia (i.e., caudate nucleus, globus pallidus and putamen) are involved in voluntary movement but also cognitive functions such as emotion regulationand sMRI studies have reported reduced volume in these regions in children with ADHD (Hoogman et al. 2017). The WM of the basal ganglia has also been investigated using an ROI approach. ...
... Related to this, large-scale meta-analyses conducted by the Enhancing Neuro-Imaging through Meta-Analysis (ENIGMA) ADHD consortium indicate that brain structural alterations are more evident in children with ADHD, with minimal differences between adults with ADHD and controls (Hoogman et al. 2017(Hoogman et al. , 2019. As resting-state networks, including the DMN, continue to mature throughout the adolescent period (Fair et al. 2009;Jolles et al. 2011), hypo-and hyperconnectivity in youths with ADHD might indicate delayed development and reflect less mature network organization (Bos et al. 2017). ...
Chapter
Full-text available
Attention-Deficit/Hyperactivity Disorder (ADHD) is increasingly viewed as a disorder of brain connectivity. We review connectivity-based theories of ADHD including the default mode network (DMN) interference and multiple network hypotheses. We outline the main approaches used to study brain connectivity in ADHD: diffusion tensor imaging and resting-state functional connectivity. We discuss the basic principles underlying these methods and the main analytical approaches used and consider what the findings have told us about connectivity alterations in ADHD. The most replicable finding in the diffusion tensor imaging literature on ADHD is lower fractional anisotropy in the corpus callosum, a key commissural tract which connects the brain's hemispheres. Meta-analyses of resting-state functional connectivity studies have failed to identify spatial convergence across studies, with the exception of meta-analyses focused on specific networks which have reported within-network connectivity alterations in the DMN and between the DMN and the fronto-parietal control and salience networks. Overall, methodological heterogeneity between studies and differences in sample characteristics are major barriers to progress in this area. In addition, females, adults and medication-naïve/unmedicated individuals are under-represented in connectivity studies, comorbidity needs to be assessed more systematically, and longitudinal research is needed to investigate whether ADHD is characterized by maturational delays in connectivity.
... Under the neurodiversity perspective, which entails a strength-based approach to mental disorders, ADHD symptoms are connected with multiple positive attributes such as creativity, risk taking, and intense concentration (White & Shah, 2011). The concept of neurodiversity was rooted in the research linking mental disorders with structural brain differences (Singer, 1999;Hoogman et al., 2017). These brain differences, which have remained in the gene pool throughout the natural process of evolution, can deliver positive implications. ...
Article
Full-text available
This study examines how entrepreneurial team conflict is influenced by Attention-Deficit Hyperactivity Disorder (ADHD) symptoms and gender factor as well as how team conflict impacts entrepreneurial well-being and firm performance. Surveying 1,053 entrepreneurs in the U.S and Australia, we found that ADHD symptoms are negatively associated with both cognitive team conflict and emotional team conflict. Moreover, although women entrepreneurs experience less both cognitive team conflict and emotional team conflict than men entrepreneurs, gender factor has no moderating effect on the relationship between ADHD and the two types of team conflict. In terms of the outcomes of team conflict, emotional conflict is negatively related to entrepreneurial well-being while cognitive conflict has no significant relationship with well-being. In addition, our findings suggested that both cognitive conflict and emotional conflict are negatively associated with firm performance. Overall, our study advances literature on entrepreneurial team (new venture team) as well as contributes to growing entrepreneurship research on ADHD, gender and well-being.
... Executive dysfunctions are critically dependent on the prefrontal cortex and can result from dysregulated catecholaminergic neurotransmission in the basal ganglia-thalamocortical circuit [9][10][11][12][13][14][15]. Pharmacological interventions that modulate the dysregulated catecholaminergic neurotransmission are recommended by the international guidelines (ESCAP European Guidelines), and psychostimulants, first, methylphenidate (MPH), are indicated as first-line treatment for ADHD. ...
Article
Full-text available
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inappropriate levels of attention, hyperactivity, and impulsivity that interfere with individual functioning. The international guidelines recommend targeting ADHD-related neurochemical brain abnormalities by intervening via drug treatment, such as methylphenidate (MPH), as first choice. Drug treatments are usually associated with a huge amount of cost for families and the healthcare system, suspension for low compliance, poor long-term efficacy, and side effects. Transcranial direct current stimulation (tDCS) has been suggested as a possible noninvasive means to safely manipulate brain activity and, in turn, improve behavior and cognition in developmental ages. Several studies have shown that tDCS has the potential to improve ADHD-related cognitive deficits, but the effect of tDCS compared with MPH has never been evaluated. The aim of the present within-subject, sham-controlled, randomized proof-of-concept study is to demonstrate the positive effect of one-session anodal tDCS analogous to the MPH drug on inhibitory control and working memory in children and adolescents with ADHD. We strongly believe that this study protocol will serve to accelerate research into low-cost, drug-free, feasible interventions for ADHD.
... Neuroinflammation has been suggested to interfere with brain development through causing chronic inflammation and increased oxidative stress in the brain (Donev and Thome, 2010;Min and Min, 2017), microglial activation (Reus et al., 2015), migration of neural progenitors (Belmadani et al., 2006), and altered neurotransmitter function (Kronfol and Remick, 2000), which would increase the risk of developing neurodevelopmental disorders subsequently. Furthermore, children with ADHD were found to have an about 4% reduction in overall brain gray matter volume in both cerebrum and cerebellum (Castellanos et al., 2002), especially over prefrontal cortex (Arnsten and Rubia, 2012), orbitofrontal cortex, anterior cingulate cortex (Amico et al., 2011), and basal ganglia (Hoogman et al., 2017). Exposure to environmental toxicants, such as PAHs, during early life has been found to disturb the development of the white matter in the left hemisphere, dorsal prefrontal region, and caudate nucleus, and increase the risk of attention-deficit hyperactivity disorder symptoms and behavioral problems in children (Mortamais et al., 2017;Peterson et al., 2015). ...
Article
Full-text available
Evidence regarding the negative neurodevelopmental effects of compound exposure to petrochemicals remains limited. We aimed to evaluate the association between exposure to petrochemical facilities and generated emissions during early life and the risk of attention-deficit/hyperactivity disorder (ADHD) development in children. We conducted a population-based birth cohort study using the 2004 to 2014 Taiwanese Birth Certificate Database and verified diagnoses of ADHD using the National Health Insurance Database. The level of petrochemical exposure in each participant's residential township was evaluated using the following 3 measurements: distance to the nearest petrochemical industrial plant (PIP), petrochemical exposure probability (accounting for monthly prevailing wind measurements), and monthly benzene concentrations estimated using kriging-based land-use regression models. We applied Cox proportional hazard models to evaluate the association. During the study period, 48,854 out of 1,863,963 children were diagnosed as having ADHD. The results revealed that residents of townships in close proximity to PIPs (hazard ratio [HR] = 1.20, 95% confidence interval [CI]: 1.16–1.23, <3 vs. ≥10 km), highly affected by petrochemical-containing prevailing winds (HR = 1.12, 95% CI: 1.08–1.16, ≥40% vs. <10%), and with high benzene concentrations (HR = 1.26, 95% CI: 1.23–1.29, ≥0.75 vs. <0.55 ppb) were consistently associated with the increased risk of ADHD development in children. The findings of the sensitivity analysis remained robust, particularly for the 2004 to 2009 birth cohort and for models accounting for a longer duration of postnatal exposure. This work provided clear evidence that living near petrochemical plants increases the risk of ADHD development in children. Further studies are warranted to confirm our findings.
... One of such approaches is cognitive-quantitative neuropsychology. From this perspective, the authors consider that ADHD occurs due to developmental failure of the brain circuits responsible for inhibition of attention and behavioral and emotional self-regulation [3;4], as well as due to impaired executive functions and working memory [9]. ...
Article
Full-text available
Previous studies report the absence of a single pattern of attention-deficit, as isolated clinical picture, according to neuropsychological and electrophysiological characteristics during ontogeny. The aim of this study was to use qualitative approach of cultural historical neuropsychology introduced by A.R. Luria to detect the neuropsychological functional factors which underline the cases of attention deficit and hyperactivity disorder in adolescence. The study included 20 adolescents, 10 with ADHD, and 10 control subjects. The method of analysis of neuropsychological syndrome was used to identify the functional state of neuropsychological brain factors according to the results of neuropsychological qualitative assessment. The electroencephalogram method was also applied, using a visual qualitative study to evaluate the functional level of cortical and subcortical brain structures. The results obtained using qualitative analysis of the data confirm the presence of different clinical pictures in adolescents with ADHD from neuropsychological and electrophysiological level of analysis. There is no any kind of unique isolated patterns, but rather, diffuse and more global participation of subcortical regulation of different levels. The results show that ADHD is not a single clinical picture as several neuropsychological profiles were detected. Qualitative analysis of syndromes, according to cultural historical approach, suggest the necessity of an individual approach for the precision of brain functional mechanisms (or neuropsychological factors) in each concrete case.
... Arterial hypertension can induce the progressive remodeling of brain vessels and lead to constant cognitive decline [26]. SHRs are usually used as a model of cerebral small vessel disease (cSVD) [8,27,28] or attention-deficit hyperactivity disorder (ADHD) disease [5,29,30], which are related to stable brain impairment [31][32][33][34]. In the current study, histology staining showed marked corpus callosum atrophy and hippocampal neuronal loss in SHRs, which may explain the demonstrated cognitive function deficits. ...
Article
Full-text available
Hydrocephalus is a complicated disorder that affects both adult and pediatric populations. The mechanism of hydrocephalus development, especially when there is no mass lesion present causing an obstructive, is poorly understood. Prior studies have demonstrated that spontaneously hypertensive rats (SHRs) develop hydrocephalus by week 7, which was attenuated with minocycline. The aim of this study was to determine sex differences in hydrocephalus development and to examine the effect of minocycline administration after hydrocephalus onset. Male and female Wistar–Kyoto rats (WKYs) and SHRs underwent magnetic resonance imaging at weeks 7 and 9 to determine ventricular volume. Choroid plexus epiplexus cell activation, cognitive deficits, white matter atrophy, and hippocampal neuronal loss were examined at week 9. In the second phase of the experiment, male SHRs (7 weeks old) were treated with either saline or minocycline (20 mg/kg) for 14 days, and similar radiologic, histologic, and behavior tests were performed. Hydrocephalus was present at week 7 and increased at week 9 in both male and female SHRs, which was associated with greater epiplexus cell activation than WKYs. Male SHRs had greater ventricular volume and epiplexus cell activation compared to female SHRs. Minocycline administration improved cognitive function, white matter atrophy, and hippocampal neuronal cell loss. In conclusion, while both male and female SHRs developed hydrocephalus and epiplexus cell activation by week 9, it was more severe in males. Delayed minocycline treatment alleviated hydrocephalus, epiplexus macrophage activation, brain pathology, and cognitive impairment in male SHRs.
