ORCID Profile
0000-0003-0186-8349
Current Organisations
Monash University
,
Trinity College Dublin
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Publisher: Springer Science and Business Media LLC
Date: 14-08-2023
DOI: 10.1038/S41593-023-01404-6
Abstract: The substantial in idual heterogeneity that characterizes people with mental illness is often ignored by classical case–control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive–compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in % of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience–ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2012.08.012
Abstract: A number of recent studies suggest that DNA variation in the dopamine transporter gene (DAT1) influences spatial attention asymmetry in clinical populations such as ADHD, but confirmation in non-clinical s les is required. Since non-spatial factors such as attentional load have been shown to influence spatial biases in clinical conditions, here we sought to determine whether any association between DAT1 genotype and spatial bias might be moderated by non-spatial attentional load. Healthy adults were asked to react to sudden onset peripheral targets while demand on non-spatial attention was manipulated via a central task. Participants were genotyped for a DAT1 variable number of tandem repeat (VNTR) polymorphism. The 10-repeat allele of this variant is a replicated susceptibility allele for ADHD and has been shown to associate with spatial bias. As expected, an overall leftward asymmetry seudoneglect was observed when the data were averaged across the entire s le. When data were stratified by DAT1 genotype, in iduals lacking homozygosity for the 10-repeat DAT1 allele (non-10/10) showed a pronounced leftward bias that was significantly different from zero. In line with past reports from children with ADHD, this leftward bias was attenuated in in iduals who were homozygous for the DAT1 10-repeat allele (10/10), suggestive of relatively weaker right hemisphere dominance for spatial attention. This effect of DAT1 genotype on spatial bias was not modulated by non-spatial attention load. These data confirm in healthy adult participants both the existence and the direction of the relationship previously reported between DAT1 genotype and spatial bias in children with ADHD. These data add to a growing body of evidence showing that spatial attentional asymmetry is a stable quantitative trait, with in idual differences in this trait significantly predicted by common DNA variation in the DAT1 gene.
Publisher: Public Library of Science (PLoS)
Date: 15-05-2015
Publisher: Center for Open Science
Date: 29-06-2022
Abstract: Marek et al. analyzed three very large magnetic resonance imaging (MRI) datasets and concluded that thousands of participants are necessary to ensure replicable results in “brain-wide associations studies,” which they defined as “studies of the associations between common inter-in idual variability in human brain structure/function and cognition or psychiatric symptomatology.” This conclusion overgeneralizes the implications of their findings and is likely to have an unwarranted chilling effect on neuroimaging research focused on in idual differences, preventing good research with s les in the hundreds from being funded and conducted. To fend off these negative consequences, we explain why their conclusion is not fully justified, discuss methods that can yield larger effects, and suggest practical guidelines for s le size, recognizing the potential utility of s les in the hundreds.
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.BIOPSYCHO.2007.11.009
Abstract: Recent advances in neuroimaging technologies have allowed ever more detailed studies of the human brain. The combination of neuroimaging techniques with genetics may provide a more sensitive measure of the influence of genetic variants on cognitive function than behavioural measures alone. Here we present a review of functional magnetic resonance imaging (fMRI) studies of genetic links to executive functions, focusing on sustained attention, working memory and response inhibition. In addition to studies in the normal population, we also address findings from three clinical populations: schizophrenia, ADHD and autism spectrum disorders. While the findings in the populations studied do not always converge, they all point to the usefulness of neuroimaging techniques such as fMRI as potential endophenotypes for parsing the genetic aetiology of executive function.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2014.01.023
Abstract: Response inhibition is an executive function that allows the detection and modification of unwanted actions. Its underlying neurochemistry and neurobiology have been explored by combining classic neuropsychological paradigms, such as the go/no-go task (GNG), with targeted pharmacology and functional neuroimaging. We sought to further this literature by using single doses of methylphenidate (30 mg), atomoxetine (60 mg), citalopram (30 mg) and placebo to probe dopaminergic, noradrenergic and serotonergic aspects of response inhibition. Twenty-seven (27) healthy, right-handed males participated in a randomised, double blind, placebo-controlled, within subject, crossover fMRI study to examine stop-related BOLD activation correlates of a modified GNG task. Methylphenidate demonstrated activation versus placebo in the pregenual cingulate (dorsal anterior cingulate), right inferior frontal, left middle frontal, left angular and right superior temporal gyri and right caudate. Atomoxetine demonstrated activation versus placebo across a broad network of cortical regions. Both methylphenidate and atomoxetine, but not citalopram, activated superior temporal, right inferior frontal and left middle frontal clusters. Citalopram only activated the left inferior occipital lobe. Taking the above as functionally defined regions of interest, we examined the specificity of stop-related drug activity by comparing mean activations across the four conditions. Only methylphenidate demonstrated drug-specific effects with increased activation of the pregenual cingulate and decreased activation of the caudate. Direct comparison of methylphenidate and atomoxetine showed broad recruitment of prefrontal regions but specific effects of methylphenidate in the pregenual cingulate and caudate revealing dissociable modulations of response inhibition networks.
Publisher: Elsevier BV
Date: 10-2022
Publisher: Frontiers Media SA
Date: 06-12-2017
Publisher: Springer Science and Business Media LLC
Date: 05-06-2007
Abstract: In everyday life, our sensory system is bombarded with visual input and we rely upon attention to select only those inputs that are relevant to behavioural goals. Typically, humans can shift their attention from one visual field to the other with little cost to perception. In cases of 'unilateral neglect', however, there is a persistent bias of spatial attention towards the same side as the damaged cerebral hemisphere. We used a visual orienting task to examine the influence of functional polymorphisms of the dopamine transporter gene (DAT1) on in idual differences in spatial attention in normally developing children. DAT1 genotype significantly influenced spatial bias. Healthy children who were homozygous for alleles that influence the expression of dopamine transporters in the brain displayed inattention for left-sided stimuli, whereas heterozygotes did not. Our data provide the first evidence in healthy in iduals of a genetically mediated bias in spatial attention that is related to dopamine signalling.
Publisher: Informa UK Limited
Date: 12-03-2019
DOI: 10.1080/15402002.2018.1443455
Abstract: A high proportion of children with Attention Deficit Hyperactivity Disorder- Combined type (ADHD-CT) experience sleep and motor problems. This study investigated (a) whether motor proficiency moderated the relationship between ADHD symptoms and sleep problems in children with and without ADHD-CT and (b) whether this moderation differed as a function of ADHD diagnosis. A s le of 70 primary school male children between 8-15 years were recruited children with ADHD-CT (n = 38 mean age 10 years, 2 months [SD = 1 year, 6 months]) and a typically developing (TD) (n = 32 mean age 9 years, 6 months [SD = 1 year, 5 months]) group. Motor proficiency was measured using the Movement Assessment Battery for Children-2nd Edition (MABC-2), ADHD symptoms were measured using the Conners' Parent Rating Scale (CPRS) and parent reported sleep problems were measured using the Children's Sleep Habits Questionnaire (CSHQ). Children who reported higher ADHD symptoms and lower motor proficiency scores reported more sleep problems. The moderation effect only held in children with a diagnosis of ADHD-CT and not in the typically developing group. These findings indicate that children who experience greater severity of ADHD symptoms who also have lower motor proficiency may be at increased risk of experiencing sleep problems. These findings also illustrate the importance of considering motor proficiency when exploring risk factors for sleep problems in children with ADHD-CT as well as sleep interventions.
Publisher: Wiley
Date: 18-05-2020
DOI: 10.1002/HBM.25029
Abstract: Neuroimaging has been extensively used to study brain structure and function in in iduals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small s le sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA‐ADHD and ENIGMA‐ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA‐ADHD and ‐ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow‐up analyses continue that include more imaging modalities (diffusion MRI and resting‐state functional MRI), collaborations with other large databases, and s les with dual diagnoses.
Publisher: Frontiers Media SA
Date: 27-06-2022
DOI: 10.3389/FPSYT.2022.914668
Abstract: Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with other neurodevelopmental diagnoses, such as autism spectrum disorder (autism), which can make clinical decision making around symptom management challenging for clinicians. There is a paucity of research examining pharmacotherapeutic management of children who have ADHD with co-occurring diagnoses. We aimed to report on the co-occurring diagnoses and symptom profile of children, and report on medication use, stratified by ADHD, autism and ADHD + autism diagnoses. Caregivers of 505 children (2–18 years) with ADHD ( n = 239), autism ( n = 117), and co-occurring ADHD + autism ( n = 149) completed a questionnaire on current medication use and clinical rating scales about their child's symptoms, as part of a broader project investigating diagnosis and management of symptoms in children with ADHD or autism. The parents of the ADHD group reported a higher proportion of their children had learning disorders (17.15%) and speech and language disorders (4.60%) compared to the parents of the autism and ADHD + autism groups. Parents of the ADHD + autism group reported higher proportions of intellectual disability (5.37%), oppositional defiant disorder (20.13%), anxiety (38.93%), depression (6.71%) and genetic conditions (3.36%) in their children, in comparison to the parents of the ADHD and autism groups. Children with ADHD were reported to be taking a higher proportion of psychotropic medication (90%), followed by ADHD + autism (86%) and autism (39%). The parents of children with ADHD + autism reported a higher proportion of non-stimulant ADHD medication (25.5%), antipsychotic (18.79%), antidepressant (22.15%) and melatonin (31.54%) use by their children, compared to the parents of the ADHD and autism groups. A similar proportion of children with ADHD + autism and ADHD were reported to be taking medication. However, the types of medication taken were different, as expected with reported co-occurring diagnoses. The complexity of symptoms and diagnoses in ADHD + autism warrants targeted research to optimize management and therapeutic outcomes.
Publisher: Wiley
Date: 18-09-2018
DOI: 10.1002/AJMG.B.32592
Abstract: Converging evidence from candidate gene, genome-wide linkage, and association studies support a role of cadherins in the pathophysiology of five major psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). These molecules are transmembrane proteins which act as cell adhesives by forming adherens junctions (AJs) to bind cells within tissues. Members of the cadherin superfamily are also involved in biological processes such as signal transduction and plasticity that have been implicated in the etiology of major psychiatric conditions. Although there are over 110 genes mapped to the cadherin superfamily, our literature survey showed that evidence of association with psychiatric disorders is strongest for CDH7, CHD11, and CDH13. Gene enrichment analysis showed that those cadherin genes implicated in psychiatric disorders were overrepresented in biological processes such as in cell-cell adhesion (GO:0007156 & GO:0098742) and adherens junction organization (GO:0034332). Further, cadherin genes were also mapped to processes that have been linked to the development of psychiatric disorders such as nervous system development (GO:0007399). To further understand the role of cadherin SNPs implicated in psychiatric disorders, we utilized an in silico computational pipeline to functionally annotate associated variants. This analysis yielded eight variants mapped to PCDH1-13, CDH7, CDH11, and CDH13 that are predicted to be biologically functional. Functional genomic evaluation is now required to understand the molecular mechanism by which these variants might confer susceptibility to psychiatric disorders.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2013
DOI: 10.1038/TP.2013.41
Publisher: Springer Science and Business Media LLC
Date: 05-2006
Publisher: Wiley
Date: 21-11-2008
DOI: 10.1111/J.1469-7610.2008.01936.X
Abstract: An important theory of attention suggests that there are three separate networks that execute discrete cognitive functions. The 'alerting' network acquires and maintains an alert state, the 'orienting' network selects information from sensory input and the 'conflict' network resolves conflict that arises between potential responses. This theory holds promise for dissociating discrete patterns of cognitive impairment in disorders where attentional deficits may often be subtle, such as in attention deficit hyperactivity disorder (ADHD). The Attentional Network Test (ANT), a behavioural assay of the functional integrity of attention networks, was used to examine the performance of 73 children with ADHD and 73 controls. Performance on the ANT clearly differentiated the children with and without ADHD in terms of mean and standard deviation (SD) of reaction time (RT), the number of incorrect responses made and the number of omission errors made. The ADHD group demonstrated deficits in the conflict network in terms of slower RT and a higher number of incorrect responses. The ADHD group showed deficits in the alerting network in terms of the number of omission errors made. There was no demonstration of a deficit in the orienting network in ADHD on this task. The children with ADHD demonstrated deficits in the alerting and conflict attention networks but normal functioning of the orienting network.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 26-02-2013
DOI: 10.1038/MP.2013.16
Abstract: Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in in iduals from erse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2012
DOI: 10.1038/NN.3092
Abstract: The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large s le (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2005.03.011
Abstract: ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a s le of children and adolescents with ADHD (n=22) in relation to dopamine transporter genotype (DAT1) and also controls (n=20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub- ided into those in iduals with two copies of the "high-risk" 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD.
Publisher: Center for Open Science
Date: 27-10-2022
Abstract: Our capacity to measure erse aspects of human biology in vivo has developed rapidly in the past decades, but the rate at which these techniques have generated translatable insights into the biology of psychopathological conditions has lagged far behind. This slow progress is partly due to the poor sensitivity, specificity, and replicability of many findings in the literature, which have in turn been attributed to small effect sizes, small s le sizes, and low statistical power. A commonly proposed solution is to rely on large, consortia-sized s les to facilitate discovery of replicable findings. Here, we argue that increasing s le sizes will have limited impact unless a more fundamental issue is addressed: the precision with which target behavioral phenotypes are measured. We discuss key problems and outline several ways forward, largely centered on the use of appropriate statistical models with deep, transdiagnostic assessment of hierarchically organized and homogeneous psychopathology dimensions across the full range of the severity spectrum. We provide worked ex les to demonstrate key problems and potential solutions. Arguably, a precision phenotyping approach can enhance the discovery and replicability of associations between biology and behavior, thereby facilitating insights into the pathophysiological mechanisms underlying psychiatric disorders.
Publisher: Informa UK Limited
Date: 10-2012
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2013.01.019
Abstract: Converging evidence suggests that right-hemisphere dominant spatial attention systems can be modulated by non-spatial processes such as attentional capacity. The severity of neglect in right-hemisphere stroke patients for ex le, is correlated with impairments in non-lateralized attention. Evidence also suggests the coexistence of lateralized inattention and reduced capacity in developmental disorders of attention, such as attention deficit hyperactivity disorder (ADHD), which is marked by cognitive impairments suggestive of right hemisphere dysfunction. These lines of evidence argue against a coincident damage hypothesis and suggest instead a direct modulation of spatial attention by non-spatial processes. Here we sought experimental evidence for this relationship in both acquired and developmental disorders of attention. Six adult stroke patients with focal right brain injury and 19 children with ADHD were studied in comparison to control groups of both healthy older adults and typically developing children. The participants were required to detect transient, unilateral visual targets while simultaneously monitoring a stream of alphanumeric characters at fixation. Load at fixation was manipulated by asking participants either to ignore the central stream and focus on the peripheral detection task (no report condition), or to monitor the central stream for a probe item that was defined by either a unique feature (low load condition) or a conjunction of features (high load condition). As expected, in all participants greater load at fixation slowed responses to peripheral targets. Crucially, in right brain injured patients but not older healthy adults left target detection was slowed significantly more than central and right target detection. A qualitatively similar pattern was seen in children with ADHD, but not in typically developing children. The imposition of load at fixation slowed responses to left compared with right targets, and this response time asymmetry was correlated with the severity of ADHD symptoms. These results suggest that a direct manipulation of non-spatial attention can reveal lateralised attention deficits in both acquired and developmental forms of inattention. Our findings support the view that spatial attention networks are tightly integrated with non-lateralized aspects of attention.