... Altered structural or functional maturation of several brain areas might point toward a neurodevelopmental link of ADHD with reactive aggression. Among small morphological differences in several areas, the structural alterations implicated in ADHD involve reduced volumes within the limbic system, e.g., the amygdala and the hippocampus (15), as well as differential cortical thickness in frontal and parietotemporal brain regions (16). Besides structural implications in ADHD, these regions also exhibit altered functional connectivity and altered activity profiles in ADHD [as reviewed by Rubia (17)]; they have been linked to altered emotional reactivity and memory [limbic system, orbito, and ventromedial frontal cortex (18,19)] as well as executive functioning and attentional frontal and parietotemporal networks (20). ...
Article
Full-text available
Despite not being part of the core diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), emotion dysregulation is a highly prevalent and clinically important component of (adult) ADHD. Emotionally dysregulated behaviors such as reactive aggression have a significant impact on the functional outcome in ADHD. However, little is known about the mechanisms underlying reactive aggression in ADHD. In this study, we aimed to identify the neural correlates of reactive aggression as a measure of emotionally dysregulated behavior in adults with persistent ADHD during implicit emotion regulation processes. We analyzed associations of magnetic resonance imaging-based whole-brain activity during a dynamic facial expression task with levels of reactive aggression in 78 adults with and 78 adults without ADHD, and also investigated relationships of reactive aggression with symptoms and impairments. While participants with ADHD had higher reactive aggression scores than controls, the neural activation patterns of both groups to processing of emotional faces were similar. However, investigating the brain activities associated with reactive aggression in individuals with and without ADHD showed an interaction of diagnosis and reactive aggression scores. We found high levels of activity in the right insula, the hippocampus, and middle and superior frontal areas to be particularly associated with high reactive aggression scores within the ADHD group. Furthermore, the limbic activity was associated with more hyperactivity/impulsivity symptoms. These results suggest a partly differential mechanism associated with reactive aggression in ADHD as compared to controls. Emotional hyper-reactivity in the salience network as well as more effortful top–down regulation from the self-regulation network might contribute to emotionally dysregulated behavior as measured by reactive aggression.
... Brauer et al. (2011) stellten zum Beispiel fest, dass strukturelle Veränderungen des Gehirns der funktionellen Spezialisierung beim Spracherwerb vorausgehen. Hoogman et al. (2017) fanden durch die vergleichende Analyse von strukturellen Bildgebungsdaten von Kindern und Erwachsenen mit und ohne Aufmerksamkeitsdefizit-Hyperaktivitätsstörung (ADHS) Belege für eine Theorie der verzögerten Gehirnentwicklung als Ursache für ADHS. Neurowissenschaftliche Studien konnten außerdem zeigen, dass einerseits der Funktionserwerb in der frühkindlichen und kindlichen Entwicklung mit einer zunehmenden Spezialisierung von neuronalen Systemen einhergeht (Cantlon et al., 2011) und andererseits kognitiver Abbau und Funktions-verlust im höheren Lebensalter durch De-Differenzierung, also den Verlust dieser neuronalen Spezialisierung, begleitet wird (Park et al. 2012). ...
... Because we used cluster-based inference, effects were observed consistently across a large number of connected fixels; thus, maximum effect sizes at any specific fixel within a cluster can be much smaller than in standard statistical tests. Similar small effect sizes have been found in other MRI studies on the neurobiological correlates of ADHD (Hoogman et al., 2017;Zhang-James et al., 2021). It is more likely that small effects across many different regions and imaging modalities each slightly contribute to explaining individual differences in ADHD symptom trajectories. ...
Article
Full-text available
Background Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 – 34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). Conclusions Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory.
... The results seemed contradictory because of the assumption that electric field intensity in a brain area directly associates with the behavioral effect of tDCS (Evans et al., 2020). One highly possible explanation may lie in that efficient execution of brain function is based on networks of brain areas rather than individual brain regions (Hoogman et al., 2017;Ester and Kullmann, 2021); and multitarget stimulation tries to modulate the associated brain network and may result in additive effects of tDCS on performance compared with singletarget stimulation (Brem et al., 2018;Ester and Kullmann, 2021;Friehs et al., 2021a;Gregoret et al., 2021). Additionally, there is some evidence for the potentially inverted U-shaped nature of tDCS interactions with behavior performance, in which an intensity may lead to better performance when it lies closer to the peak of the inverted-U curve (Ehrhardt et al., 2021). ...
Article
Full-text available
Prior studies have focused on single-target anodal transcranial direct current stimulation (tDCS) over the right inferior frontal gyrus (rIFG) or pre-supplementary motor area (pre-SMA) to improve response inhibition in healthy individuals. However, the results are contradictory and the effect of multitarget anodal stimulation over both brain regions has never been investigated. The present study aimed to investigate the behavioral and neurophysiological effects of different forms of anodal high-definition tDCS (HD-tDCS) on improving response inhibition, including HD-tDCS over the rIFG or pre-SMA and multitarget HD-tDCS over both areas. Ninety-two healthy participants were randomly assigned to receive single-session (20 min) anodal HD-tDCS over rIFG + pre-SMA, rIFG, pre-SMA, or sham stimulation. Before and immediately after tDCS intervention, participants completed a stop-signal task (SST) and a go/nogo task (GNG). Their cortical activity was recorded using functional near-infrared spectroscopy (fNIRS) during the go/nogo task. The results showed multitarget stimulation produced a significant reduction in stop-signal reaction time (SSRT) relative to baseline. The pre-to-post SSRT change was not significant for rIFG, pre-SMA, or sham stimulation. Further analyses revealed multitarget HD-tDCS significantly decreased SSRT in both the high-performance and low-performance subgroups compared with the rIFG condition which decreased SSRT only in the low-performance subgroup. Only the multitarget condition significantly improved neural efficiency as indexed by lower △oxy-Hb after stimulation. In conclusion, the present study provides important preliminary evidence that multitarget HD-tDCS is a promising avenue to improve stimulation efficacy, establishing a more effective montage to enhance response inhibition relative to the commonly used single-target stimulation.
... Because neuroimaging has revealed that, in ADHD patients, the volume in several subcortical structures is reduced, including the hippocampus [24], a brain developmental delay has been proposed as the cause for the disorder [25]. A hallmark in neurodevelopment is the maturation of dendritic spines. ...
Article
Full-text available
In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.
... This approach began by identifying important LIWC 3 characteristics using the measure of "Pearson weighted" 4 to calculate the correlation between LIWC and narcissistic disorder. Then, using the metaphor package existing in language R, an estimate was computed for each extracted effect by computing the confidence intervals (CI) (Hoogman et al. 2017). This study showed that there were positive correlations between LIWC and narcissism disorder, citing, for example, that the narcissistic person uses more words related to sport, as well as the pronoun of the second person. ...
Article
Full-text available
Research in the medical field does not stop evolving. This evolution obliges doctors to be up-to-date in order to well manage every situation that may occur with their patients. However, the medical field is very sensitive and requires a great deal of precision, all of that poses a major problem. Consequently, there is a recourse to computer science, to resolve all of these issues. In this context, we propose in this paper an architecture, taking advantage of artificial intelligence (AI) and text mining techniques to: (i) identify individuals with personality disorder from their textual production on social networks by classifying their set of tweets into distinct classes representing respectively the presence, the category and the type of the disease and (ii) guarantee personalized monitoring by filtering inappropriate tweets according to patient’s circumstance. The first phase was achieved by taking advantage of a deep neuronal approach that benefits of: (i) CNN layers for features extraction from the textual part, (ii) two LSTM layers to preserve long-term dependencies between different lexical units, (iii) SVM classifier to detect the sick person using the dependency links found from the previous layer. The second phase was accomplished by applying a hybrid approach that combined linguistic and statistical techniques in order to filter inappropriate tweets according to the state of each patient. Following the evaluation of our approach, we acquire an F-measure rate equivalent to 84% for the detection of personality disorder, 64% for the detection of the type of disease and 70% for the task of filtering inappropriate content. The obtained results are motivating and may encourage researchers to improve them in view of the interest and the importance of this research axis.
... e hippocampus Evidence-Based Complementary and Alternative Medicine 9 serves a key function in memory, navigation, and cognition [50]. Studies have shown that the three brain regions (PFC, corpus striatum, and hippocampus) are closely related to the onset of ADHD [51][52][53]. e DA system in the brain is a large and complex neural network. Further study will be required to determine the causes of defects in DA formation. ...
Article
Full-text available
Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder. It may impact the cognitive and social functions throughout childhood and determine adult outcomes. Dopamine (DA) deficiency theory is the pathogenesis of ADHD that is recognized by most international literature. Existing studies have shown that DA deficiency is caused by the abnormal function of the DA transporter and an imbalance in the DA receptor functionality. Recent clinical and experimental studies have found that the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway acts a pivotal part in DA vesicle circulation and ADHD pathogenesis. An Shen Ding Zhi Ling (ASDZL) is a traditional Chinese medicine (TCM) prescription, which was widely prescribed to treat ADHD in Jiangsu, China, but its therapeutic mechanism is unclear. Therefore, we constructed a spontaneously hypertensive rat (SHR) model to explain its mechanism. SHRs were randomly assigned to four groups: SHR model group (vehicle), methylphenidate hydrochloride group (MPH), ASDZL group, and 7,8-dihydroxyflavone group (7,8-DHF). At the same time, the above groups were given continuous medication for four weeks. The results show that ASDZL, MPH, and 7,8-DHF group could significantly improve the spatial memory of SHRs in the Morris water maze tests. ASDZL increased the levels of BDNF, TrkB, p75 neurotrophin receptor (p75), C-Jun N-terminal kinases 1 (JNK1), and nuclear factor kappa B (NF-κB) in the prefrontal cortex (PFC) and hippocampus synaptosome of SHRs. The results of this study suggest that ASDZL can relieve the symptoms of ADHD in SHRs by regulating the balance between the BDNF/TrkB signaling pathway (promoting vesicle circulation) and the BDNF/P75/JNK1/NF-κB signaling pathway (inhibiting vesicle circulation) within the PFC and hippocampus synaptosome to increase the DA concentration in the synaptic cleft. The BDNF/TrkB signal pathway within the PFC and hippocampus synaptosome was activated by 7,8-DHF to increase DA concentration in the synaptic cleft. Whether 7,8-DHF can activate or inhibit the BDNF/P75 signaling pathway remains unclear.
... 7; 2016)(Alosco et al., 2014;McCrory et al., 2017) extending the 'physical exercise' clusters.Furthermore, when focusing on 2021, we identified two additional recent clusters on 'functional connectivity', #2(S=0.851; 2013)(Hoogman et al., 2017) and on 'gut microbiota', #6(S=0.861; 82; 2015)(Sharma and Couture, 2014). ...
Article
Full-text available
We performed a scientometric analysis of the scientific literature on ADHD to evaluate key themes and trends over the past decades, informing future lines of research. We conducted a systematic search in Web of Science Core Collection up to 15 November, 2021 for scientific publications on ADHD. We retrieved 28,381 publications. We identified four major research trends: 1) ADHD treatment, risks factors and evidence synthesis; 2) neurophysiology, neuropsychology and neuroimaging; 3) genetics; 4) comorbidity. In chronological order, identified clusters of themes included: tricyclic antidepressants, ADHD diagnosis/treatment, bipolar disorder, EEG, polymorphisms, sleep, executive functions, pharmacology, genetics, environmental risk factors, emotional dysregulation, neuroimaging, non-pharmacological interventions, default mode network, Tourette, polygenic risk score, sluggish cognitive tempo, evidence-synthesis, toxins/chemicals, psychoneuroimmunology, Covid-19, and physical exercise. In conclusion, research on ADHD over the past decades has been driven mainly by a medical model. Whereas the neurobiological correlates of ADHD are undeniable and crucial, we look forward to further research on relevant psychosocial aspects related to ADHD, such as societal pressure, the concept of neurodiversity, and stigma.
... Therefore, a decrease in the resting-state signal variability may be a component of the normative trajectories of functional brain maturation (16). ADHD is considered a developmental delay in the ability to maintain focus and/or control impulses (17)(18)(19); thus, delayed maturation in the signal variability of the brain may contribute to its development. Researchers have also examined the relationship between resting-state brain signal variability and ADHD (20). ...
Article
Full-text available
In this study, we sought to determine the nature of the abnormality in resting-state default mode network (DMN) activation and explore its correlation with functional connectivity in attention-deficit/hyperactivity disorder (ADHD). We obtained resting-state functional magnetic resonance images of youth with ADHD and typically developing counterparts from the publicly available ADHD-200 database. We used data from Peking University (232 scans) and New York University (172 scans); the scan repetition time was 2 s for both data collection sites. We applied generalized estimating equations to estimate the variability of the averaged blood-oxygen-level-dependent (BOLD) time series extracted from the DMN at rest. We performed network-based statistics to determine the association between the observed differences in BOLD signal variability and altered functional connectivity. We analyzed data from 105 youth with ADHD (age: mean 12.17, standard deviation 2.31, median 12.25; 15.2% female, 84.8% male) and 140 typically developing youth (age: mean 11.99, standard deviation 2.28, median 11.85; 47.1% female, 52.9% male), who aged 7–17 years. The imaging data were cross-sectionally collected for each participant at one time point. We observed a greater number of significant BOLD signal changes and higher-order polynomial significant associations in youth with ADHD. Moreover, there were significant between-group differences in BOLD signal change after the first 140 s, which coincided with decreased resting-state functional connectivity within the DMN in youth with ADHD. Increased variability of neural signaling was intermittently observed in the brains of youth with ADHD at rest, thereby indicating their default mode state was more unstable than that of typically developing youth.
... It would be interesting as a follow-up study to investigate the relationship between ICV and genetic risk for illness in other disorders. There is evidence that ICV is linked to for instance autism, attention deficit hyperactivity disorder (ADHD), 22q11DS, clinical high risk for psychosis and early onset psychosis based on clinical meta-and/or mega-analysis studies in which brain imaging data of patients and controls were compared [38,39,[42][43][44]. With the ever-increasing sample sizes of the latest GWASs, it would be interesting to see whether they show a relationship with ICV, to increase understanding of the role of very early development in the onset of different severe mental illnesses. ...
Article
Full-text available
Schizophrenia and bipolar disorder are neurodevelopmental disorders with overlapping symptoms and a shared genetic background. Deviations in intracranial volume (ICV)—a marker for neurodevelopment—differ between schizophrenia and bipolar disorder. Here, we investigated whether genetic risk for schizophrenia and bipolar disorder is related to ICV in the general population by using the UK Biobank data (n = 20,196). Polygenic risk scores for schizophrenia (SZ-PRS) and bipolar disorder (BD-PRS) were computed for 12 genome wide association study P-value thresholds (PT) for each individual and correlations with ICV were investigated. Partial correlations were performed at each PT to investigate whether disease specific genetic risk variants for schizophrenia and bipolar disorder show different relationships with ICV. ICV showed a negative correlation with SZ-PRS at PT ³ 0.005 (r < -0.02, P < 0.005). ICV was not associated with BD-PRS; however, a positive correlation between BD-PRS and ICV at PT = 0.2 and PT = 0.4 (r = +0.02, P < 0.005) appeared when the genetic overlap between schizophrenia and bipolar disorder was accounted for. Despite small effect sizes, a higher load of schizophrenia risk genes is associated with a smaller ICV in the general population, while risk genes specific for bipolar disorder are correlated with a larger ICV. These findings suggest that schizophrenia and bipolar disorder risk genes, when accounting for the genetic overlap between both disorders, have opposite effects on early brain development.
Article
Full-text available
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Advances in diffusion magnetic resonance imaging (MRI) acquisition sequences and analytic techniques have led to growing body of evidence that abnormal white matter microstructure is a core pathophysiological feature of ADHD. This systematic review provides a qualitative assessment of research investigating microstructural organisation of white matter amongst children and adolescents with ADHD. This review included 46 studies in total, encompassing multiple diffusion MRI imaging techniques and analytic approaches, including whole-brain, region of interest and connectomic analyses. Whole-brain and region of interest analyses described atypical organisation of white matter microstructure in several white matter tracts: most notably in frontostriatal tracts, corpus callosum, superior longitudinal fasciculus, cingulum bundle, thalamic radiations, internal capsule and corona radiata. Connectomic analyses, including graph theory approaches, demonstrated global underconnectivity in connections between functionally specialised networks. Although some studies reported significant correlations between atypical white matter microstructure and ADHD symptoms or other behavioural measures there was no clear pattern of results. Interestingly however, many of the findings of disrupted white matter microstructure were in neural networks associated with key neuropsychological functions that are atypical in ADHD. Limitations to the extant research are outlined in this review and future studies in this area should carefully consider factors such as sample size, sex balance, head motion and medication status.
Article
Although altered microstructure properties of white-matter tracts have been reported in children with attention-deficit/hyperactivity disorder (ADHD), findings from relatively few adult ADHD studies are inconsistent. This study aims to examine microstructural property over the whole brain in adults with ADHD and explore structural connectivities. Sixty-four medication-naïve adults with ADHD and 81 healthy adults received diffusion spectrum imaging. Generalized fractional anisotropy (GFA), an index indicating microstructural property, was calculated stepwise among 76 white-matter tracts. With the threshold-free clustering weighted method, the segments with the largest group difference were selected, and mean GFA (mGFA) values were calculated. Adults with ADHD had increased mGFA values in the segments located in the left frontal aslant tract, the right inferior longitudinal fasciculus, and the left perpendicular fasciculus, and reduced mGFA values in the segments located in the right superior longitudinal fasciculus (SLF) I, the left SLF II, the right frontostriatal tracts from dorsolateral prefrontal cortex (FS-DLPFC) and the ventrolateral prefrontal cortex, the right medial lemniscus, the right inferior thalamic radiation to the auditory cortex, and the callosal fibers. Additionally, the mGFA value of the right SLF I segment was associated with hyperactivity-impulsivity symptoms. Our findings suggest that white-matter tracts with altered microstructure properties are located within the attention networks, fronto-striato-thalamocortical regions, and those associated with attention and visual perception in adults with ADHD.
Article
Attention-deficit/hyperactivity disorder (ADHD) has been the focus of magnetic resonance imaging studies for more than 30 years, with more than 2200 articles listed in PubMed. Nevertheless, the brain substrates of ADHD remain poorly understood. This reflects the crisis of replicability across nearly all scientific endeavors, deriving from factors such as small sample sizes combined with a proliferation in analytical approaches, yielding high rates of false positive results. The field of molecular genetics confronted this by adopting open and immediate sharing of raw data and insistence on rigorous corrections for multiple comparisons. These strategies are yielding more robust genetic findings, albeit with much smaller effect sizes than before. This brief review focuses on two recent consortium efforts, i.e., the international Enhancing Neuro-Imaging Genetics through Meta-Analysis (ENIGMA), and the U.S. Adolescent Behavior & Cognitive Developm ent Study (ABCD). Both embrace the culture of open science, and are beginning to yield credible findings, despite being limited initially to cross-sectional analyses. As the field continues to mature, these and other ongoing longitudinal large-scale studies are poised to transform our understanding of the pathophysiology of ADHD to bring closer the day when neuroimaging can contribute to clinical utility.
Article
Full-text available
Purpose Intrauterine exposures influence offspring health and development. Here we investigated maternal intake of sweetened carbonated beverages (SCB) during pregnancy and its association with ADHD symptoms in the offspring. Methods This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. Maternal diet mid-pregnancy was assessed using a food frequency questionnaire (FFQ). All mothers who responded to the FFQ and a questionnaire when their child was 8 years of age were included (n = 39,870). The exposure was defined as maternal intake (daily servings) of SCB, using no daily intake as reference. Outcome was offspring ADHD symptoms, evaluated as a continuous standardized ADHD score and as a binary outcome of six or more ADHD symptoms vs. five symptoms or less. Associations were analysed using log-binomial regression and linear mixed regression models with adjustment for covariates. Results The adjusted regression coefficients for the standardized ADHD offspring symptom score were 0.31 [95% confidence intervals (0.001, 0.62)] and 0.46 (0.15, 0.77) for maternal daily intake of ≥ 1 glasses of SCB, when the models included adjustments for total energy intake or energy intake from other sources than SCBs and sweet drinks, respectively. The corresponding adjusted relative risks were 1.16 (1.004, 1.34) and 1.21. (1.05, 1.39) for drinking ≥ 1 glasses daily. Conclusion In a large pregnancy cohort with offspring followed until 8 years of age, we found an association between maternal daily intake of SCB and offspring ADHD symptoms. These results suggest a weak positive relationship between prenatal exposure to SCB and offspring ADHD.