Publisher: Springer Science and Business Media LLC
Date: 15-01-2005
DOI: 10.1007/S00221-004-2180-Y
Abstract: ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282-284). Here we re-examined this finding with an extended s le of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n = 61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD.
Publisher: eLife Sciences Publications, Ltd
Date: 22-02-2019
Publisher: Wiley
Date: 26-11-2019
DOI: 10.1111/DESC.12918
Abstract: Executive Function (EF) and Effortful Control (EC) have traditionally been viewed as distinct constructs related to cognition and temperament during development. More recently, EF and EC have been implicated in top-down self-regulation - the goal-directed control of cognition, emotion, and behavior. We propose that executive attention, a limited-capacity attentional resource subserving goal-directed cognition and behavior, is the common cognitive mechanism underlying the self-regulatory capacities captured by EF and EC. We addressed three related questions: (a) Do behavioral ratings of EF and EC represent the same self-regulation construct? (b) Is this self-regulation construct explained by a common executive attention factor as measured by performance on cognitive tasks? and (c) Does the executive attention factor explain additional variance in attention deficit hyperactivity disorder (ADHD) problems to behavioral ratings of self-regulation? Measures of performance on complex span, general intelligence, and response inhibition tasks were obtained from 136 preadolescent children (M = 11 years, 10 months, SD = 8 months), along with self- and parent-reported EC, and parent-reported EF, and ADHD problems. Results from structural equation modeling demonstrated that behavioral ratings of EF and EC measured the same self-regulation construct. Cognitive tasks measured a common executive attention factor that significantly explained 30% of the variance in behavioral ratings of self-regulation. Executive attention failed to significantly explain additional variance in ADHD problems beyond that explained by behavioral ratings of self-regulation. These findings raise questions about the utility of task-based cognitive measures in research and clinical assessment of self-regulation and psychopathology in developmental s les.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2016
DOI: 10.1038/MP.2016.2
Abstract: Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.
Publisher: Informa UK Limited
Date: 2004
DOI: 10.1080/13576500244000319
Abstract: Lateral biases in visual perception have been demonstrated in normal in iduals and in patients with unilateral brain lesions. It has been suggested that the absence of structural and functional asymmetries in schizophrenia could be due to a failure in lateralisation that may be most pronounced in those patients whose illness onset is at an early age. Here we examined lateral biases in patients with schizophrenia of an early onset (N = 21) and a late onset (N = 19), and their respective age-matched control groups, using the greyscales task, a sensitive measure of asymmetries in visual processing. The stimuli consisted of two rectangles, one above the other, shaded in opposite directions and matched overall for darkness. Participants judged which of the two rectangles looked darker overall. Previous studies using this task in healthy participants have reported a reliable bias, such that the rectangle with the darker end on the left is selected preferentially. Whereas the late-onset patients in this study exhibited a perceptual bias of similar direction and magnitude to that of controls, this was not the case for the early-onset patients, who exhibited significantly less bias than their control group. The reduced perceptual bias seen in the early-onset group, but not the late-onset group, suggests an attenuation of right hemisphere mechanisms dedicated to processing visuospatial information. The attenuated perceptual asymmetry in the early-onset group only may be consistent with the view that (i) an earlier illness onset reflects a greater loss of hemispheric differentiation and (ii) reduced functional asymmetries in the early-onset group are a manifestation of a failure to allocate functions to one or the other hemisphere.
Publisher: SAGE Publications
Date: 28-04-2021
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0028-3932(96)00081-4
Abstract: Although planning is important for the functioning of patients with dementia of the Alzheimer Type (DAT), little is known about response programming in DAT. This study used a cueing paradigm coupled with quantitative kinematic analysis to document the preparation and execution of movements made by a group of 12 DAT patients and their age and sex matched controls. Participants connected a series of targets placed upon a WACOM SD420 graphics tablet, in response to the pattern of illumination of a set of light emitting diodes (LEDs). In one condition, participants could programme the upcoming movement, whilst in another they were forced to reprogramme this movement on-line (i.e. they were not provided with advance information about the location of the upcoming target). DAT patients were found to have programming deficits, taking longer to initiate movements, particularly in the absence of cues. While problems spontaneously programming a movement might cause a greater reliance upon on-line guidance, when both groups were required to guide the movement on-line, DAT patients continued to show slower and less efficient movements implying declining sensori-motor function these differences were not simply due to strategy or medication status.
Publisher: Cold Spring Harbor Laboratory
Date: 17-04-2020
DOI: 10.1101/2020.04.13.20063404
Abstract: Major depressive disorder (MDD) is a debilitating illness characterized by the persistence of negative thoughts and emotions. Although antidepressant medications are effective, less than half of patients achieve complete remission despite multiple treatment trials. Repetitive transcranial magnetic stimulation (rTMS) has proven effective in the treatment of depression, especially for patients resistant to antidepressant medications. Remission rates when using rTMS for treatment-resistant depression (TRD) patients are between 30% and 40%. The responsiveness to pharmacotherapy and rTMS therapy may be influenced by genetic factors. Here we aim to characterize the genetic profile of refractory in iduals with MDD and their rTMS responsiveness. We used an extreme-phenotype design (rTMS responders vs. non-responders) and conducted a genome wide association study on 48 participants and 593,260 SNPs. We identified 53 significant SNP associations. Gene-set enrichment analysis showed that significantly associated genes loaded onto synaptic plasticity regulation pathways. Among the genes found differentially expressed in rTMS responders compared to non-responders were APP, GRID2 and SPPL2A genes. Based on these findings, we suggest that the identified genes may influence of rTMS responsiveness. Furthermore, the rTMS responsiveness may be associated with several pathways and not just to the influence of a single gene. To the best of our knowledge, this is the first report on the genetic profile of rTMS response using a GWAS approach. Nevertheless, further studies are necessary to enlight the molecular mechanism by which these genes affect response to rTMS treatment.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2020
Publisher: Center for Open Science
Date: 27-10-2022
Abstract: Background: Impulsivity is a multidimensional transdiagnostic construct that is a key feature of many forms of psychopathology, but its underlying latent architecture and genetic correlates remain unclear. Methods: We comprehensively measured impulsivity-related constructs with 105 self-report questionnaire items across 16 scales and subscales in 859 non-clinical adult participants. We used exploratory structural equation modeling and item response theory to measure the target impulsivity traits with high precision. We also calculated polygenic risk scores for impulsivity traits and attention deficit hyperactivity disorder (ADHD) based on genome-wide association studies of independent discovery s les.Results: A hypothesized three-factor model of impulsivity, comprising Disinhibition – affect-free lack of premeditation Urgency – emotion-based rash action and Reward Sensitivity – sensation-, novelty-, and excitement-seeking provided a better fit to the data compared to one- and two-factor models. Disinhibition was associated with impulsivity polygenic risk scores reflecting lack of perseverance (r2 = .017, p = .252 x 10-3) and with ADHD polygenic risk scores (r2 = .014, p =. 826 x 10-3). Reward sensitivity was also associated with ADHD polygenic risk scores (r2 = .018, p = .193 x 10-3). Conclusions: The pattern of observed genetic correlations was consistent with the proposed three-factor model of impulsivity and suggest that disinhibition and reward sensitivity represent independent risk pathways for ADHD, consistent with a dual pathways model. We propose that Disinhibition, Urgency, and Reward Sensitivity represent candidate phenotypes for better understanding the multidimensional nature of Impulsivity.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2020
DOI: 10.1038/S41398-020-01077-W
Abstract: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood with a strong genetic component. Despite the success of mapping ADHD risk loci, little work has been done to experimentally verify the contribution of these loci to ADHD phenotypes. Meta-analysis of four genome-wide association studies in ADHD suggested CHMP7 as a predisposing gene for ADHD. A DNA variant (rs2294123) mapped to CHMP7 has been shown (via bioinformatic analysis) to have a high likelihood for functionality and correlate with reduced transcript levels. We used CRISPR-Cas9 genome editing to generate a chmp7 zebrafish model for ADHD. chmp7 +/− fish showed comparable reductions in mRNA levels to in iduals homozygous for the CHMP7 ADHD risk allele. These fish displayed significant hyperactivity over a 24-h period at 6 days post-fertilisation compared to chmp7 +/+ , but this effect did not persist into juvenile and adulthood stages. In addition, chmp7 +/− fish had significantly smaller total brain volumes than chmp7 +/+ fish. Finally, the hyperactivity at 6 days post-fertilisation was significantly reduced through the application of methylphenidate, a mainstay pharmacological treatment for ADHD. Overall, this study highlights an important role for CHMP7 in the neurodevelopment of ADHD, and demonstrates the utility of zebrafish for modelling the functional effects of genes conferring risk to ADHD.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2021
DOI: 10.1038/S41562-021-01127-3
Abstract: Impulsive behaviours are a major contributor to the global burden of disease, but existing measures of cognitive impulsivity have suboptimal reliability and validity. Here, we introduce the Cognitive Impulsivity Suite, comprising three computerized/online tasks using a gamified interface. We conceptualize rapid-response impulsive behaviours (disinhibition) as arising from the failure of three distinct cognitive mechanisms: attentional control, information gathering and monitoring/shifting. We demonstrate the construct and criterion validity of the Cognitive Impulsivity Suite in an online community s le (N = 1,056), show test-retest reliability and between-subjects variability in a face-to-face community s le (N = 63), and replicate the results in a community and clinical s le (N = 578). The results support the theoretical architecture of the attentional control, information gathering and monitoring/shifting constructs. The Cognitive Impulsivity Suite demonstrated incremental criterion validity for prediction of real-world, addiction-related problems and is a promising tool for large-scale research on cognitive impulsivity.
Publisher: SAGE Publications
Date: 13-10-2020
Abstract: To determine the financial and non-financial costs of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan. The population costs of ADHD in Australia were estimated for the financial year 2018 to 2019 using a prevalence approach to cost estimation across all ages. Financial (healthcare, productivity, education and justice systems, and deadweight losses) and non-financial costs were measured (Disability Adjusted Life Years (DALYs)). The total social and economic cost of ADHD in 2018 to 2019 were US$12.76 billion (range US$8.40 billion to US$17.44 billion, with per person costs of US$15,664 per year). Productivity costs made up 81% of the total financial costs, followed by deadweight losses (11%), and health system costs (4%). Loss in terms of wellbeing was significant (US$5.31 billion). There is a need to raise public awareness of the considerable socioeconomic impact and burden of ADHD in order to drive investment and policy decisions that improve identification and treatment of ADHD.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2017
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2013.02.004
Abstract: The ability to form spatial representations of object locations is an important component of successful spatial navigation. Evidence from behavioral studies suggests that environmental features that have a salient coordinate axis (e.g., a rectangular building or a geometrical room) may provide a reference frame for the encoding of object-location information. Here we used functional magnetic resonance imaging (fMRI) to determine the brain networks engaged when object-location representations are stored with respect to an extrinsic reference frame. Participants learned the layout of an object array in an active, virtual-navigation paradigm. A square mat positioned on the floor of the virtual arena acted as the extrinsic reference frame. Knowledge of the spatial arrangement of the object array was probed while participants underwent fMRI, using a spatial judgment task that required them to imagine orientations of the learned array that were either aligned or misaligned with the geometry of the mat. Consistent with previous findings, participants responded faster and were more accurate when the imagined orientation was aligned, as opposed to misaligned, with the extrinsic reference frame. Analysis of the fMRI data revealed important differences in brain activity between the two conditions. Significantly greater activity was observed in the aligned condition compared with the misaligned condition across a bilateral network of brain areas that included the inferior occipital gyri, inferior and middle temporal gyri, and fusiform gyri. By contrast, activity in the misaligned condition was significantly greater than in the aligned condition in bilateral dorsolateral prefrontal and anterior cingulate cortex, and in the right anterior prefrontal and anterior insular cortex. These results suggest that retrieval of spatial locations that are aligned with an extrinsic reference frame involve direct access to detailed and accurate representations within the ventral visual pathway, whereas spatial locations that are misaligned with this reference frame are only weakly represented and require active inferential processes through the recruitment of prefrontal cortical networks. Our findings are consistent with a "reference direction" account of spatial memory, which posits that inter-object spatial relationships are primarily encoded with respect to specified reference directions.
Publisher: Springer Science and Business Media LLC
Date: 06-2022
DOI: 10.1007/S10803-021-05091-9
Abstract: Parents of children with ASD who had attended an Australian emergency department (ED n = 421) completed a questionnaire relating to their experiences in the ED, including (1) child's reason for presentation and existing comorbidities, (2) quality of care during the visit (3) child's behaviour during visit, e.g. sensory responses to the ED environment, and disruptive behaviours. Children with comorbid ASD and intellectual disability were more likely to present with gastrointestinal issues and seizures, while those with comorbid ASD and oppositional defiant disorder were more likely to present with self-injury. ED staff awareness of ASD-related issues, including communication and expression of pain, were common difficulties for parents. The ED environment (e.g. lights, sounds, waiting areas), exacerbated child anxiety and led to disruptive behaviour.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2020
DOI: 10.1038/S41386-020-0664-5
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total s le of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent in iduals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.BIOPSYCH.2019.02.013
Abstract: Psychotic symptoms are proposed to lie on a continuum, ranging from isolated psychosis-like experiences (PLEs) in nonclinical populations to frank disorder. Here, we investigated the neurobiological correlates of this continuum by examining whether functional connectivity of dorsal corticostriatal circuitry, which is disrupted in psychosis patients and in iduals at high risk for psychosis, is associated with the severity of subclinical PLEs. A community s le of 672 adults with no history of psychiatric or neurological illnesses completed a battery of seven questionnaires spanning various PLE domains. Principal component analysis of 12 subscales taken from seven questionnaires was used to estimate major dimensions of PLEs. Dimension scores from principal component analysis were then correlated with whole-brain voxelwise functional connectivity maps of the dorsal striatum in a subset of 353 participants who completed a resting-state neuroimaging protocol. Principal component analysis identified two dimensions of PLEs that accounted for 62.57% of variance in the measures, corresponding to positive (i.e., subthreshold delusions and hallucinations) and negative (i.e., subthreshold social and physical anhedonia) symptom-like PLEs. Reduced functional connectivity between the dorsal striatum and prefrontal and motor cortices correlated with more severe positive PLEs. Increased functional connectivity between the dorsal striatum and motor cortex was associated with more severe negative PLEs. Consistent with past findings in patients and in iduals at high risk for psychosis, subthreshold positive symptomatology is associated with reduced functional connectivity of the dorsal circuit. This finding suggests that the connectivity of this circuit tracks the expression of psychotic phenomena across a broad spectrum of severity, extending from the subclinical domain to clinical diagnosis.