Article
Antisocial and aggressive behaviors show considerable heritability and are central to disruptive behavior disorders (DBDs), but are also frequently observed in attention deficit hyperactivity disorder (ADHD). While the amygdala is implicated as a key neural structure, it remains unclear whether common genetic variants underlie this brain-behavior association. We hypothesized that polygenic (risk) scores for antisocial and aggressive behaviors (ASB-PRS) would be related to amygdala morphology. Using the Broad Antisocial Behavior Consortium genome-wide association study (GWAS; mostly population based cohorts), we calculated ASB-PRS in the NeuroIMAGE I ADHD case-control sample with varying levels of DBD symptomatology (n=679 from 379 families, aged 7 – 29). We first investigated associations of several ASB-PRS p value thresholds with the presence of DBD symptoms and self-reported antisocial behavior (ASB) to determine the threshold for further analyses. This PRS was then related to amygdala volume and shape using regression and vertex-wise analyses. Our results showed associations of ASB-PRS with the presence of DBD symptoms, self-reported ASB, and left basolateral amygdala shape, independent of ADHD symptom severity and ADHD-PRS, with a relative outward displacement of the vertices. No associations of ASB-PRS, DBD symptoms or self-reported ASB with amygdala volume were found. Our results indicate that genetic risk for antisocial and aggressive behaviors is related to amygdala shape alterations, and point to genetic sharing across different DBD and ASB and aggression-related phenotypes as a spectrum of genetically related quantitative traits. Additionally, our findings support the utility of vertex-based shape analyses in genetic studies of ASB, aggression, and DBDs.
Article
Full-text available
The Forkhead box P2 (FOXP2) encodes for a transcription factor with a broad role in embryonic development. It is especially represented among GWAS hits for neurodevelopmental disorders and related traits, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, neuroticism, and risk-taking behaviors. While several functional studies are underway to understand the consequences of FOXP2 variation, this study aims to expand previous findings to clinically and genetically related phenotypes and neuroanatomical features among subjects with ADHD. The sample included 407 adults with ADHD and 463 controls. Genotyping was performed on the Infinium PsychArray-24 BeadChip, and the FOXP2 gene region was extracted. A gene-wide approach was adopted to evaluate the combined effects of FOXP2 variants (n = 311) on ADHD status, severity, comorbidities, and personality traits. Independent risk variants presenting potential functional effects were further tested for association with cortical surface areas in a subsample of cases (n = 87). The gene-wide analyses within the ADHD sample showed a significant association of the FOXP2 gene with harm avoidance (P = 0.001; PFDR = 0.015) and nominal associations with hyperactivity symptoms (P = 0.026; PFDR = 0.130) and antisocial personality disorder (P = 0.026; PFDR = 0.130). An insertion/deletion variant (rs79622555) located downstream of FOXP2 was associated with the three outcomes and nominally with the surface area of superior parietal and anterior cingulate cortices. Our results extend and refine previous GWAS findings pointing to a role of FOXP2 in several neurodevelopment-related phenotypes, mainly those involving underlying symptomatic domains of self-regulation and inhibitory control. Taken together, the available evidence may constitute promising insights into the puzzle of the FOXP2-related pathophysiology.
Article
Recent clinical studies, in both children/adolescents and adults, have shown the extreme neuropsychological heterogeneity of attention‐deficit hyperactivity disorder (ADHD): specific neuropsychological deficits have been found only in a minority of individuals, with no direct correlation between discrete cognitive performances and the trajectory of clinical symptoms. Deficits in specific neuropsychological functions may be common in ADHD, but nevertheless no cognitive or neuropsychological profile may fully explain the disorder. Sex differences in the ADHD presentation, both at a neuropsychological and clinical level, also contribute to this clinical and neuropsychological heterogeneity. At a neuropsychological level, females with ADHD may show greater working memory problems, poorer vocabulary skills and worse visual spatial reasoning. Structural and functional imaging study also show discrete differences across sex; however, the great majority of clinical studies mainly or exclusively include male participants with insufficient data to draw firm conclusions on sex differences within the disorder. Here, we report the recent literature data, discussing still open research questions about the clinical presentation, neuroimaging findings, and neuropsychological functioning in ADHD with a focus on the impact of sex differences—a deeper insight in these unresolved issues may have relevant clinical and therapeutic implications for tailored, effective, and long‐lasting interventions.
Article
Objective The pathophysiology of attention deficit hyperactivity disorder (ADHD) are still not fully elucidated. Immune system dysregulation has emerged as a major etiological focus as a result of the high comorbidity of allergic disease, inflammatory biomarkers, and genetic research. The present study aimed to evaluate peripheral lymphocyte subpopulations and regulatory T cells (Tregs) in children with ADHD. Methods This single-center cross-sectional case-control study assessed 49 children with ADHD and 35 age- and gender-matched healthy children aged 7–12 years (9.10 ± 2.37 and 9.45 ± 2.13, respectively). The participants were screened for psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version, while the severity of ADHD symptoms was measured by means of the distracted-Continuous Performance Test. Peripheral lymphocyte subpopulations and Tregs were analyzed with flow-cytometry. Results There is no significant difference in peripheral blood lymphocyte subsets between ADHD and control groups The children diagnosed with ADHD exhibited significantly higher levels of CD3⁺ CD4⁺ CD25⁺ Foxp3⁺ (Tregs) than the healthy control subjects (8.23 ± 2.09 vs. 6.61 ± 2.89; z = 2.965, p = .004). The Tregs cell (Exp(B) = 1.334; p = .042; CI = 1.011–1.761) levels were determined to be statistically significant according to regression analysis and were associated with an increased probability of ADHD. Conclusion Elevated Treg levels were linked to an increased likelihood of ADHD. This study suggested that changes in immune regulatory cells represent an important part of research in treatment of ADHD.
Article
Multiple psychosocial interventions to treat ADHD symptoms have been developed and empirically tested. However, no clear recommendations exist regarding the utilization of these interventions for treating core ADHD symptoms across different populations. The objective of this systematic review and meta-analysis by the CADDRA Guidelines work Group was to generate such recommendations, using recent evidence. Randomized controlled trials (RCT) and meta-analyses (MA) from 2010 to 13 February 020 were searched in PubMed, PsycINFO, EMBASE, EBM Reviews and CINAHL. Studies of populations with significant levels of comorbidities were excluded. Thirty-one studies were included in the qualitative synthesis (22 RCT, 9 MA) and 24 studies (19 RCT, 5 MA) were included in the quantitative synthesis. Using three-level meta-analyses to pool results of multiple observations from each RCT, as well as four-level meta-analyses to pool results from multiples outcomes and multiple studies of each MA, we generated recommendations using the GRADE approach for: Cognitive Behavioral Therapy; Physical Exercise and Mind–Body intervention; Caregiver intervention; School-based and Executive intervention; and other interventions for core ADHD symptoms across Preschooler, Child, Adolescent and Adult populations. The evidence supports a recommendation for Cognitive Behavioral Therapy for adults and Caregiver intervention for Children, but not for preschoolers. There were not enough data to provide recommendations for the other types of psychosocial interventions. Our results are in line with previous meta-analytic assessments; however, they provide a more in-depth assessment of the effect of psychosocial intervention on core ADHD symptoms.
Article
Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 10 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC). Animals were tested 30 min (short-term memory) or 24 h later (long-term memory). We found that inhibition of CAs with infusion of ACTZ either in the CA1 or in the mPFC impaired short-term SRM and that this effect was completely abolished by the combined infusion of D-Phen and ACTZ. We also found that activation of CAs with D-Phen facilitated the consolidation of long-term SRM in the mPFC but not in CA1. Finally, we show that activation of CAs in CA1 and in the mPFC enhances the persistence of SRM for up to 7 days. In both cases, the co-infusion of ACTZ fully prevented D-Phen-induced procognitive effects. These results suggest that CAs are key modulators of SRM and unveil a differential involvement of these enzymes in the mPFC and CA1 on memory consolidation.
Thesis
This thesis investigated the potential reading benefits of motivation, and particularly story choice (intrinsic motivator) and reward (extrinsic motivator) in children with ADHD-related characteristics (inattention, hyperactivity/impulsivity, poor interference control), who attended mainstream primary schools. Children with ADHD-related characteristics are at risk of reading underachievement, irrespective of the presence of an ADHD diagnosis. Using a repeated measures design with two conditions (Choice, No Choice), Study 1 tested choice effects on the reading of a community sample of children (N = 108, aged 8 to 9 years old, 56 boys) with minimal and severe ADHD-related characteristics, with focus on inattention. Using a repeated measures design with three conditions (Choice, Reward, No Motivation), Study 2 explored choice and reward effects on the reading of children with and without diagnosed ADHD (N = 24, aged 8 to 11 years old, 16 boys). Using the Study 2 sample, Study 3 sought the perspectives of children with and without ADHD about reading motivation and checked for any group qualitative differences. Drawing on the quantitative findings, story choice increased the reading comprehension, and less consistently the reading enjoyment, of both children with minimal and severe ADHD-related characteristics. Study 2 findings pointed towards the benefits of story choice and reward for the reading comprehension and enjoyment of children with and without ADHD, however, results were relatively inconclusive. Choice and reward effects were not found to be more pronounced for children with severe ADHD-related characteristics and/or ADHD than those with such minimal characteristics. In Study 3, children with and without ADHD acknowledged similarly the contribution of motivators, including choice and reward, to reading. Overall, findings offer empirical support for the positive impact of story choice and reward on children with varying degrees of ADHD-related characteristics, stressing the need to consider further their manipulation during reading instruction in the classroom.
Article
We aim to systematically explore the potential genetic correlations between five major psychiatric disorders and gestational ages. Genome‐wide association study (GWAS) summary datasets of attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) in discovery were downloaded from the Psychiatric GWAS Consortium (PGC) website. Suggestive (Raw p < 0.05) genetic associations in the discovery phrase were further replicated in independent GWASs which downloaded from PGC, the FinnGen study or Integrative Psychiatric Research (iPSYCH) website. GWASs of gestational duration, preterm and post‐term birth were derived from previous studies of infants from the Early Growth Genetics (EGG) Consortium, the iPSYCH study, and the Genomic and Proteomic Network for Preterm Birth Research (GPN). We calculated genetic correlations using linkage disequilibrium score (LDSC) regression. Mendelian randomization (MR) analyses were performed to investigate the causal effects. We identified four suggestive genetic correlations between psychiatric disorders and gestational age factors in discovery LDSC and two replicated in a confirmation LDSC: gestational duration and ADHD (rg = −0.1405, FDR p = 0.0406), post‐term birth and SCZ (rg = −0.2003, FDR p = 0.0042). We also observed causal effect of post‐term birth on SCZ by MR (PWeighted median = 0.037, PInverse variance weighted = 0.007). Our analysis suggested no significant evidence of horizontal pleiotropy and heterogeneity. This study showed the genetic correlation evidences between gestational age phenotypes and psychiatric disorders, providing novel clues for understanding the pathogenic factors of common psychiatric disorders. Whereas gestational age factors were reported to be associated with psychiatric disorders, the genetic relationship and causality remain to be revealed. The present study reported the first large‐scale genetic correlations investigation of the associations between gestational age phenotypes and psychiatric disorders. Results indicate causal relationships between post‐term birth and schizophrenia (SCZ), as well as suggestive genetic correlations between gestational duration and attention deficit/hyperactivity disorder (ADHD). This study provided novel clues for understanding the pathogenic factors of common psychiatric disorders.