Publisher: Mary Ann Liebert Inc
Date: 04-2014
Abstract: Epidemiological research links aggression to low serum concentrations of omega-3 fatty acids, such as those found in fish oil. However, no studies have specifically examined whether fish oil supplementation can reduce the frequency and severity of impulsive aggression in children with disruptive behavior disorders. Children presenting with impulsive aggression and meeting research criteria for diagnosis of disruptive behavior disorders were randomized to receive either: 1) Fish oil capsules (4 g daily) for 6 weeks followed by placebo (identical-looking capsules) for 6 weeks or 2) placebo for 6 weeks, followed by fish oil for 6 weeks, in a double-blind, crossover design. Primary outcomes were the Children's Aggression Scale and the Modified Overt Aggression Scale. Secondary outcomes included emotional and behavioral functioning (Strengths and Difficulties Questionnaire [SDQ]), hyperactivity symptoms (Attention-Deficit/Hyperactivity Disorder [ADHD] Rating Scale), family functioning (Family Assessment Device), and cognitive functioning (Stop Signal Task, Trail-Making Task, and Eriksen Flanker Task). Serum concentrations of omega-3 and omega-6 fatty acids were measured at baseline, and at 6 and 12 weeks. Twenty-one children participated (81% male mean age 10.3±2.2 years range 7-14). Fish oil treatment increased serum concentrations of eicosapentanoic acid (F=14.76, p<0.05) and total omega-3s (F=20.56, p<0.05), but did not influence primary ratings of aggression. In fact, a trend suggested that fish oil worsened a secondary measure of aggression (SDQ Conduct Subscale, F=4.34, p=0.06). Fish oil treatment was associated with an improvement in one rating of hyperactivity (SDQ Hyperactivity Subscale, F=2.22, p<0.05), but did not influence any other outcome measures. These findings suggest that fish oil treatment does not improve aggression in children with disruptive behavior disorders.
Publisher: Informa UK Limited
Date: 04-2004
DOI: 10.1076/JCEN.26.2.169.28086
Abstract: One consistent functional imaging finding from patients with major depression has been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been most commonly reported, but some studies suggest relative hyperperfusion is associated with response to somatic treatments. Despite these indications of the possible importance of the ACC in depression there have been relatively few cognitive studies ACC function in patients with major depression. The present study employed a series of reaction time (RT) tasks involving selection with melancholic and nonmelancholic depressed patients, as well as age-matched controls. Fifteen patients with unipolar major depression (7 melancholic, 8 nonmelancholic) and 8 healthy age-matched controls performed a series of response selection tasks (choice RT, spatial Stroop, spatial stimulus-response compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and error data were collected. Melancholic patients were significantly slower than controls on all tasks but were slower than nonmelancholic patients only on the Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from the control group on any task. The Stroop task seems crucial in differentiating the two depressive groups, they did not differ on the choice RT or SRC tasks. This may reflect differential task demands, the SRC involved symbolic manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the melancholic group showed a greater ventral ACC-OFC deficit than the nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.
Publisher: SAGE Publications
Date: 31-05-2012
Abstract: The purpose of this study was to investigate a possible association between norepinephrine genes and cardiovascular side effects of the Osmotic Controlled-Release Oral Delivery System–methylphenidate (OROS-MPH) in Korean children with attention-deficit/hyperactivity disorder (ADHD). One hundred and one children with ADHD (8.7 ± 1.7 years) were recruited from child psychiatric centers at six university hospitals in South Korea. All participants were drug-naive ADHD children treated with OROS-MPH for 12 weeks. During the treatment period the investigators titrated the OROS-MPH dosage on the basis of symptom severity and side effects. Resting heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were examined before and after treatment. The percentage change score (post-treatment – pretreatment retreatment × 100) of each parameter was calculated. Genotyping of SLC6A2 −3081(A/T) and G1287A, and alpha-2A-adrenergic receptor (ADRA2A) MspI and DraI polymorphisms was performed. Clinically significant changes were not found in cardiovascular monitoring during the course of treatment. An increase of HR after OROS-MPH treatment was found to be statistically significant ( t = 3.54, p = 0.001). Changes in SBP and DBP were not significant and no specific change was found in the ECGs. However, an additive regression analysis demonstrated a significant association between SLC6A2 −3081(A/T) and percentage change in HR post-treatment ( p = 0.01) after controlling for age, gender, dosage of MPH and response and baseline pulse rate. Children with ADHD having the T/T genotype of SLC6A2 showed a 12.5% increase in HR compared to baseline, whereas children with the A/T or A/A genotype showed a 3.5% and 2.5% increase after OROS-MPH treatment, respectively. There was also a significant association between the ADRA2A MspI genotype and percentage change of DBP post-treatment after controlling for age, gender, dosage of MPH and response and baseline DBP ( p = 0.009). Children with ADHD having the C/C genotype of ADRA2A MspI showed an 18.5% increase in DBP compared to baseline, but children with the G/G or G/C genotype showed a 0.2% decrease after OROS-MPH treatment. The overall cardiovascular effects of OROS-MPH were modest. However, our findings show a positive association between norepinephrine-related gene polymorphisms and cardiovascular response induced by MPH in Korean children with ADHD. Consideration must be given to such children oradults with specific norepinephrine-related genotypes, especially if they show significant changes in HR or DBP after OROS-MPH administration.
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2023
Publisher: BMJ
Date: 06-2022
DOI: 10.1136/BMJOPEN-2021-055385
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders and is a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with daily functioning. Children with ADHD are developmentally vulnerable, with the disorder linked to emotional regulation difficulties, behavioural disturbances, as well as academic challenges. Emerging evidence suggests that children with ADHD may benefit from cognitive training interventions, including those focused on attention. This study aims to assess the immediate and long-term efficacy of an attention training intervention in children with ADHD. This study is a preregistered, parallel, double blind, randomised controlled trial. Participants will comprise 104 children with a diagnosis of ADHD aged 5–8 years 11 months. Participants will be randomly allocated to either an adaptive, digital game-based (1) attention training programme (intervention) or (2) a numeracy programme (control). Both programmes will be delivered on a touchscreen tablet, and children will complete five 20 min sessions per week for a 5-week period at home (25 sessions in total). Assessments of the primary outcome (ie, attention and inhibitory control) and secondary outcomes (ie, selective attention, interference control, sustained attention, inhibition, behavioural attention, impairment in everyday functioning, working memory and executive functioning) will occur at preintervention, immediately postintervention and at 3-month follow-up. Multivariate linear regression will be employed to examine primary and secondary outcomes. The data analyst will be blinded to group membership. Ethics approval has been obtained from the Monash University HREC (20495). Results will be disseminated through peer-reviewed journals, conference presentations, media outlets, the internet and various community/stakeholder activities. ACTRN12620000964910, UTN U1111-1250-2620.
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2023
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2010.04.019
Abstract: Asymmetries of spatial attention are observed in both clinical and non-clinical populations. While lesions of the right hemisphere frequently result in symptoms of left neglect (right bias), the opposite pattern is often observed in healthy subjects, a phenomenon known as pseudoneglect. Pharmacological and animal studies have suggested a critical role for the catecholamines, in particular dopamine and noradrenaline, in modulating the direction and magnitude of spatial attentional bias. In the present study we investigated the effect of two catecholaminergic genes, DBH and DAT1, on performance in the Landmark task, a perceptual measure of spatial bias. 204 healthy participants performed the Landmark task and were genotyped for the DBH C-1021T and DAT1 3'UTR variants. Homozygosity for the DBH T allele, which is associated with relatively increased dopamine and decreased noradrenaline levels, resulted in a significant increase in rightwards spatial bias relative to the C allele. Similarly, homozygosity for the DAT1 9-repeat allele, which is associated with reduced dopamine transporter density, and consequently increased dopamine availability relative to the 10-repeat allele, was found to result in a greater degree of rightward bias. An additive effect of the two markers was also observed, such that the greatest degree of rightward spatial bias was observed in participants who possessed the 'high dopamine' alleles of both genes and the lowest degree in those without these alleles. These results provide the first evidence of genetic modulation of spatial bias in healthy adults.
Publisher: Springer Science and Business Media LLC
Date: 05-2007
Abstract: Attention deficit hyperactivity disorder, combined type (ADHD-CT) is associated with spatial working memory deficits. These deficits are known to be subserved by dysfunction of neural circuits involving right prefrontal, striatal and parietal brain regions. This study determines whether decreased right prefrontal, striatal and parietal activation with a mental rotation task shown in adolescents with ADHD-CT is also evident in children with ADHD-CT. A cross-sectional study of 12 pre-pubertal, right-handed, 8-12-year-old boys with ADHD-CT and 12 pre-pubertal, right-handed, performance IQ-matched, 8-12-year-old healthy boys, recruited from local primary schools, was completed. Participants underwent functional magnetic resonance imaging while performing a mental rotation task that requires spatial working memory. The two groups did not differ in their accuracy or response times for the mental rotation task. The ADHD-CT group showed significantly less activation in right parieto-occipital areas (cuneus and precuneus, BA 19), the right inferior parietal lobe (BA 40) and the right caudate nucleus. Our findings with a child cohort confirm previous reports of right striatal-parietal dysfunction in adolescents with ADHD-CT. This dysfunction suggests a widespread maturational deficit that may be developmental stage independent.
Publisher: Oxford University Press (OUP)
Date: 24-01-2019
DOI: 10.1093/BRAIN/AWY341
Abstract: Disorders of motivation, such as apathy, are common in Parkinson's disease, and a key feature of such disorders is a greater aversion to effort. In humans, the experience of cognitive effort is ubiquitous, and cognitive apathy has traditionally been considered distinct and separable from other subtypes. Surprisingly, however, the neurobiology of cognitive motivation is poorly understood. In particular, although dopamine has a well-characterized role in incentivizing physically effortful behaviour, a critical, unresolved issue is whether its facilitatory role generalizes to other domains. Here, we asked how dopamine modulates the willingness of patients with Parkinson's disease to invest cognitive effort in return for reward. We tested 20 patients with idiopathic Parkinson's disease across two counterbalanced sessions-ON and OFF their usual dopaminergic medication-and compared their performance to 20 healthy age-matched controls. We applied a novel task in which we manipulated cognitive effort as the number of rapid serial visual presentation streams to which participants had to attend. After training participants to ceiling performance, we then asked them to choose between a low-effort/low-reward baseline option, and a higher-effort/higher-reward offer. Computational models of choice behaviour revealed four key results. First, patients OFF medication were significantly less cognitively motivated than controls, as manifest by steeper cognitive effort discounting functions in the former group. Second, dopaminergic therapy improved this deficit, such that choices in patients ON medication were indistinguishable from controls. Third, differences in motivation were also accompanied by independent changes in the stochasticity of in iduals' decisions, such that dopamine reduced the variability in choice behaviour. Finally, choices on our task correlated uniquely with the subscale of the Dimensional Apathy Scale that specifically indexes cognitive motivation, which suggests a close relationship between our laboratory measure of cognitive effort discounting and subjective reports of day-to-day cognitive apathy. Importantly, participants' choices were not confounded by temporal discounting, probability discounting, physical demand, or varying task performance. These results are the first to reveal the central role of dopamine in overcoming cognitive effort costs. They provide an insight into the computational mechanisms underlying cognitive apathy in Parkinson's disease, and demonstrate its amenability to dopaminergic therapy. More broadly, they offer important empirical support for prominent frameworks proposing a domain-general role for dopamine in value-based decision-making, and provide a critical link between dopamine and multidimensional theories of apathy.
Publisher: SAGE Publications
Date: 06-03-2022
DOI: 10.1177/10870547221081266
Abstract: Difficulty with sustaining attention to a task is a hallmark of ADHD. It would be useful to know which measures of sustained attention best predict a diagnosis of ADHD. Participants were 129 children with a diagnosis of ADHD and 129 matched controls who completed the fixed Sustained Attention to Response Task (SART). The number of commission and omission errors, standard deviation of response time (SDRT), tau, fast and slow frequency variability, d-prime, and mu were able to successfully classify children with and without ADHD. The mean response time, criterion, and sigma were not able to classify participants. The best classifiers were d-prime (0.75 Area Under the Receiver Operated Characteristic), tau (.74), SDRT (0.74), omission errors (0.72), commission errors (0.71), and SFAUS (0.70). This list of the best classifier measures derived from the SART may prove useful for the planning of future studies.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
DOI: 10.1038/S41380-021-01142-W
Abstract: Although the full aetiology of autism spectrum disorder (ASD) is unknown, familial and twin studies demonstrate high heritability of 60–90%, indicating a predominant role of genetics in the development of the disorder. The genetic architecture of ASD consists of a complex array of rare and common variants of all classes of genetic variation usually acting additively to augment in idual risk. The relative contribution of heredity in ASD persists despite selective pressures against the classic autistic phenotype a phenomenon thought to be explained, in part, by the incidence of spontaneous (or de novo) mutations. Notably, environmental exposures attributed as salient risk factors for ASD may play a causal role in the emergence of deleterious de novo variations, with several ASD-associated agents having significant mutagenic potential. To explore this hypothesis, this review article assesses published epidemiological data with evidence derived from assays of mutagenicity, both in vivo and in vitro, to determine the likely role such agents may play in augmenting the genetic liability in ASD. Broadly, these exposures were observed to elicit genomic alterations through one or a combination of: (1) direct interaction with genetic material (2) impaired DNA repair or (3) oxidative DNA damage. However, the direct contribution of these factors to the ASD phenotype cannot be determined without further analysis. The development of comprehensive prospective birth cohorts in combination with genome sequencing is essential to forming a causal, mechanistic account of de novo mutations in ASD that links exposure, genotypic alterations, and phenotypic consequences.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2011.01.001
Abstract: The DAT1 gene codes for the dopamine transporter, which clears dopamine from the synaptic cleft, and a variant of this gene has previously been associated with compromised response inhibition in both healthy and clinical populations. This variant has also been associated with ADHD, a disorder that is characterised by disturbed dopamine function as well as problems with response inhibition. In the present study we used fMRI to investigate the role of dopaminergic genetic variation on executive functioning by comparing how activation associated with successful and unsuccessful inhibitions differs based on DAT1-genotype and ADHD-diagnosis in adolescents performing a go/nogo task. The results identify regional specificity concerning which functional differences can be attributed to the possession of the high risk DAT1 genotype, the clinical condition or an interaction between the two. During response inhibition, in iduals with two copies of the 10-repeat allele showed increased activation in frontal, medial, and parietal regions, which may indicate that inhibition is more effortful for this group. Conversely, this group displayed a reduced error response in the parahippoc al gyrus, suggestive of reduced learning from errors. There were also a number of frontal, parietal, medial and occipital regions, where the relationship between genotype and fMRI-activation differed between the ADHD group and the typically developing adolescents. Finally, the ADHD group displayed decreased activation in parietal and (pre)frontal regions during response inhibition, and in frontal and medial brain regions on error trials.