Article
Full-text available
Background Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with longer screen time utilization (STU) at the behavioral level. However, whether there are shared neural links between ADHD symptoms and prolonged STU is not clear and has not been explored in a single large-scale dataset. Methods Leveraging the genetics, neuroimaging and behavioral data of 11,000+ children aged 9–11 from the Adolescent Brain Cognitive Development cohort, this study investigates the associations between the polygenic risk and trait for ADHD, STU, and white matter microstructure through cross-sectionally and longitudinal analyses. Findings Children with higher polygenic risk scores for ADHD tend to have longer STU and more severe ADHD symptoms. Fractional anisotropy (FA) values in several white matter tracts are negatively correlated with both the ADHD polygenic risk score and STU, including the inferior frontal-striatal tract, inferior frontal-occipital fasciculus, superior longitudinal fasciculus and corpus callosum. Most of these tracts are linked to visual-related functions. Longitudinal analyses indicate a directional effect of white matter microstructure on the ADHD scale, and a bi-directional effect between the ADHD scale and STU. Furthermore, reduction of FA in several white matter tracts mediates the association between the ADHD polygenic risk score and STU. Interpretation These findings shed new light on the shared neural overlaps between ADHD symptoms and prolonged STU, and provide evidence that the polygenic risk for ADHD is related, via white matter microstructure and the ADHD trait, to STU. Funding This study was mainly supported by NSFC and National Key R&D Program of China.
Article
Study Objectives This study investigates whether longitudinally measured changes in adolescent brain electrophysiology corroborate the maturational lag associated with attention deficit hyperactivity disorder (ADHD) reported in MRI studies and cross-sectional sleep EEG data. Methods Semiannually nine adolescents diagnosed with ADHD (combined presentation, DSM-V criteria, mean age 12.39±0.61 years at first time-point, 2 females) and nine typically developing controls (12.08±0.35 years, 4 females) underwent all night laboratory polysomnography, yielding 4 recordings. Results Sleep macrostructure was similar between groups. A quadratic model of the age change in NREM delta (1.07-4 Hz) power, with sex effects accounted for, found that delta power peaked 0.92±0.37 years later in the ADHD group. A Gompertz function fit to the same data showed that the age of most rapid delta power decline occurred 0.93±0.41 years later in the ADHD group (p=0.037), but this group difference was not significant (p=0.38) with sex effects accounted for. For very low frequency (0.29-1.07 Hz) EEG, the ADHD lag (1.07±0.42 years later, p=0.019) was significant for a Gompertz model with sex effects accounted for (p=0.044). Theta (4-7.91 Hz) showed a trend (p=0.064) toward higher power in the ADHD group. Analysis of the EEG decline across the night found that standardized delta and theta power in NREMP1 were significantly (p<0.05 for both) lower in adolescents with ADHD. Conclusions This is the first longitudinal study to reveal electrophysiological evidence of a maturational lag associated with ADHD. In addition, our findings revealed basically unaltered sleep macrostructure but altered sleep homeostasis associated with ADHD.
Article
Structural and functional magnetic resonance imaging (MRI) studies have suggested a neuroanatomical basis that may underly attention-deficit–hyperactivity disorder (ADHD), but the anatomical ground truth remains unknown. In addition, the role of the white matter (WM) microstructure related to attention and impulsivity in a general pediatric population is still not well understood. Using a state-of-the-art structural connectivity pipeline based on the Brainnetome atlas extracting WM connections and its subsections, we applied dimensionality reduction techniques to obtain biologically interpretable WM measures. We selected the top 10 connections-of-interests (located in frontal, parietal, occipital, and basal ganglia regions) with robust anatomical and statistical criteria. We correlated WM measures with psychometric test metrics (Conner’s Continuous Performance Test 3) in 171 children (27 Dx ADHD, 3Dx ASD, 9–13 years old) from the population-based GESTation and Environment cohort. We found that children with lower microstructural complexity and lower axonal density show a higher impulsive behavior on these connections. When segmenting each connection in subsections, we report WM alterations localized in one or both endpoints reflecting a specific localization of WM alterations along each connection. These results provide new insight in understanding the neurophysiology of attention and impulsivity in a general population.
Article
There is substantial evidence linking the prefrontal cortex (PFC) to a variety of cognitive abilities, with adolescence being a critical period in its development. In the current study, we investigated the neural basis of differences in learning in pre-adolescent common marmosets. At 8 months old, marmosets were given anatomical and resting state MRI scans (n=24). At 9 months old, association learning and inhibitory control was tested using a ‘go/no go’ visual discrimination (VD) task. Marmosets were grouped into ‘learners’ (n=12) and ‘non-learners’ (n=12), and associations between cognitive performance and sub-regional PFC volumes, as well as PFC connectivity patterns, were investigated. ‘Learners’ had significantly (p<0.05) larger volumes of areas 11, 25, 47 and 32 than ‘non-learners’, although ‘non-learners’ had significantly larger volumes of areas 24a and 8 v than ‘learners’. There was also a significant correlation between average % correct responses to the ‘punished’ stimulus and volume of area 47. Further, ‘non-learners’ had significantly greater global PFC connections, as well as significantly greater numbers of connections between the PFC and basal ganglia, cerebellum and hippocampus, compared to ‘non-learners’. These results suggest that larger sub-regions of the orbitofrontal cortex and ventromedial PFC, as well more refined PFC connectivity patterns to other brain regions associated with learning, may be important in successful response inhibition. This study therefore offers new information on the neurodevelopment of individual differences in cognition during pre-adolescence in non-human primates.
Article
Executive function task (EF) deficits are hypothesized to underlie difficulties with self-regulation. However, tasks assessing EF impairments have only been weakly correlated with rating scales that index self-regulation difficulties. A community sample of children and youth aged between 8 and 20 years old were assessed longitudinally. Growth curve analyses and correlations were conducted to better understand how these two types of measures relate to one another across development, as well as the impact of age-related variance. EF was assessed using the Stroop Task and Trail Making test and behavioral ratings of self-regulation were captured using the SWAN scale. EF task performance improved steeply until age 14–15, whereas the SWAN Scale showed small age-related decreases. EF task performance was moderately correlated with age among 8–13-year-olds and to a lesser extent among 14–20-year-olds. SWAN scores were not significantly related to age in either group. Correlations were similar in an ADHD “at-risk” subgroup. EF task performance and parent ratings of attention regulation have different developmental trajectories, which may partly explain why correlations are low to modest in these samples. In particular, age-related variance is an important methodological consideration with significant implications for the assessment of self-regulation in children and youth with ADHD.
Thesis
Full-text available
Zusammenfassung 1) Fragestellung und zentrale Untersuchung Unter der Hypothese, dass die Transportrate des Glukosetransporters Typ 3 (GLUT3) abhängig von der Kopienanzahl (CNV) des für ihn kodierenden Gens SLC2A3 ist, wurden Zelllinien mit drei Kopien (Duplikation) mit Kontroll-Zelllinien mit nur zwei Kopien bezüglich ihrer Glukoseaufnahme miteinander verglichen (n=2; N=9). Hierzu wurde die zelluläre Glukoseaufnahme mittels radioaktiv markierter 2-Desoxyglukose in via Eppstein-Barr-Virus immortalisierten lymphoblastoiden Zelllinien (EBV-LCLs) gemessen. In den initialen Untersuchungen zeigt sich, dass das Protokoll an manchen Stellen zu viel Spielraum lässt. Die Methode wird daraufhin standardisiert und bezüglich einiger Parameter angepasst: g-Zentrifugeneinstellung, Mischen/Aliquotieren, Zellanzahl, Replikatanzahl, Inkubationszeit/-intervalle und Durchführungsdauer. 2) Wichtigste Ergebnisse Die funktionelle Untersuchung zur Duplikation des SLC2A3-Gens in Patienten mit Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) zeigt schließlich im dynamischen Aushungerungsversuch der EBV-LCLs über vier Tage (Vergleich t2 zu t1) statistisch für die Gruppen eine deutliche Differenz mit mittlerer Effektstärke (Lineares Gemischtes Modell; p = 0,06; Cohens d = 0,37). Zum zweiten Messzeitpunkt (t2) zeigt sich statistisch zwischen den Gruppen eine sehr signifikante Differenz mit hoher Effektstärke (Lineares Gemischtes Modell; p < 0,006; Cohens d = 0,55). Damit konnte in dieser Arbeit nachgewiesen werden, dass die SLC2A3-Duplikation neben dem Gendosiseffekt auf mRNA-Ebene auch hypermorph funktionelle Veränderungen auf zellulärer Ebene nach sich zieht. Nachfolgende Untersuchungen sollten vor diesem Hintergrund mögliche Kofaktoren investigieren und auf Alterationen in nachgeschalteten Signalwegen abzielen.
Chapter
This chapter reviews attention deficit/hyperactivity disorder (ADHD), a persistent neurodevelopmental disorder that can affect both children and adults. In most cases, ADHD arises from several genetic and environmental risk factors that each have a small individual effect and act together to increase susceptibility. ADHD is a multifactorial disorder, and this is consistent with its heterogeneity, which is shown by an extensive psychiatric comorbidity, multiple impaired neurocognitive domains, and the wide range of structural and functional brain alterations associated with ADHD. This chapter highlights structural and functional magnetic resonance imaging studies that have contributed to a better understanding of the neurobiology of ADHD. Cumulative evidence implicates frontoparietal, striatal, thalamic, and cerebellar involvement in ADHD, in addition to interactions among the visual and sensorimotor cortex and the default mode network and top-down regulatory networks, which are increasingly implicated. The latter are two fundamental cortical systems, and the default mode network mediates introspection and self-referential processes, whereas the top-down regulatory network initiates and maintains task-level control, selects appropriate sensorimotor mapping, and suppresses irrelevant distracting information. This variety of neural systems and brain phenotypes is unlikely to be equally involved in all patients with ADHD, and future studies are needed to better dissect the most relevant neurobiological markers. The inclusion of joint information among brain imaging modalities along with genetic studies, bioinformatic analyses, and functional analyses in cell and animal models will allow a more comprehensive understanding of the neurobiological mechanisms in ADHD. Ultimately, the ongoing clinical and neurobiological research will also advance diagnostic and therapeutic approaches to ADHD.
Preprint
Full-text available
The brain is a frustrated system that contains conflictual link arrangements named frustration. The frustration as a source of disorder prevents the system from settling into low energy states and provides flexibility for brain network organization. In this research, we tried to identify the pattern of frustration formation in the brain at the levels of region, connection, canonical network, and hemisphere. We found that frustration formation has not a uniform pattern. Some subcortical elements have an active role in frustration formation, despite many low contributed cortical elements. Frustrating connections are mostly between-network types and triadic frustrations are mainly formed between three regions from three distinct canonical networks. Although there were no significant differences between brain hemispheres. We also did not find any robust differences between the frustration formation patterns of various lifespan stages. Our results may be interesting for those who study the organization of brain links and promising for those who want to manipulate brain networks.
Article
Full-text available
Background: Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) have partially overlapping symptom profiles and are highly comorbid in adults. However, whether the behavioral similarities correspond to shared neurobiological substrates is not known. Methods: An overlapping meta-analysis of 58 ADHD and 66 BPD whole-brain articles incorporating observations from 3401 adult patients and 3238 healthy participants was performed by Seed-based d Mapping. Brain maps were subjected to meta-analytic connectivity modeling and data-driven functional decoding analyses to identify associated neural circuit alterations and relations to behavioral dimensions. Results: Both groups exhibited hypo-activated abnormalities in the left inferior parietal lobule, and altered clusters of the bilateral superior temporal gyrus were disjunctive in ADHD and BPD. No overlapping structural abnormalities were found. Multimodal alterations of ADHD were located in the right putamen and of BPD in the left orbitofrontal cortex. Conclusions: The transdiagnostic neural bases of ADHD and BPD in temporo-parietal circuitry may underlie overlapping problems of behavioral control, while disorder-specific substrates in fronto-striatal circuitry may account for their distinguishing features in motor and emotion domains respectively.
Article
Full-text available
Attention-deficit/hyperactivity disorder (ADHD) is increasingly being diagnosed in both children and adults, but the neural mechanisms that underlie its distinct symptoms and whether children and adults share the same mechanism remain poorly understood. Here, we used a nested-spectral partition approach to study resting-state brain networks of ADHD patients (n=97) and healthy controls (HCs, n=97) across the lifespan (7-50 years). Compared to the linear lifespan associations of brain segregation and integration with age in HCs, ADHD patients have a quadratic association in the whole-brain and in most functional systems, whereas the limbic system dominantly affected by ADHD has a linear association. Furthermore, the limbic system better predicts hyperactivity, and the salient attention system better predicts inattention. These predictions are shared in children and adults with ADHD. Our findings reveal a lifespan association of brain networks with ADHD and provide potential shared neural bases of distinct ADHD symptoms in children and adults.
Article
Individual differences in human brain structure, function, and behavior can be attributed to genetic variations, environmental exposures, and their interactions. Although genome-wide association studies have identified many genetic variants associated with brain imaging phenotypes, environmental exposures associated with these phenotypes remain largely unknown. Here, we propose that environmental neuroscience should pay more attention on exploring the associations between lifetime environmental exposures (exposome) and brain imaging phenotypes and identifying both cumulative environmental effects and their vulnerable age windows during the life course. Exposome-neuroimaging association studies face several challenges including the accurate measurement of the totality of environmental exposures varied in space and time, the highly correlated structure of the exposome, and the lack of standardized approaches for exposome-wide association studies. By agnostically scanning the effects of environmental exposures on brain imaging phenotypes and their interactions with genomic variations, exposome-neuroimaging association analyses will improve our understanding of causal factors associated with individual differences in brain structure and function as well as their relations with cognitive abilities and neuropsychiatric disorders.
Article
Attention deficit hyperactivity disorder is a neurodevelopmental condition for which we have an incomplete understanding, and so brain imaging methods, such as magnetic resonance imaging (MRI) may be able to assist in characterizing and understanding the presentation of the brain in an ADHD population. Statistical and computational methods were used to compare participants with attention deficit hyperactivity disorder (ADHD) and neurotypical controls at a variety of developmental stages to assess detectable abnormal neurodevelopment potentially associated with ADHD and to assess our ability to diagnose and characterize the condition from real‐world clinical magnetic resonance imaging (MRI) examinations. T1‐weighted structural MRI examinations (n=993; 0‐31 years old [YO]) were obtained from neurotypical controls and 637 examinations were obtained from patients with ADHD (0‐26 YO). Measures of average (mean) regional cortical thickness were acquired, alongside the first reporting of regional cortical thickness variability (as assessed with the standard deviation [SD]) in ADHD. A comparison between the inattentive and combined (inattentive and hyperactive) subtypes of ADHD is also provided. A preliminary independent validation was also performed on the publicly available ADHD200 dataset. Relative to controls, subjects with ADHD had, on average, lowered SD of cortical thicknesses and increased mean thicknesses across several key regions potentially linked with known symptoms of ADHD, including the precuneus, supramarginal gyrus, etc.
Article
In 1978, G. Klerman published an essay in which he named the then-nascent “neo-Kraepelinian” movement and formulated a “credo” of nine propositions expressing the movement's essential claims and aspirations. Klerman's essay appeared on the eve of the triumph of neo-Kraepelinian ideas in the DSM-III. However, this diagnostic system has subsequently come under attack, opening the way for competing proposals for the future of psychiatric nosology. To better understand what is at stake, in this paper I provide a close reading and consideration of Klerman's credo in light of the past forty years of research and reflection. The credo is placed in the context of two equally seminal publications in the same year, one by S. Guze, the leading neo-Kraepelinian theorist, and the other by R. Spitzer and J. Endicott, defining mental disorder. The divergences between Spitzer and standard neo-Kraepelinianism are highlighted and argued to be much more important than is generally realized. The analysis of Klerman's credo is also argued to have implications for how to satisfactorily resolve the current nosological ferment in psychiatry. In addition to issues such as creating descriptive syndromal diagnostic criteria, overthrowing psychoanalytic dominance of psychiatry, and making psychiatry more scientific, neo-Kraepelinians were deeply concerned with the conceptual issue of the nature of mental disorder and the defense of psychiatry's medical legitimacy in response to antipsychiatric criticisms. These issues cannot be ignored, and I argue that proposals currently on offer to replace the neo-Kraepelinian system, especially popular proposals to replace it with dimensional measures, fail to adequately address them.
Article
Full-text available
Importance Patients with attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) share impaired inhibitory control. However, it is unknown whether impairments are mediated by shared or disorder-specific neurostructural and neurofunctional abnormalities. Objective To establish shared and disorder-specific structural, functional, and overlapping multimodal abnormalities in these 2 disorders through a voxel-based meta-analytic comparison of whole-brain gray matter volume (GMV) and functional magnetic resonance imaging (fMRI) studies of inhibition in patients with ADHD and OCD. Data Sources Literature search using PubMed, ScienceDirect, Web of Knowledge, and Scopus up to September 30, 2015. Study Selection Whole-brain voxel-based morphometry (VBM) or fMRI studies during inhibitory control comparing children and adults with ADHD or OCD with controls. Data Extraction and Synthesis Voxel-wise meta-analyses of GMV or fMRI differences were performed using Seed-based d-Mapping. Regional structure and function abnormalities were assessed within each patient group and then a quantitative comparison was performed of abnormalities (relative to controls) between ADHD and OCD. Main Outcomes and Measures Meta-analytic disorder-specific and shared abnormalities in GMV, in inhibitory fMRI, and in multimodal functional and structural measures. Results The search revealed 27 ADHD VBM data sets (including 931 patients with ADHD and 822 controls), 30 OCD VBM data sets (928 patients with OCD and 942 controls), 33 ADHD fMRI data sets (489 patients with ADHD and 591 controls), and 18 OCD fMRI data sets (287 patients with OCD and 284 controls). Patients with ADHD showed disorder-contrasting multimodal structural (left z = 1.904, P < .001; right z = 1.738, P < .001) and functional (left z = 1.447, P < .001; right z = 1.229, P < .001) abnormalities in bilateral basal ganglia/insula, which were decreased in GMV and function in patients with ADHD relative to those with OCD (and controls). In OCD patients, they were enhanced relative to controls. Patients with OCD showed disorder-specific reduced function and structure in rostral and dorsal anterior cingulate/medial prefrontal cortex (fMRI z = 2.113, P < .001; VBM z = 1.622, P < .001), whereas patients with ADHD showed disorder-specific underactivation predominantly in the right ventrolateral prefrontal cortex (z = 1.229, P < .001). Ventromedial prefrontal GMV reduction was shared in both disorders relative to controls. Conclusions and Relevance Shared impairments in inhibitory control, rather than representing a transdiagnostic endophenotype in ADHD and OCD, were associated with disorder-differential functional and structural abnormalities. Patients with ADHD showed smaller and underfunctioning ventrolateral prefrontal/insular-striatal regions whereas patients with OCD showed larger and hyperfunctioning insular-striatal regions that may be poorly controlled by smaller and underfunctioning rostro/dorsal medial prefrontal regions.
Article
Full-text available
Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10(-7)) and thalamus (d=-0.148; P=4.27 × 10(-3)) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10(-5)) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.Molecular Psychiatry advance online publication, 9 February 2016; doi:10.1038/mp.2015.227.
Article
Full-text available
The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.Molecular Psychiatry advance online publication, 30 June 2015; doi:10.1038/mp.2015.69.
Article
Full-text available
The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.Molecular Psychiatry advance online publication, 2 June 2015; doi:10.1038/mp.2015.63.
Article
Full-text available
Aggression is widely observed in children with attention deficit/hyperactivity disorder (ADHD) and has been frequently linked to frustration, or the unsatisfied anticipation of reward. Although animal studies and human functional neuroimaging implicate altered reward processing in aggressive behaviors, no prior studies have documented the relationship between fronto-accumbal circuitry-a critical cortical pathway to subcortical limbic regions- and aggression in medication naive children with ADHD. To examine this, we collected behavioral measures and parental reports of aggression and impulsivity as well structural and diffusion MRI from 30 children with ADHD and 31 healthy controls (HC) (mean age, 10±2.1 SD). Using morphometry and probabilistic tractography combined with multivariate statistical modeling (partial least squares regression and support vector regression), we identified anomalies within the fronto-accumbal circuit in childhood ADHD, which were associated with increased aggression. Specifically, children with ADHD showed reduced right accumbal volumes and frontal-accumbal white matter connectivity compared with HC. The magnitude of the accumbal volume reductions within the ADHD group was significantly correlated with increased aggression, an effect mediated by the relationship between the accumbal volume and impulsivity. Furthermore, aggression, but not impulsivity, was significantly explained by multivariate measures of fronto-accumbal white matter connectivity and cortical thickness within the orbitofrontal cortex. Our multi-modal imaging, combined with multivariate statistical modeling, suggests that the fronto-accumbal circuit is an important substrate of aggression in children with ADHD. These findings suggest that strategies aimed at probing the fronto-accumbal circuit may be beneficial for the treatment of aggressive behaviors in childhood ADHD.