Publisher: SAGE Publications
Date: 25-04-2023
DOI: 10.1177/10870547231168334
Abstract: To investigate the longitudinal associations between COVID-19 induced stress (related to COVID-19 restrictions/changes), attention-deficit/hyperactivity disorder (ADHD) symptoms, oppositional symptoms, and mental health outcomes (negative affect, anxiety, depression, and irritability) in children with ADHD during the COVID-19 pandemic. Parents of 140 Australian children with ADHD (aged 5–17 years) completed an online survey in May 2020 during stay-at-home restrictions and 12-months later. Baseline COVID-19 stress was associated with increased total ADHD symptom severity (β = .21, p = .007) and hyperactivity/impulsivity symptoms (β = .23, p = .002) at 12-months, after accounting for covariates (i.e., child age, gender, ADHD medication, socio-economic status, and baseline symptoms). Despite some indication of associations between baseline COVID-19 stress and 12-month oppositional symptoms and negative affect, these were attenuated when adjusting for baseline symptoms. The study provides initial evidence of the medium-term impacts of pandemic-related stress for children with ADHD.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2016
DOI: 10.1038/MP.2016.117
Abstract: Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2012
DOI: 10.1007/S00213-012-2875-X
Abstract: Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder (ADHD). Until recently, the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates. In this study, 91 SNP markers of 14 noradrenergic genes (an average density of one SNP per 4.5 kbp) were examined in ADHD s les from Ireland and Australia. Although suggestive evidence of association (nominal p ≤ 0.05) with the genes SLC6A2, ADRA1A, ADRA1B and ADRA2B was observed, none remained significant after permutation adjustments. In contrast, haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ(2) = 9.39, p-corrected = 0.019, OR = 1.51). A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ(2) = 7.79, p-corrected = 0.042 OR = 2.74) with the disorder. These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD. The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2023
DOI: 10.1038/S41380-023-02187-9
Abstract: Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries ( N = 14,877) using cognitive traits derived from the stop-signal task, namely – go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger s le sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Informa UK Limited
Date: 15-05-2015
DOI: 10.3109/15622975.2015.1036771
Abstract: Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD however, small s le sizes have led to inconsistency. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ(2) = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.
Publisher: Cambridge University Press (CUP)
Date: 12-12-2005
DOI: 10.1017/S0033291705006409
Abstract: Background. The ability to inhibit inappropriate or unwanted actions is a key element of executive control. The existence of executive function deficits in schizophrenia is consistent with frontal lobe theories of the disorder. Relatively few studies have examined response inhibition in schizophrenia, and none in adolescent patients with early-onset schizophrenia (EOS). Methods. Twenty-one adolescents with the onset of clinically impairing psychosis before 19 years of age and 16 matched controls performed a stop-signal task to assess response inhibition. The patients with EOS were categorized as paranoid ( n =10) and undifferentiated subtypes ( n =11). The undifferentiated group had higher levels of negative symptomatology. Stop-signal reaction time (SSRT) and go-signal reaction time (Go-RT) were analysed with respect to hand of response. Results. The undifferentiated early-onset patients had significantly longer SSRTs, indicative of poor response inhibition, for the left hand compared to the paranoid early-onset patients and control participants. No differences existed for inhibitory control with the right hand. The three groups did not differ in Go-RT. Conclusions. Our results indicate a specific lateralized impairment of response inhibition in patients with undifferentiated, but not paranoid, EOS. These findings are consistent with reports of immature frontostriatal networks in EOS and implicate areas such as the pre-motor cortex and supplementary motor area (SMA) that are thought to play a role in both voluntary initiation and inhibition of movement.
Publisher: Informa UK Limited
Date: 12-2012
DOI: 10.1080/02699931.2012.666205
Abstract: Spatial asymmetries are an intriguing feature of directed attention. Recent observations indicate an influence of temperament upon the direction of these asymmetries. It is unknown whether this influence generalises to visual orienting behaviour. The aim of the current study was therefore to explore the relationship between temperament and measures of spatial orienting as a function of target hemifield. An exogenous cueing task was administered to 92 healthy participants. Temperament was assessed using Carver and White's (1994) Behavioural Inhibition System and Behavioural Activation System (BIS/BAS) scales. In iduals with high sensitivity to punishment and low sensitivity to reward showed a leftward asymmetry of directed attention when there was no informative spatial cue provided. This asymmetry was not present when targets were preceded by spatial cues that were either valid or invalid. The findings support the notion that in idual variations in temperament influence spatial asymmetries in visual orienting, but only when lateral targets are preceded by a non-directional (neutral) cue. The results are discussed in terms of hemispheric asymmetries and dopamine activity.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2019
DOI: 10.1038/S41380-018-0049-X
Abstract: A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, and microRNA genes and their target sites. Overall, we found that the regulatory variants in ASD cases were enriched in ASD-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of the regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were several rare inherited SNVs found in the mature sequence of microRNAs predicted to affect the regulation of ASD-risk genes. We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited loss-of-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of-function regulatory DNA variations that may contribute to the genetic etiology of complex disorders.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2022
DOI: 10.1038/S41598-022-10634-W
Abstract: Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose–response curve and increased gain variability. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates aspects of attentional processing in parietal cortex.
Publisher: SAGE Publications
Date: 30-05-2023
DOI: 10.1177/00048674231166329
Abstract: The objective of this article was to provide an overview of the development and recommendations from the Australian evidence-based clinical practice guideline for attention deficit hyperactivity disorder (ADHD). The guideline aims to promote accurate and timely identification and diagnosis, and optimal and consistent treatment of ADHD. Development integrated the best available evidence with multidisciplinary clinical expertise and the preferences of those with lived experience, underpinned by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. The 23 guideline development group members included psychiatrists, paediatricians, general practitioners, psychologists, speech pathologists, occupational therapists, educators, Indigenous psychologists, and people with a lived experience with two independent chairs and a methodologist. Where appropriate, evidence reviews from the National Institute for Health and Care Excellence (NICE) 2018 ‘Attention Deficit Hyperactivity Disorder: Diagnosis and Management’ guideline were updated. Fifty prioritised clinical questions were addressed in 14 systematic reviews (new and updated from NICE 2018) and 28 narrative reviews. The 113 clinical recommendations apply to young children (5 years and under), children, adolescents and adults. They provide guidance for clinicians on identification, screening, diagnosis, multimodal treatment and support, including pharmacological and non-pharmacological interventions. The guideline and supporting information are available online: adhdguideline.aadpa.com.au/ The guideline was approved by the National Health and Medical Research Council (NHMRC) of Australia and relevant medical and allied health professional associations. It is anticipated that successful implementation and uptake of the guideline by organisations, health care providers and other professionals will increase delivery of evidence-based treatment and improve health outcomes for the more than 800,000 Australians with ADHD.
Publisher: Cambridge University Press (CUP)
Date: 22-03-2021
DOI: 10.1017/S1355617721000242
Abstract: Mental fatigue, ‘brain fog’, and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time. To address this, we developed the Continuous Temporal Expectancy Task (CTET) where in iduals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690 ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020 ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage ( N = 14), a cohort in which sustained attention deficits have been extensively reported. Stroke survivors had overall lower target detection accuracy compared with neurologically healthy age-matched older controls ( N = 18). Critically, stroke survivors performance was characterised by significantly steeper within-block performance decrements, which occurred within short temporal windows (˜3 ½ min), and were restored by the break periods between blocks. These findings suggest that continuous temporal monitoring taxes sustained attention processes to capture clinical deficits in this capacity over time, and outline a precise measure of the endogenous processes hypothesised to underpin sustained attention deficits following right hemisphere stroke.
Publisher: Springer Science and Business Media LLC
Date: 26-01-2023
Publisher: Wiley
Date: 05-2008
Publisher: Wiley
Date: 05-07-2005
DOI: 10.1002/AJMG.B.30193
Abstract: Associations between attention deficit hyperactivity disorder (ADHD) and genetic variants within the dopamine D4 receptor gene have been much reported. Variants investigated include the 7-repeat allele of a VNTR within the third exon, and two SNPs (-521 and -616) located with the promoter region. We investigated the relationship between the VNTR, -521, and -616 SNPs and sustained attention performance in 54 ADHD probands, relative to a non-genotyped control group. Participants performed the Sustained Attention to Response Task (SART) in which the response to an unpredictably occurring target digit must be inhibited. This task, therefore, challenged sustained attention and included a response inhibition component. Consistent with previous reports, ADHD participants possessing the 7-repeat allele of the VNTR outperformed those children not possessing this allele, both in terms of errors and response variability. In family based analyses, better performance on the SART tended to predict biased transmission of the 7-repeat allele from heterozygous parents. For the -521 SNP, A allele homozygotes showed greater impairment than heterozygotes or those not possessing this allele, both in terms of total errors and response variability. Family based analysis showed that higher total errors on the SART predicted transmission of the A allele from heterozygous parents. There were no effects of the -616 SNP. Our results suggest dissociable effects of the "associated alleles" of DRD4 gene variants on sustained attention: while the 7-repeat allele of the VNTR is associated with relatively better performance, the A allele of the -521 SNP is associated with poorer performance.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.SCR.2018.11.014
Abstract: Peripheral blood mononuclear cells were donated by a male teenager with clinically diagnosed attention deficit hyperactivity disorder (ADHD) under the Diagnostic and Statistical Manual of Mental Disorders IV criteria and his unaffected male sibling. Induced pluripotent stem cells were developed using integration-free Sendai Reprogramming factors containing OCT4, SOX2, KLF4, and c-MYC. All four iPSC lines displayed pluripotent cell morphology, pluripotency-associated factors at the DNA and protein level, alkaline phosphatase enzymatic activity and a male karyotype of 46, XY. All lines had capacity for in vitro differentiation into all the three germ layers. All were negative for Mycoplasma.
Publisher: Wiley
Date: 20-10-2008
DOI: 10.1002/AJMG.B.30872
Publisher: Elsevier BV
Date: 11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-03-2015
Publisher: Springer Science and Business Media LLC
Date: 30-08-2011
DOI: 10.1038/MP.2011.104
Abstract: The ability to inhibit unwanted actions is a heritable executive function that may confer risk to disorders such as attention deficit hyperactivity disorder (ADHD). Converging evidence from pharmacology and cognitive neuroscience suggests that response inhibition is instantiated within frontostriatal circuits of the brain with patterns of activity that are modulated by the catecholamines dopamine and noradrenaline. A total of 405 healthy adult participants performed the stop-signal task, a paradigmatic measure of response inhibition that yields an index of the latency of inhibition, termed the stop-signal reaction time (SSRT). Using this phenotype, we tested for genetic association, performing high-density single-nucleotide polymorphism mapping across the full range of autosomal catecholamine genes. Fifty participants also underwent functional magnetic resonance imaging to establish the impact of associated alleles on brain and behaviour. Allelic variation in polymorphisms of the dopamine transporter gene (SLC6A3: rs37020 rs460000) predicted in idual differences in SSRT, after corrections for multiple comparisons. Furthermore, activity in frontal regions (anterior frontal, superior frontal and superior medial gyri) and caudate varied additively with the T-allele of rs37020. The influence of genetic variation in SLC6A3 on the development of frontostriatal inhibition networks may represent a key risk mechanism for disorders of behavioural inhibition.
Publisher: Informa UK Limited
Date: 04-2008
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent disorder of childhood with a strong genetic contribution. Recently there has been a massive increase in research across multiple fronts, including genetics, neuropsychology and neuroimaging, with impressive gains made. Here, we review the extant literature on the genetic correlates of cognitive deficits in ADHD, focusing on deficits of sustained attention, heightened reaction-time variability and asymmetries of directed spatial attention. The new era of multidisciplinary research means that links can be forged across multiple levels (e.g., gene-cognition) with potentially important implications for treatment. In this review, we highlight how gene-cognition linkages in ADHD might be profitably used to suggest novel approaches to monitoring stimulant-medication responses, as well as strategies for targeting cognitive remediation techniques towards particular subgroups of children and adults with ADHD.
Publisher: BMJ
Date: 09-2022
DOI: 10.1136/BMJOPEN-2022-061626
Abstract: Attention deficit hyperactivity disorder (ADHD) is characterised by significant deficits in attention and inhibition. These deficits are associated with negative sequelae that emerge in childhood and often continue throughout adolescence. Despite these difficulties adolescents with ADHD often demonstrate poor treatment compliance with traditional interventions (eg, psychostimulant medication). Virtual reality (VR) presents an innovative means of delivering engaging cognitive interventions for adolescents with ADHD and offers the potential to improve compliance with such interventions. The current parallel, randomised controlled trial aims to evaluate the effects of a VR intervention (Alfi) designed to improve inhibition in adolescents with ADHD. A s le of 100 adolescents (aged 13–17) with elevated ADHD symptoms will be recruited from secondary schools and ADHD organisations located in the state of Victoria, Australia. Participants will be randomly assigned to either an 8-week VR intervention or a usual care control. The VR intervention involves the completion of 14 sessions, each 20 min in duration. Participants will complete computerised assessments of inhibition and risk-taking preintervention and immediately postintervention. Parents/guardians will complete online questionnaires about their child’s ADHD symptoms and social functioning at each of these timepoints. The primary outcome is change in inhibition performance in adolescents who received the intervention from preintervention to postintervention compared with adolescents in the control condition. Secondary outcomes include change in risk-taking, ADHD symptoms and social functioning in adolescents who received the intervention from preintervention to postintervention compared with adolescents in the control condition. If the intervention is shown to be effective, it may offer a supplementary approach to traditional interventions for adolescents with ADHD experiencing inhibitory control difficulties. This trial has ethics approval from the Monash University Human Research Ethics Committee (HREC) (21530) and the Victorian Department of Education and Training HREC (2020_004271). Results will be disseminated through peer-reviewed journals, conference proceedings and community activities. In idual summaries of the results will be provided to participants on request. ACTRN12620000647932.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2013.03.027
Abstract: Biases of spatial attention may be moderated by non-spatial factors such as attentional load and time-on-task. Although these effects are thought to arise from depletion of right hemisphere processing resources, their neurophysiological bases have yet to be confirmed. We recorded posterior α-band EEG--a marker of cortical excitability linked to spatial attention orienting--from 66 non-clinical participants who detected transient, unilateral visual targets while also monitoring stimuli at fixation. Asymmetry indices were derived for both lateral target reaction times and hemispheric differences in α-activity before and after lateral target onsets. Pre-target α became more prominent over the right, relative to left, hemisphere as the task progressed over 48-min, and this change was correlated with a significant rightward shift in spatial bias. Contrary to past studies of posterior α-asymmetry and orienting, here participants did not receive pre-target cues. Thus we show that asymmetries in the hemispheric distribution of anticipatory α are not only apparent during externally-cued attention orienting, but are also sensitive to decreasing alertness over time. These data are the first to link rightward attention drift over time with change in hemispheric activation asymmetry, providing important implications for our understanding of interacting spatial attention and non-spatial alertness networks.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Springer Science and Business Media LLC
Date: 10-05-2023
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.BPSC.2016.01.004
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with prominent impairments in directing and sustaining attention. The aim of this study was to identify the neurophysiologic bases of attention deficits in ADHD, focusing on electroencephalography markers of attentional selection (posterior contralateral N2 [N2pc]) and suppression (distractor positivity [P The electroencephalography data were collected from 135 children 9-15 years old with and without ADHD while they searched for a shape target in either the absence (experiment 1) or the presence (experiment 2) of a salient but irrelevant color distractor. In experiment 1, the shape target elicited a smaller N2pc in children with ADHD (n = 38) compared with typically developing children (n = 36). The smaller N2pc litude predicted higher levels of inattentive symptoms in children with ADHD. Moreover, the target-elicited N2pc was followed by a positivity in typically developing children but not in children with ADHD. In experiment 2, the salient but irrelevant color distractor elicited a smaller P The correlation between N2pc/P
Publisher: Wiley
Date: 22-03-2021
DOI: 10.1111/JCPP.13396
Abstract: Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small s les. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total s le, to test exhaustively for potential associations of ADHD with structural brain asymmetries. There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls ( t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD ( t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing. Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
Publisher: Frontiers Media SA
Date: 02-08-2018
Publisher: Psychology Press
Date: 14-04-0384
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2008.10.003
Abstract: Sustained attention is modulated by the neurotransmitter noradrenaline. The balance of dopamine and noradrenaline in the cortex is controlled by the DBH gene. The principal variant in this gene is a C/T change at position -1021, and the T allele at this locus is hypothesised to result in a slower rate of dopamine to noradrenaline conversion than the C allele. Two hundred participants who were genotyped for the DBH C-1021T marker performed the Sustained Attention to Response Task (SART). DBH genotype was found to significantly predict performance participants with more copies of the T allele made more errors of commission, indicative of lapses in sustained attention. A significant negative correlation was also observed for all participants between errors of commission and mean reaction time. The decrease in noradrenaline occasioned by the T allele may impair sustained attention by reducing participants' ability to remain alert throughout the task and by increasing their susceptibility to distractors.