Article
Full-text available
Functional and anatomical asymmetries are prevalent features of the human brain, linked to gender, handedness, and cognition. However, little is known about the neurodevelopmental processes involved. In zebrafish, asymmetries arise in the diencephalon before extending within the central nervous system. We aimed to identify genes involved in the development of subtle, left-right volumetric asymmetries of human subcortical structures using large datasets. We first tested the feasibility of measuring left-right volume differences in such large-scale samples, as assessed by two automated methods of subcortical segmentation (FSL|FIRST and FreeSurfer), using data from 235 subjects who had undergone MRI twice. We tested the agreement between the first and second scan, and the agreement between the segmentation methods, for measures of bilateral volumes of six subcortical structures and the hippocampus, and their volumetric asymmetries. We also tested whether there were biases introduced by left-right differences in the regional atlases used by the methods, by analyzing left-right flipped images. While many bilateral volumes were measured well (scan-rescan r = 0.6-0.8), most asymmetries, with the exception of the caudate nucleus, showed lower repeatabilites. We meta-analyzed genome-wide association scan results for caudate nucleus asymmetry in a combined sample of 3,028 adult subjects but did not detect associations at genome-wide significance (P < 5 × 10(-8)). There was no enrichment of genetic association in genes involved in left-right patterning of the viscera. Our results provide important information for researchers who are currently aiming to carry out large-scale genome-wide studies of subcortical and hippocampal volumes, and their asymmetries. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
Article
Full-text available
Although it has long been recognized that many individuals with attention deficit hyperactivity disorder (ADHD) also have difficulties with emotion regulation, no consensus has been reached on how to conceptualize this clinically challenging domain. The authors examine the current literature using both quantitative and qualitative methods. Three key findings emerge. First, emotion dysregulation is prevalent in ADHD throughout the lifespan and is a major contributor to impairment. Second, emotion dysregulation in ADHD may arise from deficits in orienting toward, recognizing, and/or allocating attention to emotional stimuli; these deficits implicate dysfunction within a striato-amygdalo-medial prefrontal cortical network. Third, while current treatments for ADHD often also ameliorate emotion dysregulation, a focus on this combination of symptoms reframes clinical questions and could stimulate novel therapeutic approaches. The authors then consider three models to explain the overlap between emotion dysregulation and ADHD: emotion dysregulation and ADHD are correlated but distinct dimensions; emotion dysregulation is a core diagnostic feature of ADHD; and the combination constitutes a nosological entity distinct from both ADHD and emotion dysregulation alone. The differing predictions from each model can guide research on the much-neglected population of patients with ADHD and emotion dysregulation.
Article
Full-text available
Children with attention-deficit/hyperactivity disorder (ADHD) have smaller volumes of total brain matter and subcortical regions, but it is unclear whether these represent delayed maturation or persist into adulthood. We performed a structural MRI study in 119 adult ADHD patients and 107 controls and investigated total gray and white matter and volumes of accumbens, caudate, globus pallidus, putamen, thalamus, amygdala and hippocampus. Additionally, we investigated effects of gender, stimulant treatment and history of major depression (MDD). There was no main effect of ADHD on the volumetric measures, nor was any effect observed in a secondary voxel-based morphometry (VBM) analysis of the entire brain. However, in the volumetric analysis a significant gender by diagnosis interaction was found for caudate volume. Male patients showed reduced right caudate volume compared to male controls, and caudate volume correlated with hyperactive/impulsive symptoms. Furthermore, patients using stimulant treatment had a smaller right hippocampus volume compared to medication-naïve patients and controls. ADHD patients with previous MDD showed smaller hippocampus volume compared to ADHD patients with no MDD. While these data were obtained in a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that developmental brain differences in ADHD largely normalize in adulthood. Reduced caudate volume in male patients may point to distinct neurobiological deficits underlying ADHD in the two genders. Smaller hippocampus volume in ADHD patients with previous MDD is consistent with neurobiological alterations observed in MDD.
Article
Full-text available
Objective: In children with conduct problems, high levels of callous-unemotional traits are associated with amygdala hypoactivity to consciously perceived fear, while low levels of callous-unemotional traits may be associated with amygdala hyperactivity. Behavioral data suggest that fear processing deficits in children with high callous-unemotional traits may extend to stimuli presented below conscious awareness (preattentively). The authors investigated the neural basis of this effect. Amygdala involvement was predicted on the basis of its role in preattentive affective processing in healthy adults and its dysfunction in previous studies of conduct problems. Method: Functional MRI was used to measure neural responses to fearful and calm faces presented preattentively (for 17 ms followed by backward masking) in boys with conduct problems and high callous-unemotional traits (N=15), conduct problems and low callous-unemotional traits (N=15), and typically developing comparison boys (N=16). Amygdala response to fearful and calm faces was predicted to differentiate groups, with the greatest response in boys with conduct problems and low callous-unemotional traits and the lowest in boys with conduct problems and high callous-unemotional traits. Results: In the right amygdala, a greater amygdala response was seen in boys with conduct problems and low callous-unemotional traits than in those with high callous-unemotional traits. The findings were not explained by symptom levels of conduct disorder, attention-deficit hyperactivity disorder, anxiety, or depression. Conclusions: These data demonstrate differential amygdala activity to preattentively presented fear in children with conduct problems grouped by callous-unemotional traits, with high levels associated with lower amygdala reactivity. The study's findings complement increasing evidence suggesting that callous-unemotional traits are an important specifier in the classification of children with conduct problems.
Article
Full-text available
Purpose Callous–unemotional (CU) traits are currently viewed as the defining signs and symptoms of juvenile psychopathy. It is unclear, however, whether CU traits have validity only in the context of conduct disorder (CD) as proposed by Frick and Moffitt (A proposal to the DSM-V childhood disorders and the ADHD and disruptive behavior disorders work groups to include a specifier to the diagnosis of conduct disorder based on the presence of callous–unemotional traits, American Psychiatric Association, Washington, DC, 2010), or also outside CD, either in combination with other forms of psychopathology or as a stand-alone construct. Methods The current review systematically studied the existent literature on CU traits in juveniles to examine their validity inside and outside CD according to the framework regarding the validity of a psychiatric diagnosis provided by Robins and Guze (Am J Psychiatry 126:983–987, 1970). Results Inside youth with conduct problems, and CD specifically, it seems that CU traits meet the Robins and Guze criteria. As many of the reviewed studies included youth with ODD and ADHD as well, there are indications the same might be true for ODD and ADHD, although probably to a lesser extent. In other disorders, CU traits may be present as well, but their role is not firmly established. As stand-alone construct, data are lacking or are scarce on all of the above-mentioned criteria. Conclusions CU traits are a useful specifier in CD, and possibly also in disruptive behaviour disorders (DBDs) more generally. High CU traits outside DBDs exist but it is as yet unknown if there is a clinical need for defining CU traits as a stand-alone construct.
Article
Full-text available
Reduced total brain volume is a consistent finding in children with Attention Deficit/Hyperactivity Disorder (ADHD). In order to get a better understanding of the neurobiology of ADHD, we take the first step in studying the dimensionality of current self-reported adult ADHD symptoms, by looking at its relation with total brain volume. In a sample of 652 highly educated adults, the association between total brain volume, assessed with magnetic resonance imaging, and current number of self-reported ADHD symptoms was studied. The results showed an association between these self-reported ADHD symptoms and total brain volume. Post-hoc analysis revealed that the symptom domain of inattention had the strongest association with total brain volume. In addition, the threshold for impairment coincides with the threshold for brain volume reduction. This finding improves our understanding of the biological substrates of self-reported ADHD symptoms, and suggests total brain volume as a target intermediate phenotype for future gene-finding in ADHD.
Article
Full-text available
Structural neuroimaging studies in attention-deficit hyperactivity disorder (ADHD) have been relatively inconsistent and have mainly been conducted with pediatric samples. Furthermore, there is evidence that stimulant medication may have an effect on brain structure. The authors conducted a meta-analysis of voxel-based morphometry studies in children and adults with ADHD and examined the potential effects of age and stimulant medication on regional gray matter volumes. The PubMed, ScienceDirect, Web of Knowledge, and Scopus databases were searched for articles published between 2001 and 2011. Manual searches were also conducted, and authors of studies were contacted for additional data. Coordinates were extracted from clusters of significant gray matter difference between ADHD patients and healthy comparison subjects. Metaregression methods were used to explore potential age and stimulant medication effects. Fourteen data sets comprising 378 patients with ADHD and 344 healthy subjects met inclusion criteria. The ADHD group had global reductions in gray matter volumes, which were robustly localized in the right lentiform nucleus and extended to the caudate nucleus. Both increasing age and percentage of patients taking stimulant medication were found to be independently associated with more normal values in this region. Patients also had slightly greater gray matter volumes in the left posterior cingulate cortex. These findings confirm that the most prominent and replicable structural abnormalities in ADHD are in the basal ganglia. They furthermore suggest that ADHD patients may progressively catch up with their developmental delay with advancing age and that use of stimulant medication may be associated with normalization of structural abnormalities in ADHD, although longitudinal studies are needed to confirm both observations.
Article
Full-text available
There is considerable epidemiological and neuropsychological evidence that attention deficit hyperactivity disorder (ADHD) is best considered dimensionally, lying at the extreme end of a continuous distribution of symptoms and underlying cognitive impairments. The authors investigated whether cortical brain development in typically developing children with symptoms of hyperactivity and impulsivity resembles that found in the syndrome of ADHD. Specifically, they examined whether a slower rate of cortical thinning during late childhood and adolescence, which they previously found in ADHD, is also linked to the severity of symptoms of hyperactivity and impulsivity in typically developing children. In a longitudinal analysis, a total of 193 typically developing children with 389 neuroanatomic magnetic resonance images and varying levels of symptoms of hyperactivity and impulsivity (measured with the Conners' Parent Rating Scale) were contrasted with 197 children with ADHD with 337 imaging scans. The relationship between the rates of regional cortical thinning and severity of symptoms of hyperactivity/impulsivity was determined. Youth with higher levels of hyperactivity/impulsivity had a slower rate of cortical thinning, predominantly in prefrontal cortical regions, bilaterally in the middle frontal/premotor gyri, extending down the medial prefrontal wall to the anterior cingulate; the orbitofrontal cortex; and the right inferior frontal gyrus. For each increase of one point in the hyperactivity/impulsivity score, there was a decrease in the rate of regional cortical thinning of 0.0054 mm/year (SE=0.0019 mm/year). Children with ADHD had the slowest rate of cortical thinning. Slower cortical thinning during adolescence characterizes the presence of both the symptoms and syndrome of ADHD, providing neurobiological evidence for dimensionality of the disorder.
Article
Full-text available
The dual pathway model explains neuro-psychological heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD) in terms of dissociable cognitive and motivational deficits each affecting some but not other patients. We explore whether deficits in temporal processing might constitute a third dissociable neuropsychological component of ADHD. Nine tasks designed to tap three domains (inhibitory control, delay aversion and temporal processing) were administered to ADHD probands (n=71; ages 6 to 17 years), their siblings (n=71; 65 unaffected by ADHD) and a group of non-ADHD controls (n=50). IQ and working memory were measured. Temporal processing, inhibitory control and delay-related deficits represented independent neuropsychological components. ADHD children differed from controls on all factors. For ADHD patients, the co-occurrence of inhibitory, temporal processing and delay-related deficits was no greater than expected by chance with substantial groups of patients showing only one problem. Domain-specific patterns of familial co-segregation provided evidence for the validity of neuropsychological subgroupings. The current results illustrate the neuropsychological heterogeneity in ADHD and initial support for a triple pathway model. The findings need to be replicated in larger samples.
Article
Full-text available
Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure. To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls. Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images. Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls. On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F(1,280) = 8.30, P =.004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F(1,280) = 12.29, P =.001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F(2,288) = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P =.002) and cerebellar volumes (-6.2%, F( 2,288) = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F(2,288) = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P =.002) and in the cerebellum (P =.003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P =.05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05). Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.
Article
Full-text available
The worldwide prevalence estimates of attention deficit hyperactivity disorder (ADHD)/hyperkinetic disorder (HD) are highly heterogeneous. Presently, the reasons for this discrepancy remain poorly understood. The purpose of this study was to determine the possible causes of the varied worldwide estimates of the disorder and to compute its worldwide-pooled prevalence. The authors searched MEDLINE and PsycINFO databases from January 1978 to December 2005 and reviewed textbooks and reference lists of the studies selected. Authors of relevant articles from North America, South America, Europe, Africa, Asia, Oceania, and the Middle East and ADHD/HD experts were contacted. Surveys were included if they reported point prevalence of ADHD/HD for subjects 18 years of age or younger from the general population or schools according to DSM or ICD criteria. The literature search generated 9,105 records, and 303 full-text articles were reviewed. One hundred and two studies comprising 171,756 subjects from all world regions were included. The ADHD/HD worldwide-pooled prevalence was 5.29%. This estimate was associated with significant variability. In the multivariate metaregression model, diagnostic criteria, source of information, requirement of impairment for diagnosis, and geographic origin of the studies were significantly associated with ADHD/HD prevalence rates. Geographic location was associated with significant variability only between estimates from North America and both Africa and the Middle East. No significant differences were found between Europe and North America. Our findings suggest that geographic location plays a limited role in the reasons for the large variability of ADHD/HD prevalence estimates worldwide. Instead, this variability seems to be explained primarily by the methodological characteristics of studies.
Article
Full-text available
There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from a delay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory of each cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developing controls (log rank test χ(1)² = 5,609, P < 1.0 × 10⁻²⁰). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported. • cortical development • structural neuroimaging
Article
Full-text available
The authors sought to map gray matter changes in Attention Deficit Hyperactivity Disorder (ADHD) using a novel technique incorporating neuro-imaging and genetic meta-analysis methods. A systematic search was conducted for voxel-based structural magnetic resonance imaging studies of patients with ADHD (or with related disorders) in relation to comparison groups. The authors carried out meta-analyses of the co-ordinates of gray matter differences. For the meta-analyses they hybridised the standard method of Activation Likelihood Estimation (ALE) with the rank approach used in Genome Scan Meta-Analysis (GSMA). This system detects three-dimensional conjunctions of co-ordinates from multiple studies and permits the weighting of studies in relation to sample size. For gray matter decreases, there were 7 studies including a total of 114 patients with ADHD (or related disorders) and 143 comparison subjects. Meta-analysis of these studies identified a significant regional gray matter reduction in ADHD in the right putamen/globus pallidus region. Four studies reported gray matter increases in ADHD but no regional increase was identified by meta-analysis. In ADHD there is gray matter reduction in the right putamen/globus pallidus region. This may be an anatomical marker for dysfunction in frontostriatal circuits mediating cognitive control. Right putamen lesions have been specifically associated with ADHD symptoms after closed head injuries in children.
Article
The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Article
Objective: The suggested neurobiological bases of ADHD focus on the amygdala as a center of emotions processing. Therefore, we hypothesize that patients with ADHD will show an irregular pattern of emotional-related activity of the amygdala region as well as some structural abnormalities. Method: Nine adult patients with ADHD and nine group-matched healthy volunteers were studied using a 1.5-T magnetic resonance imaging (MRI) scanner. Morphometric measurements were obtained manually, and they were later processed and compared. Absolute volumes of several structures and nuclei were calculated with FSL-FIRST. For the functional magnetic resonance examination, a set of two paradigms was prepared, using a block design, incorporating images of the International Affective Picture System (IAPS). The patients were unmedicated at the time of the MRI scan. Results: Negative correlation was found between the right amygdala volume and Barrat's impulsivity scores (r = -.756, p = .018). The age of patients did not turn out to be a significant factor. No significantly higher activation areas were found in patients with unpleasant content images. For the left amygdala, an Region Of Interest (ROI)-based analysis showed moderately higher level of activation in the patients than in the controls with pleasant content images. Conclusion: Patients with ADHD tend to have smaller amygdala volumes. ADHD patients presented less activation in the area of the left frontal pole than the controls. There was no amygdala activation stated when presenting the pleasant images. Whereas bigger activation of the left amygdala was found in patients while presenting them unpleasant images. These results might suggest that lower emotional processing and less control of impulsivity is associated with dysfunctional amygdala in ADHD patients.
Article
Background: Magnetic resonance imaging (MRI) studies have shown decreased caudate volumes in individuals with attention deficit hyperactivity disorder (ADHD). However, most of these studies have been carried out in male children. Very little research has been done in adults, and the results obtained in children are difficult to extrapolate to adults. We sought to compare the volume of the caudate of adults with ADHD with that of healthy controls; we also compared these volumes between men and women. Methods: We performed an MRI scan on 20 adults with ADHD (10 men and 10 women) aged 25-35 years and 20 healthy controls matched by age and sex. We used voxel-based morphometry with the DARTEL algorithm for image analyses. We used the specifically designed Friederichsen, Almeida, Serrano, Cortes Test (FASCT) to measure the severity of ADHD; both the self-reported (FASCT-SR) and the observer (FASCT-O) versions were used. Results: The statistical parametric map showed a smaller region with low grey matter volume and a smaller concentration of grey matter in this region of the right caudate in ADHD patients than in health controls, both in the entire sample and within each sex. There was a significant correlation between the volume of this region of the caudate with the number of DSM IV-TR criteria, as well as with the total scores and most of the factors of the FASCT-SR and FASCT-O scales. A separate correlation analysis by sex gave similar results. Limitations: The study design was cross-sectional. Conclusion: The region of the right caudate with low grey matter volume was smaller in adults with ADHD in both sexes and was correlated with ADHD severity.
Article
Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for developing depression. The neurobiological substrates that convey this risk remain poorly understood. On the basis of considerable data implicating hippocampal abnormalities in depressive disorders, we aimed to explore the relationship between the hippocampus and levels of depressive symptomatology in ADHD. We used structural magnetic resonance imaging (MRI) to examine the functional magnetic resonance imaging (fMRI) to assess the resting state functional connectivity (rs-fcMRI) of the hippocampus in a sample of 32 medication-naive children with ADHD (ages 6–13) and 33 age- and sex-matched healthy control (HC) participants. Compared with the HC participants, the participants with ADHD had (i) reduced volumes of the left hippocampus and (ii) reduced functional connectivity (rs-fcMRI) between the left hippocampus and the left orbitofrontal cortex (OFC); these hippocampal effects were associated with more severe depressive symptoms, even after controlling for the severity of inattentive and hyperactive/impulsive symptoms. Altered hippocampal structure and connectivity were not associated with anxiety or more general internalizing symptoms. Though preliminary, these findings suggest that the relationship between hippocampal anomalies and ADHD youth’s susceptibility to developing depression and other mood disorders may merit further investigation with follow-up longitudinal research.
Article
The prevalence, age of onset, and symptomatology of many neuropsychiatric conditions differ between males and females. To understand the causes and consequences of sex differences it is important to establish where they occur in the human brain. We report the first meta-analysis of typical sex differences on global brain volume, a descriptive account of the breakdown of studies of each compartmental volume by six age categories, and whole-brain voxel-wise meta-analyses on brain volume and density. Gaussian-process regression coordinate-based meta-analysis was used to examine sex differences in voxel-based regional volume and density. On average, males have larger total brain volumes than females. Examination of the breakdown of studies providing total volumes by age categories indicated a bias towards the 18-59 year-old category. Regional sex differences in volume and tissue density include the amygdala, hippocampus and insula, areas known to be implicated in sex-biased neuropsychiatric conditions. Together, these results suggest candidate regions for investigating the asymmetric effect that sex has on the developing brain, and for understanding sex-biased neurological and psychiatric conditions.
Article
How best to capture heterogeneity in attention-deficit/hyperactivity disorder (ADHD) using biomarkers has been elusive. This study evaluated whether emotion reactivity and regulation provide a means to achieve this. Participants were classified into three groups: children with ADHD plus low prosocial behavior (hypothesized to be high in callous/unemotional traits; n = 21); children with ADHD with age-appropriate prosocial behavior (n = 54); and typically developing children (n = 75). Children completed a task with four conditions: negative induction, negative suppression, positive induction, and positive suppression of affect. The task required children to view an emotion-laden film clip, while either facially mimicking (induction) or masking (suppression) the emotion of the main character. Parasympathetic and sympathetic nervous system activity were assessed via respiratory sinus arrhythmia (RSA) and cardiac pre-ejection period (PEP), respectively. Symptoms of anxiety, conduct, and oppositional defiant disorders were treated as covariates. The ADHD-typical-prosocial group displayed atypically elevated parasympathetic reactivity (emotion dysregulation) during positive induction, along with increased sympathetic activity (elevated arousal) across conditions. In contrast, the ADHD-low-prosocial group displayed reduced parasympathetic reactivity and reduced sympathetic activity (low emotional arousal) across baseline and task conditions. Thus, both ADHD groups had altered patterns of autonomic functioning, but in two distinct forms. Although ADHD is heterogeneous clinically, results suggest that ADHD is also heterogeneous with regard to physiological indices of emotion and regulation. Future studies of emotion, regulation, and ADHD should take this into account. Further study of physiological responding in ADHD may yield clinically and etiologically distinct domains or groups.