Publisher: Elsevier BV
Date: 04-2001
Publisher: Springer Science and Business Media LLC
Date: 09-07-2021
DOI: 10.1038/S41467-021-24306-2
Abstract: Brain network hubs are both highly connected and highly inter-connected, forming a critical communication backbone for coherent neural dynamics. The mechanisms driving this organization are poorly understood. Using diffusion-weighted magnetic resonance imaging in twins, we identify a major role for genes, showing that they preferentially influence connectivity strength between network hubs of the human connectome. Using transcriptomic atlas data, we show that connected hubs demonstrate tight coupling of transcriptional activity related to metabolic and cytoarchitectonic similarity. Finally, comparing over thirteen generative models of network growth, we show that purely stochastic processes cannot explain the precise wiring patterns of hubs, and that model performance can be improved by incorporating genetic constraints. Our findings indicate that genes play a strong and preferential role in shaping the functionally valuable, metabolically costly connections between connectome hubs.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2018
DOI: 10.1038/S41398-018-0262-Z
Abstract: Intra-in idual response time variability (IIRTV) is proposed as a viable endophenotype for many psychiatric disorders, particularly attention-deficit hyperactivity disorder (ADHD). Here we assessed whether IIRTV was associated with common DNA variation genome-wide and whether IIRTV mediated the relationship between any associated loci and self-reported ADHD symptoms. A final data set from 857 Australian young adults (489 females and 368 males M age = 22.14 years, SD age = 4.82 years) who completed five response time tasks and self-reported symptoms of ADHD using the Conners’ Adult ADHD Rating Scale was used. Principal components analysis (PCA) on these response time measures (standard deviation of reaction times and the intra-in idual coefficient of variation) produced two variability factors (labelled response selection and selective attention). To understand the genetic drivers of IIRTV we performed a genome-wide association analysis (GWAS) on these PCA-derived indices of IIRTV. For the selective attention variability factor, we identified one single-nucleotide polymorphism (SNP) attaining genome-wide significance rs62182100 in the HDAC4 gene located on chromosome 2q37. A bootstrapping mediation analysis demonstrated that the selective attention variability factor mediated the relationship between rs62182100 and self-reported ADHD symptoms. Our findings provide the first evidence of a genome-wide significant SNP association with IIRTV and support the potential utility of IIRTV as a valid endophenotype for ADHD symptoms. However, limitations of this study suggest that these observations should be interpreted with caution until replication s les become available.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2009.01.011
Abstract: The ability to detect and correct errors is critical to adaptive control of behaviour and represents a discrete neuropsychological function. A number of studies have highlighted that attention-deficit hyperactivity disorder (ADHD) is associated with abnormalities in behavioural and neural responsiveness to performance errors. One limitation of previous work has been a failure to determine the extent to which these differences are attributable to failures of conscious error awareness, a process that is dependent on the integrity of the frontal lobes. Recent advances in electrophysiological research make it possible to distinguish unconscious and conscious aspects of error processing. This study constitutes an extensive electrophysiological investigation of error awareness and error processing in ADHD. A Go/No-Go response inhibition task specifically designed to assess error awareness was administered to a group of adults diagnosed with ADHD and a group of matched control participants. The ADHD group made significantly more errors than the control group but was less likely to consciously detect these errors. An analysis of event-related potentials elicited by errors indicated that an early performance monitoring component (early positivity) was significantly attenuated in the ADHD group as was a later component that specifically reflects conscious error processing (Pe). Dipole source modelling suggested that abnormal Pe litudes were attributable to decreased activation of the anterior cingulate cortex. Decreased electrodermal activity in the ADHD group also suggested a motivational insensitivity to performance errors. Our data provide evidence that neuropsychological deficits associated with ADHD can be exacerbated by error processing abnormalities. Error awareness may represent an important cognitive and physiological phenotype for ADHD.
Publisher: Center for Open Science
Date: 07-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2020
DOI: 10.1101/2020.05.15.097675
Abstract: Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose-response curve and increased gain variability. Dopamine modulated attention-related rate changes and Fano Factors in broad and narrow-spiking units, respectively. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability in broad-spiking units. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates attentional processing in parietal cortex.
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2022
DOI: 10.1101/2022.05.11.22274981
Abstract: Large-scale genome-wide association studies (GWAS) have identified multiple disease-associated genetic variations across different psychiatric dis-orders raising the question of how these genetic variants relate to the corresponding pharmacological treatments. Here we investigated whether functional information from a range of open bioinformatics datasets can elucidate the relationship between GWAS-identified genetic variation and the genes targeted by current drugs for psychiatric disor-ders. We introduce a novel measure of weighted similarity between gene targets for pharmacological treatments and GWAS risk variants for psychiatric disorders according to SNP position, gene distance on the protein interaction network (PPI), brain eQTL, and gene expression pattern across the brain. Focusing on four psychiatric disorders—ADHD, bipolar disorder, schizophrenia, and major de-pressive disorder—we assess relationships between the gene targets of drug treatments and GWAS hits across these weighted similarity metrics. Our results indicate that while incorporating information derived from functional bioinformatics data, such as the PPI network and spatial gene expression, revealed links for bipolar disorder, the overall correspondence between treatment targets and GWAS-implicated genes in psychiatric disorders rarely exceeds null expectations. This relatively low degree of correspondence across modalities suggests that the genetic mechanisms driving the risk for psychiatric disorders may be distinct from the pathophysiological mechanisms used for targeting symptom manifestations through pharmacological treatments and that novel approaches for under-standing and treating psychiatric disorders may be required.
Publisher: American Physiological Society
Date: 12-2007
Abstract: Intelligent behavior depends on the ability to suppress inappropriate actions and resolve interference between competing responses. Recent clinical and neuroimaging evidence has demonstrated the involvement of prefrontal, parietal, and premotor areas during behaviors that emphasize conflict and inhibition. It remains unclear, however, whether discrete subregions within this network are crucial for overseeing more specific inhibitory demands. Here we probed the functional specialization of human prefrontal cortex by combining repetitive transcranial magnetic stimulation (rTMS) with integrated behavioral measures of response inhibition (stop-signal task) and response competition (flanker task). Participants undertook a combined stop-signal/flanker task after rTMS of the inferior frontal gyrus (IFG) or dorsal premotor cortex (dPM) in each hemisphere. Stimulation of the right IFG impaired stop-signal inhibition under conditions of heightened response competition but did not influence the ability to suppress a competing response. In contrast, stimulation of the right dPM facilitated execution but had no effect on inhibition. Neither of these results was observed during rTMS of corresponding left-hemisphere regions. Overall, our findings are consistent with existing evidence that the right IFG is crucial for inhibitory control. The observed double dissociation of neurodisruptive effects between the right IFG and right dPM further implies that response inhibition and execution rely on distinct neural processes despite activating a common cortical network.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2021
Publisher: American Psychiatric Association Publishing
Date: 09-2020
Publisher: Informa UK Limited
Date: 20-01-2018
DOI: 10.1080/15622975.2016.1273549
Abstract: Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie in idual differences in impulsiveness, however, few have shown this. The current study examined the relationship between catecholamine gene variants and self-reported impulsivity, as measured by the Barratt Impulsiveness Scale (Version 11 BIS-11) Methods: Six hundred and seventy-seven non-clinical adults completed the Barratt Impulsiveness Scale (BIS-11). DNA was analysed for a set of 142 single-nucleotide polymorphisms (SNPs) across 20 autosomal catecholamine genes. Association was tested using an additive regression model with permutation testing used to control for the influence of multiple comparison. Analysis revealed an influence of rs4245146 of the dopamine D2 receptor (DRD2) gene on the BIS-11 attention first-order factor, such that self-reported attentional impulsiveness increased in an additive fashion with each copy of the T allele. These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.SCHRES.2006.04.025
Abstract: This study determines that visuospatial working memory (VSWM) deficits are evident in adolescent-onset schizophrenia, while the spatial strategy and spatial span components of VSWM are spared. These findings imply that frontal-striatal-parietal neural networks are dysfunctional in adolescent-onset schizophrenia, while mid-dorsolateral and ventrolateral PFC functions remain intact: the current conceptualisation of schizophrenia as a progressive neurodevelopmental disorder is consistent with these results.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2021
DOI: 10.1186/S13229-021-00457-3
Abstract: ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has h ered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters. The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics. The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.
Publisher: Diving and Hyperbaric Medicine Journal
Date: 31-03-2021
Abstract: Introduction: Idiopathic sudden sensorineural hearing loss (ISSHL) is an otolaryngologic emergency. The Undersea and Hyperbaric Medicine Society (UHMS) revised practice guidelines in 2014 adding ISSHL to approved indications. This study investigated whether the UHMS guidelines influenced referral and practice in Australia and New Zealand. Methods: Retrospective review of 319 patient referrals in two time periods (five years prior to addition of ISSHL to indications (T-PRE) and three years post (T-POST)). Results: Seven of eight participating hyperbaric facilities provided data down to the level of the indication for HBOT for analysis. In T-PRE 136 patients were treated with HBOT for ISSHL, representing between 0% and 18% of the total cases to each facility. In the T-POST period 183 patients were treated for ISSHL, representing from 0.35% to 24.8% of the total patients in each facility. Comparison between the two periods shows the proportion of patients treated with ISSHL among all indications increased from 3.2% to 12.1% (P 0.0009). One facility accounted for 74% (101/136) of ISSHL patients receiving HBOT in T-PRE and 63% (116/183) in T-POST. ISSHL case load at that facility increased from 18% to 24.8% (P = 0.009) after the UHMS guideline publication. Three of the seven units had a significant increase in referrals after the guideline change. Conclusion: There remains equipoise regarding HBOT in the management of ISSHL. Only three out of seven units had a significant increase in ISSHL patients after the UHMS guidelines publication. Without well controlled RCTs to develop guidelines based on good evidence this is unlikely to change and practice variation will continue.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1007/S11682-016-9620-8
Abstract: We examined the effect of a single dose of methylphenidate (MPH) on whole brain functional connectivity, assessed using resting state functional MRI (rsfMRI), in young people with ADHD. 16 young people with ADHD participated in two rsfMRI scans in a randomized, placebo-controlled study with an acute dose of MPH (20 mg). 15 typically developing controls also performed the task under placebo conditions. The network-based statistic (NBS) was used to identify differential connectivity patterns between the MPH and placebo conditions in the ADHD group. Mean connectivity of the resulting sub-network was examined in the ADHD and control groups. Resting state functional connectivity (RSFC) analysis revealed significantly reduced connectivity under MPH compared to placebo in young people with ADHD. Findings were robust across a range of thresholds. No sub-networks of increased connectivity were found at any threshold. Mean connectivity of the identified sub-network was significantly higher in ADHD in iduals in the placebo condition compared to controls, however there was no difference between MPH condition and controls. We demonstrated a significant MPH-related reduction in RSFC in a large, robust network primarily involving occipital, temporal and cerebellar regions, and visual, executive and default mode networks. These findings suggest that MPH is 'normalising' a higher RSFC in young people with ADHD. This study is a novel addition to the understanding of treatment effects on the brain in ADHD.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 07-10-2018
DOI: 10.1101/437376
Abstract: Psychotic symptoms are proposed lie on a continuum, ranging from isolated psychosis-like experiences (PLEs) in non-clinical populations to frank disorder. Here, we investigate neurobiological correlates of this symptomatologic continuum by examining whether functional connectivity of dorsal corticostriatal circuitry, which is disrupted in patients and high-risk in iduals, is associated with the severity of subclinical PLEs. A community s le of 672 adults with no history of psychiatric or neurological illnesses completed a battery of seven questionnaires spanning various PLE domains. Principal component analysis (PCA) estimated major dimensions of PLEs from the questionnaires. PCA dimension scores were then correlated with whole-brain voxelwise functional connectivity (FC) maps of the striatum in a subset of 353 participants who completed a resting-state neuroimaging protocol. PCA identified two dimensions of PLEs accounting for 62.57% of variance in the measures, corresponding to positive and negative PLEs. Reduced FC between the dorsal striatum and prefrontal cortex correlated with higher positive PLEs. Negative PLEs correlated with increased FC between the dorsal striatum and visual and sensorimotor areas. In the ventral corticostriatal system, positive and negative PLEs were both associated with FC between the ventro-rostral putamen and sensorimotor cortices. Consistent with past findings in patients and high-risk in iduals, subthreshold positive symptomatology is associated with reduced FC of the dorsal circuit. These findings suggest that the connectivity of this circuit tracks the expression of psychotic phenomena across a broad spectrum of severity, extending from the subclinical domain to clinical diagnosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2004
DOI: 10.1097/00001756-200404290-00027
Abstract: The co-existence of deficits in sustained and spatial attention in patients with acquired damage to the right cerebral hemisphere has led to the proposition that sustained attention could be a marker for left spatial inattention, or neglect. We investigated the possibility that reductions in leftward spatial attentional asymmetries could arise from in idual differences in the capacity for sustained attention even within healthy adult populations. We observed that healthy participants who performed poorly on a test of sustained attention had a significantly attenuated left spatial bias, relative to those with good sustained attention capacity, on a free-viewing spatial attention test. Our results provide further support for the notion that sustained attention may exert a modulatory influence on spatial attention.
Publisher: American Medical Association (AMA)
Date: 2021
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2007.12.018
Abstract: The present study examines a new alertness training strategy (Self-Alert Training, SAT) designed to explore the relationship between the top-down control processes governing arousal and sustained attention. In order to maximally target frontal control systems SAT combines a previously validated behavioural self-alerting technique [Robertson, I. H., Tegner, R., Tham, K., Lo, A., & Nimmo-Smith, I. (1995). Sustained attention training for unilateral neglect: Theoretical and rehabilitation implications. Journal of Clinical and Experimental Neuropsychology, 17, 416-430] with an autonomic arousal biofeedback protocol in which participants learn to modulate their own arousal levels. The SAT protocol was first validated with a group of 23 neurologically healthy participants and then independently tested in a group of 18 adults with ADHD to determine its clinical utility. Half of the participants in each group were assigned to a placebo condition to control for non-specific effects. All participants performed the sustained attention to response task (SART) during pre- and post-training testing sessions to assess training effects on sustained attention. By the end of SAT all participants were able to modulate their own arousal levels without external prompting. Comparison of pre- and post-training baseline data indicated that, as predicted, SAT was associated with increased levels of autonomic arousal accompanied by improved accuracy on the SART. In contrast, participants in the placebo condition exhibited a gradual reduction in arousal over time and increased reaction time variability indicative of a vigilance decrement. These data demonstrate that the recruitment of top-down control processes during volitional modulation of arousal leads to improved sustained attention. These findings have important implications for the rehabilitation of attention deficits arising from frontal dysfunction.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Public Library of Science (PLoS)
Date: 23-04-2014
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1097/00004583-200502000-00009
Abstract: To examine the relationship between time reproduction, performance variability, and sustained attention deficits in children with attention-deficit/hyperactivity disorder (ADHD) combined (ADHD-C) and inattentive (ADHD-I) subtypes, relative to matched controls. Participants (age range 7.1-14.1 years) performed a time reproduction task. A subset of the ADHD group was also tested on the Sustained Attention to Response Test. Absolute discrepancy, accuracy coefficient, and intrain idual variability scores on the time reproduction task were compared across the three groups (ADHD-C: N = 20 ADHD-I: N = 19 controls: N = 44) and correlated with the Sustained Attention to Response Test. First, significantly better performance was observed in matched controls than in children with ADHD on the time reproduction task. Second, there was a significant difference between the two ADHD subtypes in the variability of the size of errors made at high time intervals (36-60 seconds). Third, intrain idual performance variability in the direction (over- versus underestimations) of time reproductions correlated with sustained attention performance. Children with ADHD varied more in the size and direction of their time reproduction errors than control children. Those with ADHD-C demonstrated more intrain idual variability than did those with ADHD-I in the size of their errors. The data provide support for a relationship between sustained attention and time reproduction. This relationship has previously been inferred from common right-lateralized neural circuitry that is thought to subserve these processes.
Publisher: Public Library of Science (PLoS)
Date: 04-11-2011
Publisher: Cold Spring Harbor Laboratory
Date: 02-06-2022
DOI: 10.1101/2022.05.31.494251
Abstract: Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population s le derived from the Adolescent Brain and Cognition Developmental study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population s le that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.
Publisher: Elsevier BV
Date: 12-2019
Publisher: MIT Press - Journals
Date: 2009
Abstract: Disentangling the component processes that contribute to human executive control is a key challenge for cognitive neuroscience. Here, we employ event-related potentials to provide electrophysiological evidence that action errors during a go/no-go task can result either from sustained attention failures or from failures of response inhibition, and that these two processes are temporally and physiologically dissociable, although the behavioral error—a nonintended response—is the same. Thirteen right-handed participants performed a version of a go/no-go task in which stimuli were presented in a fixed and predictable order, thus encouraging attentional drift, and a second version in which an identical set of stimuli was presented in a random order, thus placing greater emphasis on response inhibition. Electrocortical markers associated with goal maintenance (late positivity, alpha synchronization) distinguished correct and incorrect performance in the fixed condition, whereas errors in the random condition were linked to a diminished N2–P3 inhibitory complex. In addition, the litude of the error-related negativity did not differ between correct and incorrect responses in the fixed condition, consistent with the view that errors in this condition do not arise from a failure to resolve response competition. Our data provide an electrophysiological dissociation of sustained attention and response inhibition.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2022
DOI: 10.1038/S41380-022-01775-5
Abstract: Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population s le derived from the Adolescent Brain Cognitive Development SM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population s le that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2016
DOI: 10.1007/S11682-015-9470-9
Abstract: A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD-Combined Type and 22 controls) aged 10-18 years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen-VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries.
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.BIOPSYCH.2006.03.062
Abstract: Dopamine beta hydroxylase (DbetaH) catalyzes the conversion of dopamine to noradrenaline. Attention-deficit/hyperactivity disorder (ADHD) has been associated with the A2 allele of a Taq I polymorphism of the DBH gene. Since catecholamines regulate visual attention, we examined whether participants with ADHD were impaired on a task requiring temporal attention and how DBH genotype influenced temporal attention in ADHD. Thirty-seven children and adolescents with ADHD and 52 matched, normal control subjects participated. Participants were presented with two visual stimuli, separated in time by either 50, 100, or 200 milliseconds, and were asked to judge the temporal order of their onset. Genotypes for the Taq 1 polymorphism were available for 33 of the ADHD participants. Attention-deficit/hyperactivity disorder participants were more error prone than control subjects, particularly when stimuli were presented close together in time (i.e., at the 50 milliseconds asynchrony). Moreover, ADHD in iduals homozygous for the A2 allele performed more poorly than those without this allele, and this difference was accentuated at the 50 milliseconds asynchrony. Attention-deficit/hyperactivity disorder participants have an impaired rate of perceptual processing for rapidly presented visual events. Deficits in the temporal resolution of visual attention in ADHD are associated with the A2 allele of the Taq I DBH polymorphism or another variant with which it is in linkage disequilibrium.
Publisher: Society for Neuroscience
Date: 28-07-2023
DOI: 10.1523/JNEUROSCI.2260-21.2023
Abstract: Older adults exposed to enriched environments (EE) maintain relatively higher levels of cognitive function, even in the face of compromised markers of brain health. Response speed (RS) is often used as a simple proxy to measure the preservation of global cognitive function in older adults. However, it is unknown which specific selection, decision, and/or motor processes provide the most specific indices of neurocognitive health. Here, using a simple decision task with electroencephalography (EEG), we found that the efficiency with which an in idual accumulates sensory evidence was a critical determinant of the extent to which RS was preserved in older adults (63% female, 37% male). Moreover, the mitigating influence of EE on age-related RS declines was most pronounced when evidence accumulation rates were shallowest. These results suggest that the phenomenon of cognitive reserve, whereby high EE in iduals can better tolerate suboptimal brain health to facilitate the preservation of cognitive function, is not just applicable to neuroanatomical indicators of brain ageing, but can be observed in markers of neurophysiology. Our results suggest that EEG metrics of evidence accumulation may index neurocognitive vulnerability of the ageing brain. SIGNIFICANCE STATEMENT: Response speed in older adults is closely linked with trajectories of cognitive ageing. Here, by recording brain activity while in iduals perform a simple computer task, we identify a neural metric which is a critical determinant of response speed. Older adults exposed to greater cognitive and social stimulation throughout a lifetime could maintain faster responding, even when this neural metric was impaired. This work suggests EEG is a useful technique for interrogating how a lifetime of stimulation benefits brain health in ageing.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.BIOPSYCH.2010.12.040
Abstract: Executive control processes, such as sustained attention, response inhibition, and error monitoring, allow humans to guide behavior in appropriate, flexible, and adaptive ways. The consequences of executive dysfunction for humans can be dramatic, as exemplified by the large range of both neurologic and neuropsychiatric disorders in which such deficits negatively affect outcome and quality of life. Much evidence suggests that many clinical disorders marked by executive deficits are highly heritable and that in idual differences in quantitative measures of executive function are strongly driven by genetic differences. Accordingly, intense research effort has recently been directed toward mapping the genetic architecture of executive control processes in both clinical (e.g., attention-deficit/hyperactivity disorder) and nonclinical populations. Here we review the extant literature on the molecular genetic correlates of three exemplar but dissociable executive functions: sustained attention, response inhibition, and error processing. Our review focuses on monoaminergic gene variants given the strong body of evidence from cognitive neuroscience and pharmacology implicating dopamine, noradrenaline, and serotonin as neuromodulators of executive function. Associations between DNA variants of the dopamine beta hydroxylase gene and measures of sustained attention accord well with cognitive-neuroanatomical models of sustained attention. Equally, functional variants of the dopamine D2 receptor gene are reliably associated with performance monitoring, error processing, and reinforcement learning. Emerging evidence suggests that variants of the dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) show promise for explaining significant variance in in idual differences in both behavioral and neural measures of inhibitory control.
Publisher: American Medical Association (AMA)
Date: 10-2009
DOI: 10.1001/ARCHGENPSYCHIATRY.2009.120
Abstract: A distinct pattern of selective attention deficits in attention-deficit/hyperactivity disorder (ADHD) has been difficult to identify. Heterogeneity may reflect differences in underlying genetics. To document an objective deficit of selective attention in a large s le of children with and without ADHD using spatial orienting paradigms. By stratifying s les according to the gene dosage of a risk haplotype of the dopamine transporter gene (DAT1), we could determine whether genetic factors predict spatial inattention in ADHD. A case-control design was used. Children with ADHD were recruited from clinics or support groups in Ireland. Typically developing children were recruited from schools in and around Dublin, Ireland. One hundred fifteen children were recruited (ADHD = 50, control = 65). Groups were matched for age but differed in estimated intelligence. Two versions of a visual spatial orienting task in which attention was directed by valid, neutral, or invalid cues to target locations. Sudden-onset peripheral cues (exogenous) and centrally presented predictive cues (endogenous) were used. To isolate an attention deficit in ADHD, groups were first compared using analysis of variance on the spatial orienting tasks. Multiple regression was used to assess the main effect of DAT1 haplotype status (heterozygous vs homozygous) and the interaction of diagnosis and genotype on those variables that discriminated children with and without ADHD. Children with ADHD displayed deficits in reorienting attention from invalidly cued spatial locations, particularly for targets in the left visual field. DAT1 haplotype status predicted spatial reorienting deficits for left visual field targets (P = .007) but there was also a significant interaction of diagnosis and genotype (P = .02), which revealed the greatest impairment in children with ADHD homozygous for the DAT1 haplotype. Heterogeneity in selective attention in ADHD can be explained by a replicated genetic risk factor for ADHD, the 10/3 DAT1 haplotype.
Publisher: Society for Neuroscience
Date: 22-02-2012
DOI: 10.1523/JNEUROSCI.4052-11.2012
Abstract: How the brain monitors ongoing behavior for performance errors is a central question of cognitive neuroscience. Diminished awareness of performance errors limits the extent to which humans engage in corrective behavior and has been linked to loss of insight in a number of psychiatric syndromes (e.g., attention deficit hyperactivity disorder, drug addiction). These conditions share alterations in monoamine signaling that may influence the neural mechanisms underlying error processing, but our understanding of the neurochemical drivers of these processes is limited. We conducted a randomized, double-blind, placebo-controlled, cross-over design of the influence of methylphenidate, atomoxetine, and citalopram on error awareness in 27 healthy participants. The error awareness task, a go/no-go response inhibition paradigm, was administered to assess the influence of monoaminergic agents on performance errors during fMRI data acquisition. A single dose of methylphenidate, but not atomoxetine or citalopram, significantly improved the ability of healthy volunteers to consciously detect performance errors. Furthermore, this behavioral effect was associated with a strengthening of activation differences in the dorsal anterior cingulate cortex and inferior parietal lobe during the methylphenidate condition for errors made with versus without awareness. Our results have implications for the understanding of the neurochemical underpinnings of performance monitoring and for the pharmacological treatment of a range of disparate clinical conditions that are marked by poor awareness of errors.
Publisher: Informa UK Limited
Date: 02-05-2013
DOI: 10.1080/09297049.2013.790358
Abstract: The Test of Everyday Attention for Children (TEA-Ch) is a reliable neuropsychological assessment of attention control in children. Methylphenidate (MPH) is an effective treatment to improve attentional difficulties in children with attention deficit/hyperactivity disorder (ADHD). Previous studies investigating the effects of MPH on attention performance of children with ADHD have produced mixed results and prior MPH usage may have confounded these results. No previous study has tested the effects of MPH on the entire TEA-Ch battery. This study investigated the effects of MPH on attention performance using the entire TEA-Ch in 51 medication-naïve children with ADHD compared with 35 nonmedicated typically developing children. All children were tested at baseline and after 6 weeks: The children with ADHD were medication-naïve at baseline, received MPH for 6 weeks and were tested whilst on medication at the second testing session. A beneficial effect of MPH administration was found on at least one subtest of each of the three forms of attention (selective, sustained, and attentional control) assessed by the TEA-Ch, independent of practice effects. MPH aided performance on the TEA-Ch tasks that were inherently nonarousing and that might require top-down control of attention. It is recommended that the TEA-Ch measures--Sky Search Count (selective attention),Score! (sustained attention), Creature Counting Time Taken for older children (attentional control), and Same Worlds (attentional control) be prioritized for use in future pharmacological studies using MPH.
Publisher: Hogrefe Publishing Group
Date: 2009
DOI: 10.1027/1618-3169.56.4.247
Abstract: In the stop task, response time to the go signal is increased when the immediately preceding trial involves the presentation of a stop signal. A recent explanation suggests that these “after-effects” are due to mechanisms that occur prior to the completion of response selection processes, but it is possible that they instead may reflect a slowed motor response (i.e., deliberate slowing after response selection). The participants completed a novel stop task that allows a differentiation between the time taken to prepare a movement (which incorporates response selection processes) and the time taken to execute a movement (i.e., speed of motor response). If mechanisms underlying stop task after-effects occur prior to the completion of response selection processes, then slowing should only occur during movement preparation. Movement preparation and execution time during go trials were analysed according to the characteristics of the preceding trial. Slowing after a stop trial was found during movement preparation time (regardless of inhibition success on that stop trial), and it further increased during this period when the primary task stimulus was repeated. There was also evidence for general after-effects during movement execution time, but no effect of repetition. These findings support the current theoretical accounts that suggest that repetition-based stop task after-effects are attributable to a mechanism that occurs prior to the completion of response selection processes, and also indicate a possible switch to a more conservative response set (as in signal detection theory terms) that results in deliberate slowing of movement.
Publisher: Elsevier BV
Date: 02-2018
Publisher: Wiley
Date: 16-08-2018
Abstract: Hyperbaric oxygen therapy (HBOT) is widely used for the treatment of the late effects of radiation therapy. We report a prospective observational cohort study of 51 patients designed to examine the effectiveness of hyperbaric oxygen treatment (HBOT) for xerostomia following radiotherapy. Objective (saliva volume) and subjective (quality of life scoring and visual analogue scale (VAS) of discomfort) measurements associated with xerostomia were compared prior to commencement of HBOT, after 30 sessions (over 6 weeks) of HBOT at 243 kPa for 90 minutes daily for five days per week and at 6-week review (12 weeks from commencement). One hundred and one courses of treatment in 99 patients were examined. For 53 (53%) courses in 51 patients, data were recorded before and after HBOT and so could be included in the analysis. Thirty-four (34%) of these patients had complete data for all three time points. The unit of study was per treatment course, not per person. There were no major complications to HBOT. There was a statistically significant difference in saliva volume following HBOT (P = 0.016). The mean saliva volume increase was 0.9 mL over a 5-min collection period (95% CI 0.2-1.5). There was also a statistically significant improvement in discomfort after HBOT (P < 0.001) and QOL (P < 0.001). The mean visual analogue scale for discomfort (VAS on a 0-10 scale) score decreased by 1.4 units (95% CI 0.7-2.1), whilst the mean QOL score was 10 points lower after treatment (95% CI 5.9-14.4). Hyperbaric oxygen therapy may be a safe and effective treatment for symptoms of xerostomia after radiation therapy and should be considered when available.
Publisher: MIT Press - Journals
Date: 03-2006
DOI: 10.1162/089892906775990606
Abstract: In the course of daily living, humans frequently encounter situations in which a motor activity, once initiated, becomes unnecessary or inappropriate. Under such circumstances, the ability to inhibit motor responses can be of vital importance. Although the nature of response inhibition has been studied in psychology for several decades, its neural basis remains unclear. Using transcranial magnetic stimulation, we found that temporary deactivation of the pars opercularis in the right inferior frontal gyrus selectively impairs the ability to stop an initiated action. Critically, deactivation of the same region did not affect the ability to execute responses, nor did it influence physiological arousal. These findings confirm and extend recent reports that the inferior frontal gyrus is vital for mediating response inhibition.
Publisher: SAGE Publications
Date: 21-07-2022
DOI: 10.1177/10870547221112941
Abstract: Previous studies at child and youth mental health services (CYMHS) suggest that children with ADHD have poorer outcomes compared to those with other diagnoses. This study investigates this in more detail. Children with ADHD were compared to those with ASD and those with emotional disorders, on routinely collected outcomes at CYMHS in Australia ( N = 2,513) and the Netherlands ( N = 844). Where the emotional disorders group reached a similar level of emotional symptoms at the end-of-treatment as the ADHD and ASD groups, the latter two groups still had higher scores on ADHD and ASD symptoms (attention and peer problems). The poorer outcomes were mainly explained by higher severity at baseline. In Australia, an ADHD and/or ASD diagnosis also independently contributed to worse outcomes. Those with neurodevelopmental disorders within both countries had poorer outcomes than those with emotional disorders. Services should aim to optimize treatment to ensure best possible outcomes.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2013
DOI: 10.1007/S00213-013-3246-Y
Abstract: Error processing is a critical executive function that is impaired in a large number of clinical populations. Although the neural underpinnings of this function have been investigated for decades and critical error-related components in the human electroencephalogram (EEG), such as the error-related negativity (ERN) and the error positivity (Pe), have been characterised, our understanding of the relative contributions of key neurotransmitters to the generation of these components remains limited. The current study sought to determine the effects of pharmacological manipulation of the dopamine, noradrenaline and serotonin neurotransmitter systems on key behavioural and event-related potential correlates of error processing. A randomised, double-blinded, placebo-controlled, crossover design was employed. Monoamine levels were manipulated using the clinically relevant drugs methylphenidate, atomoxetine and citalopram, in comparison to placebo. Under each of the four drug conditions, participants underwent EEG recording while performing a flanker task. Only methylphenidate produced significant improvement in performance accuracy, which was without concomitant slowing of reaction time. Methylphenidate also increased the litude of an early electrophysiological index of error processing, the ERN. Citalopram increased the litude of the correct-response negativity, another component associated with response processing. The effects of methylphenidate in this study are consistent with theoretical accounts positing catecholamine modulation of error monitoring. Our data suggest that enhancing catecholamine function has the potential to remediate the error-monitoring deficits that are seen in a wide range of psychiatric conditions.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.CORTEX.2019.08.004
Abstract: A visual attention span (VAS) deficit has been widely reported in the Developmental Dyslexia (DD) literature, however, consensus regarding what underlies this problem and the nature of its relationship with reading ability remains elusive. Thirty-two children with DD (15 females) were compared with 23 age matched (12 females) and 17 reading matched controls (9 females) on the combined Theory of Visual Attention (CombiTVA) paradigm with traditional letter and novel symbol conditions. The DD group performed more slowly than the age matched controls in terms of processing speed, but similarly to reading matched controls. Moderation analyses revealed that the difference between the DD group and age matched controls was driven by children with equivalent, or relatively poorer, lexical compared with sublexical reading profiles. Results suggest that reduced processing speed indexes reading immaturity, particularly in DD in iduals with relative lexical reading deficits, rather than being a unique contributor to reading dysfunction.
Publisher: Cold Spring Harbor Laboratory
Date: 03-10-2018
DOI: 10.1101/433060
Abstract: The timing and accuracy of perceptual decision making is exquisitely sensitive to fluctuations in arousal. Although extensive research has highlighted the role of neural evidence accumulation in forming decisions, our understanding of how arousal impacts these processes remains limited. Here we isolated electrophysiological signatures of evidence accumulation alongside signals reflecting target selection, attentional engagement and motor output and examined their modulation as a function of both tonic and phasic arousal, indexed by baseline and task-evoked pupil diameter, respectively. For both pupillometric measures, the relationship with reaction time was best described by a second-order, U-shaped, polynomial. Additionally, the two pupil measures were predictive of a unique set of EEG signatures that together represent multiple information processing steps of perceptual decision-making, including evidence accumulation. Finally, we found that behavioural variability associated with fluctuations in both tonic and phasic arousal was largely mediated by variability in evidence accumulation.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2015
DOI: 10.1038/MP.2014.183
Abstract: Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition which affects 2-10% of school age children worldwide. Although the underlying molecular mechanism for the disorder is poorly understood, familial, twin and adoption studies suggest a strong genetic component. Here we provide a state-of-the-art review of the molecular genetics of ADHD incorporating evidence from candidate gene and linkage designs, as well as genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs) and rare copy number variations (CNVs). Bioinformatic methods such as functional enrichment analysis and protein-protein network analysis are used to highlight biological processes of likely relevance to the aetiology of ADHD. Candidate gene associations of minor effect size have been replicated across a number of genes including SLC6A3, DRD5, DRD4, SLC6A4, LPHN3, SNAP-25, HTR1B, NOS1 and GIT1. Although case-control SNP-GWAS have had limited success in identifying common genetic variants for ADHD that surpass critical significance thresholds, quantitative trait designs suggest promising associations with Cadherin13 and glucose-fructose oxidoreductase domain 1 genes. Further, CNVs mapped to glutamate receptor genes (GRM1, GRM5, GRM7 and GRM8) have been implicated in the aetiology of the disorder and overlap with bioinformatic predictions based on ADHD GWAS SNP data regarding enriched pathways. Although increases in s le size across multi-center cohorts will likely yield important new results, we advocate that this must occur in parallel with a shift away from categorical case-control approaches that view ADHD as a unitary construct, towards dimensional approaches that incorporate endophenotypes and statistical classification methods.
Publisher: American Medical Association (AMA)
Date: 20-09-2023
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 05-02-2015
DOI: 10.1002/AJMG.B.32283
Abstract: Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1 SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and in idual differences in ADHD symptoms in adults.
Publisher: Oxford University Press (OUP)
Date: 03-2007
DOI: 10.1093/BRAIN/AWL367
Abstract: Loss of insight is one of the core features of frontal/behavioural variant frontotemporal dementia (FTD). FTD shares many clinical and pathological features with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). The aim of this study was to investigate awareness of cognitive deficits in FTD, CBD and PSP using a multidimensional approach to assessment, which examines metacognitive knowledge of the disorders, online monitoring of errors (emergent awareness) and ability to accurately predict performance on future tasks (anticipatory awareness). Thirty-five patients (14 FTD, 11 CBD and 10 PSP) and 20 controls were recruited. Results indicated that loss of insight was a feature of each of the three patient groups. FTD patients were most impaired on online monitoring of errors compared to the other two patient groups. Linear regression analysis demonstrated that different patterns of neuropsychological performance and behavioural rating scores predicted insight deficits across the three putative awareness categories. Furthermore, higher levels of depression were associated with poor anticipatory awareness, reduced empathy was related to impaired metacognitive awareness and impaired recognition of emotional expression in faces was associated with both metacognitive and anticipatory awareness deficits. The results are discussed in terms of neurocognitive models of awareness and different patterns of neurobiological decline in the separate patient groups.
Publisher: Frontiers Media SA
Date: 2012
Publisher: Society for Neuroscience
Date: 19-11-2014
DOI: 10.1523/JNEUROSCI.2327-14.2014
Abstract: Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A s le of nonclinical adult humans ( N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1 SLC6A3 ), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with in iduals carrying one or two copies of the 10-repeat DAT1 allele, in iduals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed–accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.
Publisher: SAGE Publications
Date: 28-03-2023
DOI: 10.1177/00048674231161504
Abstract: The Strengths and Difficulties Questionnaire is a widely used screening tool for emotional and behavioural problems in children. Recent quantitative analyses have raised concerns regarding its structural validity in Aboriginal and Torres Strait Islander communities. This paper aims to extend upon existing findings by analysing the factor structure of both the parent- and teacher-reported Strengths and Difficulties Questionnaire in this population across a broader age range than in previous studies. Participants were the caregivers and teachers of 1624 Aboriginal and Torres Strait Islander children (820 male, 804 female) aged 2–15 years from Waves 2–11 of the Longitudinal Study of Indigenous Children. The majority of children were Aboriginal living in major cities and inner regional areas. Internal consistency was estimated with McDonald’s Omega. Exploratory structural equation modelling was conducted to investigate the factor structure of the parent-reported and teacher-reported versions of the Strengths and Difficulties Questionnaire. Responses from teachers demonstrated higher internal consistency than responses from parents, which was unacceptably low across most age groups. The purported five-factor structure of the Strengths and Difficulties Questionnaire failed to be replicated across both parent- and teacher-reported questionnaires. The results of bifactor and hierarchical exploratory structural equation models also failed to approximate the higher-order summary scales. These results indicate that the Strengths and Difficulties Questionnaire subscales and summary scores do not provide a valid index of emotional and behavioural problems in Aboriginal and Torres Strait Islander children. The Strengths and Difficulties Questionnaire should not be used with Aboriginal and Torres Strait Islander children.
Publisher: MIT Press - Journals
Date: 04-2013
DOI: 10.1162/JOCN_A_00327
Abstract: Response inhibition, comprising action cancellation and action restraint, and error awareness are executive functions of considerable clinical relevance to neuropsychiatric disorders. Nevertheless, our understanding of their underlying catecholamine mechanisms, particularly regarding dopamine, is limited. Here, we used the dopamine D2 agonist cabergoline to study its ability to improve inhibitory control and modulate awareness of performance errors. A randomized, double-blind, placebo-controlled, crossover design with a single dose of cabergoline (1.25 mg) and placebo (dextrose) was employed in 25 healthy participants. They each performed the stop-signal task, a well-validated measure of action cancellation, and the Error Awareness Task, a go/no-go measure of action restraint and error awareness, under each drug condition. Cabergoline was able to selectively reduce stop-signal RT, compared with placebo, indicative of enhanced action cancellation (p & .05). This enhancement occurred without concomitant changes in overall response speed or RT variability and was not seen for errors of commission on the Error Awareness Task. Awareness of performance errors on the go/no-go task was, however, significantly improved by cabergoline compared with placebo (p & .05). Our results contribute to growing evidence for the dopaminergic control of distinct aspects of human executive ability, namely, action cancellation and error awareness. The findings may aid the development of new, or the repurposing of existing, pharmacotherapy that targets the cognitive dysfunction of psychiatric and neurological disorders. They also provide further evidence that specific cognitive paradigms have correspondingly specific neurochemical bases.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2021
DOI: 10.1038/S41467-020-20443-2
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10 −10 , OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h 2 SNP = 0.34) when compared to ADHD without DBDs (h 2 SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r g = 0.81) and anti-social behaviors (r g = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.BIOPSYCH.2010.11.014
Abstract: Response inhibition is a prototypical executive function of considerable clinical relevance to psychiatry. Nevertheless, our understanding of its pharmacological modulation remains incomplete. We used a randomized, double-blind, placebo-controlled, crossover design to examine the effect of an acute dose of methylphenidate (MPH) (30 mg), atomoxetine (ATM) (60 mg), citalopram (CIT) (30 mg), and placebo (PLAC) (dextrose) on the stop signal inhibition task in 24 healthy, right-handed men 18-35 years of age. Participants performed the task under each of the four drug conditions across four consecutive sessions. Methylphenidate led to a reduction in both response time variability and stop-signal reaction time (SSRT), indicating enhanced response inhibition compared with all other drug conditions. Crucially, the enhancement of response inhibition by MPH occurred without concomitant changes in overall response speed, arguing against a simple enhancement of processing speed. We found no significant differences between ATM and PLAC, CIT and PLAC, or ATM and CIT for either response time variability or SSRT. An acute dose of MPH but not ATM or CIT was able to improve SSRT and reduce response time variability in nonclinical participants. Improvements in response inhibition and response variability might underlie the reported clinical benefits of MPH in disorders such as attention-deficit/hyperactivity disorder.
Publisher: Informa UK Limited
Date: 12-2006
DOI: 10.1080/09602010500200250
Abstract: Few studies have attempted direct cognitive remediation of attention deficits in attention-deficit hyperactivity disorder (ADHD). The present study investigated the efficacy of periodic non-informative alerting cues for improving sustaining attention in ADHD. This technique is known to improve sustained attention in right frontal injury patients and may be effective in ADHD, given that this disorder has also been linked with right frontal dysfunction. Fifteen children with ADHD and 15 matched controls completed four blocks of a modified version of the Sustained Attention to Response Task (SART). Eight random non-contingent alerts were introduced on two of these blocks as a cue for participants to adopt a more supervisory stance to their performance. While the alerting cues did not alter the total number of commission errors committed by ADHD children over a task block, they did produce a significant short-term reduction in commission errors in the period immediately following an alerting cue. Our data demonstrate that sustained attention performance can be enhanced in children with ADHD using a simple cognitive training strategy. Methods from the field of cognitive rehabilitation may be viably applied to the remediation of attention deficits in ADHD.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2005
Abstract: A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3' variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2005
DOI: 10.1007/S00221-005-0079-X
Abstract: Poor sustained attention or alertness is a common consequence of traumatic brain injury (TBI) and has a considerable impact on the recovery and adjustment of TBI patients. Here, we describe the development of a sensitive laboratory task in healthy subjects (Experiment 1) and its enhanced sensitivity to sustained attention errors in TBI patients (Experiment 2). The task involves withholding a key press to an infrequent no-go target embedded within a predictable sequence of numbers (primary goal) and detecting grey-coloured targets within the sequence (secondary goal). In Experiment 1, we report that neurologically healthy subjects are more likely to experience a lapse of attention and neglect the primary task goal, despite ceiling performance on the secondary task. Further, attentional lapses on the task correlated with everyday attentional failures and variability of response time. In Experiment 2, the task discriminates between TBI patients and controls with a large effect size. The dual-task yields more errors in both groups than a simple task involving only the primary goal that is commonly used to detect sustained attention deficits in neurologically impaired groups. TBI patients' errors also correlated with everyday cognitive failures and variability of response time. This was not the case in the simple version of the task. We conclude that the dual-task demand associated with this task enhances its sensitivity as a measure of sustained attention in TBI patients and neurologically healthy controls that relates to everyday slips of attention.
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.NEUBIOREV.2008.08.016
Abstract: Neural mechanisms of cognitive control enable us to initiate, coordinate and update behaviour. Central to successful control is the ability to suppress actions that are no longer relevant or required. In this article, we review the contribution of cognitive neuroscience, molecular genetics and clinical investigations to understanding how response inhibition is mediated in the human brain. In Section 1, we consider insights into the neural basis of inhibitory control from the effects of neural interference, neural dysfunction, and drug addiction. In Section 2, we explore the functional specificity of inhibitory mechanisms among a range of related processes, including response selection, working memory, and attention. In Section 3, we focus on the contribution of response inhibition to understanding flexible behaviour, including the effects of learning and in idual differences. Finally, in Section 4, we propose a series of technical and conceptual objectives for future studies addressing the neural basis of inhibition.
Publisher: Oxford University Press (OUP)
Date: 03-03-2023
Abstract: Schizotypy is a multidimensional construct that captures a continuum of risk for developing schizophrenia-spectrum psychopathology. Existing 3-factor models of schizotypy, consisting of positive, negative, and disorganized dimensions have yielded mixed evidence of genetic continuity with schizophrenia using polygenic risk scores. Here, we propose an approach that involves splitting positive and negative schizotypy into more specific subdimensions that are phenotypically continuous with distinct positive symptoms and negative symptoms recognized in clinical schizophrenia. We used item response theory to derive high-precision estimates of psychometric schizotypy using 251 self-report items obtained from a non-clinical s le of 727 (424 females) adults. These subdimensions were organized hierarchically using structural equation modeling into 3 empirically independent higher-order dimensions enabling associations with polygenic risk for schizophrenia to be examined at different levels of phenotypic generality and specificity. Results revealed that polygenic risk for schizophrenia was associated with variance specific to delusional experiences (γ = 0.093, P = .001) and reduced social interest and engagement (γ = 0.076, P = .020), and these effects were not mediated via the higher-order general, positive, or negative schizotypy factors. We further fractionated general intellectual functioning into fluid and crystallized intelligence in 446 (246 females) participants that underwent onsite cognitive assessment. Polygenic risk scores explained 3.6% of the variance in crystallized intelligence. Our precision phenotyping approach could be used to enhance the etiologic signal in future genetic association studies and improve the detection and prevention of schizophrenia-spectrum psychopathology.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2019
DOI: 10.1038/S41380-019-0495-0
Abstract: Cellular models of neurodevelopmental disorders provide a valuable experimental system to uncover disease mechanisms and novel therapeutic strategies. The ability of induced pluripotent stem cells (iPSCs) to generate erse brain cell types offers great potential to model several neurodevelopmental disorders. Further patient-derived iPSCs have the unique genetic and molecular signature of the affected in iduals, which allows researchers to address limitations of transgenic behavioural models, as well as generate hypothesis-driven models to study disorder-relevant phenotypes at a cellular level. In this article, we review the extant literature that has used iPSC-based modelling to understand the neuronal and glial contributions to neurodevelopmental disorders including autism spectrum disorder (ASD), Rett syndrome, bipolar disorder (BP), and schizophrenia. For instance, several molecular candidates have been shown to influence cellular phenotypes in three-dimensional iPSC-based models of ASD patients. Delays in differentiation of astrocytes and morphological changes of neurons are associated with Rett syndrome. In the case of bipolar disorders and schizophrenia, patient-derived models helped to identify cellular phenotypes associated with neuronal deficits (e.g., excitability) and mutation-specific abnormalities in oligodendrocytes (e.g., CSPG4). Further we provide a critical review of the current limitations of this field and provide methodological suggestions to enhance future modelling efforts of neurodevelopmental disorders. Future developments in experimental design and methodology of disease modelling represent an exciting new avenue relevant to neurodevelopmental disorders.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2015.03.015
Abstract: Within-subject, or intra-in idual, variability in reaction time (RT) is increasingly recognised as an important indicator of the efficiency of attentional control, yet there have been few investigations of the neural correlates of trial-to-trial RT variability in healthy adults. We sought to determine the neural correlates of intra-in idual RT variability during a go/no-go response inhibition task in 27 healthy, male participants. We found that reduced trial-to-trial RT variability (i.e. greater response stability) was significantly associated with greater activation in the left pregenual anterior cingulate. These results support the role of the left anterior cingulate in the dynamic control of attention and efficient response selection. Greater understanding of intra-in idual RT variability and top-down attentional control in healthy adults may help to inform disorders that impact executive/attentional control, such as attention deficit hyperactivity disorder and schizophrenia.
Publisher: MIT Press - Journals
Date: 05-2021
DOI: 10.1162/JOCN_A_01703
Abstract: Current models of perceptual decision-making assume that choices are made after evidence in favor of an alternative accumulates to a given threshold. This process has recently been revealed in human EEG recordings, but an unresolved issue is how these neural mechanisms are modulated by competing, yet task-irrelevant, stimuli. In this study, we tested 20 healthy participants on a motion direction discrimination task. Participants monitored two patches of random dot motion simultaneously presented on either side of fixation for periodic changes in an upward or downward motion, which could occur equiprobably in either patch. On a random 50% of trials, these periods of coherent vertical motion were accompanied by simultaneous task-irrelevant, horizontal motion in the contralateral patch. Our data showed that these distractors selectively increased the litude of early target selection responses over scalp sites contralateral to the distractor stimulus, without impacting on responses ipsilateral to the distractor. Importantly, this modulation mediated a decrement in the subsequent buildup rate of a neural signature of evidence accumulation and accounted for a slowing of RTs. These data offer new insights into the functional interactions between target selection and evidence accumulation signals, and their susceptibility to task-irrelevant distractors. More broadly, these data neurally inform future models of perceptual decision-making by highlighting the influence of early processing of competing stimuli on the accumulation of perceptual evidence.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.NEUROIMAGE.2021.118570
Abstract: The integration of modern neuroimaging methods with genetically informative designs and data can shed light on the molecular mechanisms underlying the structural and functional organization of the human connectome. Here, we review studies that have investigated the genetic basis of human brain network structure and function through three complementary frameworks: (1) the quantification of phenotypic heritability through classical twin designs (2) the identification of specific DNA variants linked to phenotypic variation through association and related studies and (3) the analysis of correlations between spatial variations in imaging phenotypes and gene expression profiles through the integration of neuroimaging and transcriptional atlas data. We consider the basic foundations, strengths, limitations, and discoveries associated with each approach. We present converging evidence to indicate that anatomical connectivity is under stronger genetic influence than functional connectivity and that genetic influences are not uniformly distributed throughout the brain, with phenotypic variation in certain regions and connections being under stronger genetic control than others. We also consider how the combination of imaging and genetics can be used to understand the ways in which genes may drive brain dysfunction in different clinical disorders.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2011
Publisher: Wiley
Date: 24-08-2009
DOI: 10.1111/J.1469-7610.2009.02096.X
Abstract: Evidence for a selective attention abnormality in children with attention deficit hyperactivity disorder (ADHD) has been hard to identify using conventional methods from cognitive science. This study tested whether the presence of selective attention abnormalities in ADHD may vary as a function of perceptual load and target lateralisation. Given evidence of right-hemisphere dysfunction in ADHD we predicted increased interference effects for right, but not left-sided target displays, particularly under low perceptual load. Fourteen children with ADHD-C and 14 typically developing children were tested on a modified flanker task under low and high perceptual load. We also sought evidence for our hypothesis in a re-analysis of an independent data set (42 ADHD 34 typically developing) in which load effects on selective attention in ADHD were previously examined (Huang-Pollock, Nigg, & Carr, 2005). As predicted, all children showed evidence of greater interference by flankers under low compared with high perceptual load conditions. Crucially, however, children with ADHD showed the greatest interference effect for right-sided target displays under low but not high perceptual load. In contrast, typically developing children showed the greatest interference for left-sided target displays. The magnitude of interference for right-sided targets was also positively correlated with ADHD symptom levels. Re-analysis of an independent data set (Huang-Pollock et al., 2005) further confirmed our findings. This study demonstrates that interference effects in children with ADHD and typically developing children are spatially asymmetrical but opposite in direction. The pattern of right-sided interference effects in children with ADHD suggests disruption within right hemisphere attentional networks in ADHD.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.NEUROIMAGE.2010.06.068
Abstract: Our ability to remember locations in space (spatial working memory) and our ability to direct attention to those locations (spatial attention) are two fundamental and closely related cognitive processes. A growing body of behavioural evidence suggests that spatial working memory and spatial attention share common resources, while neuroimaging studies show some overlap in the neural regions that mediate these two cognitive functions. The current study used fMRI to directly examine the extent to which spatial working memory and spatial attention rely on common underlying neural mechanisms. Twenty healthy participants underwent functional MRI while performing a dual task of spatial working memory incorporating a visual search task during the working memory retention interval. Working memory and visual search task loads were parametrically modulated. A wide network of prefrontal, premotor, and parietal regions showed increasing activity with increased spatial working memory load. Of these areas, part of the right supramarginal gyrus, lying along the intraparietal sulcus, showed a significant interaction such that the neural activity associated with spatial working memory load was significantly attenuated as visual search load in the dual task was increased. This interaction suggests that this part of the supramarginal gyrus, along the intraparietal sulcus, is critical for mediating both spatial working memory and shifts in spatial attention.
Publisher: Society for Neuroscience
Date: 04-09-2023
Publisher: eLife Sciences Publications, Ltd
Date: 18-03-2019
DOI: 10.7554/ELIFE.42541
Abstract: The timing and accuracy of perceptual decision-making is exquisitely sensitive to fluctuations in arousal. Although extensive research has highlighted the role of various neural processing stages in forming decisions, our understanding of how arousal impacts these processes remains limited. Here we isolated electrophysiological signatures of decision-making alongside signals reflecting target selection, attentional engagement and motor output and examined their modulation as a function of tonic and phasic arousal, indexed by baseline and task-evoked pupil diameter, respectively. Reaction times were shorter on trials with lower tonic, and higher phasic arousal. Additionally, these two pupil measures were predictive of a unique set of EEG signatures that together represent multiple information processing steps of decision-making. Finally, behavioural variability associated with fluctuations in tonic and phasic arousal, indicative of neuromodulators acting on multiple timescales, was mediated by its effects on the EEG markers of attentional engagement, sensory processing and the variability in decision processing.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2023
DOI: 10.1038/S41398-023-02417-2
Abstract: Both psychotic illness and subclinical psychosis-like experiences (PLEs) have been associated with cortico-striatal dysfunction. This work has largely relied on a discrete parcellation of the striatum into distinct functional areas, but recent evidence suggests that the striatum comprises multiple overlapping and smoothly varying gradients (i.e., modes) of functional organization. Here, we investigated two of these functional connectivity modes, previously associated with variations in the topographic patterning of cortico-striatal connectivity (first-order gradient), and dopaminergic innervation of the striatum (second-order gradient), and assessed continuities in striatal function from subclinical to clinical domains. We applied connectopic mapping to resting-state fMRI data to obtain the first-order and second-order striatal connectivity modes in two distinct s les: (1) 56 antipsychotic-free patients (26 females) with first-episode psychosis (FEP) and 27 healthy controls (17 females) and (2) a community-based cohort of 377 healthy in iduals (213 females) comprehensively assessed for subclinical PLEs and schizotypy. The first-order “cortico-striatal” and second-order “dopaminergic” connectivity gradients were significantly different in FEP patients compared to controls bilaterally. In the independent s le of healthy in iduals, variations in the left first-order “cortico-striatal” connectivity gradient were associated with inter-in idual differences in a factor capturing general schizotypy and PLE severity. The presumed cortico-striatal connectivity gradient was implicated in both subclinical and clinical cohorts, suggesting that variations in its organization may represent a neurobiological trait marker across the psychosis continuum. Disruption of the presumed dopaminergic gradient was only noticeable in patients, suggesting that neurotransmitter dysfunction may be more apparent to clinical illness.
Publisher: American Psychiatric Association Publishing
Date: 07-2019
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2023
Publisher: Springer Science and Business Media LLC
Date: 27-10-2021
DOI: 10.1038/S41380-021-01359-9
Abstract: Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy in iduals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The s le comprised 3004 unmedicated healthy in iduals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores ( r = 0.067, p FDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ ( r = 0.285, p spin = 0.024), but not BD ( r = 0.166, p spin = 0.205) or MDD ( r = −0.274, p spin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, p spin = 0.006), BD (rho = −0.672, p spin = 0.009), and MDD (rho = −0.692, p spin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Public Library of Science (PLoS)
Date: 12-04-2013
Publisher: Springer Science and Business Media LLC
Date: 18-12-2018
DOI: 10.1038/S41398-018-0329-X
Abstract: It is well-established that there is a strong genetic contribution to the aetiology of attention deficit hyperactivity disorder (ADHD). Here, we employed a hypothesis-free genome-wide association study (GWAS) design in a s le of 480 clinical childhood ADHD cases and 1208 controls to search for novel genetic risk loci for ADHD. DNA was genotyped using Illumina’s Human Infinium PsychArray-24v1.2., and the data were subsequently imputed to the 1000 Genomes reference panel. Rigorous quality control and pruning of genotypes at both in idual subject and single nucleotide polymorphism (SNP) levels was performed. Polygenic risk score (PGRS) analysis revealed that ADHD case–control status was explained by genetic risk for ADHD, but no other major psychiatric disorders. Logistic regression analysis was performed genome-wide to test the association between SNPs and ADHD case–control status. We observed a genome-wide significant association ( p = 3.15E−08) between ADHD and rs6686722, mapped to the Tenascin R ( TNR ) gene. Members of this gene family are extracellular matrix glycoproteins that play a role in neural cell adhesion and neurite outgrowth. Suggestive evidence of associations with ADHD was observed for an additional 111 SNPs (⩽9.91E−05). Although intriguing, the association between DNA variation in the TNR gene and ADHD should be viewed as preliminary given the small s le size of this discovery dataset.
Publisher: Elsevier BV
Date: 2004
Publisher: Society for Neuroscience
Date: 15-09-2022
DOI: 10.1523/JNEUROSCI.0836-22.2022
Abstract: Sustained attention describes our ability to keep a constant focus on a given task. This ability is modulated by our physiological state of arousal. Although lapses of sustained attention have been linked with dysregulations of arousal, the underlying physiological mechanisms remain unclear. An emerging body of work proposes that the intrusion during wakefulness of sleep-like slow waves, a marker of the transition toward sleep, could mechanistically account for attentional lapses. This study aimed to expose, via pharmacological manipulations of the monoamine system, the relationship between the occurrence of sleep-like slow waves and the behavioral consequences of sustained attention failures. In a double-blind, randomized-control trial, 32 healthy human male participants received methylphenidate, atomoxetine, citalopram or placebo during four separate experimental sessions. During each session, electroencephalography (EEG) was used to measure neural activity while participants completed a visual task requiring sustained attention. Methylphenidate, which increases wake-promoting dopamine and noradrenaline across cortical and subcortical areas, improved behavioral performance whereas atomoxetine, which increases dopamine and noradrenaline predominantly over frontal cortices, led to more impulsive responses. Additionally, citalopram, which increases sleep-promoting serotonin, led to more missed trials. Based on EEG recording, citalopram was also associated with an increase in sleep-like slow waves. Importantly, compared with a classical marker of arousal such as α power, only slow waves differentially predicted both misses and faster responses in a region-specific fashion. These results suggest that a decrease in arousal can lead to local sleep intrusions during wakefulness which could be mechanistically linked to impulsivity and sluggishness. SIGNIFICANCE STATEMENT We investigated whether the modulation of attention and arousal could not only share the same neuromodulatory pathways but also rely on similar neuronal mechanisms for ex le, the intrusion of sleep-like activity within wakefulness. To do so, we pharmacologically manipulated noradrenaline, dopamine, and serotonin in a four-arm, randomized, placebo-controlled trial and examined the consequences on behavioral and electroencephalography (EEG) indices of attention and arousal. We showed that sleep-like slow waves can predict opposite behavioral signatures: impulsivity and sluggishness. Slow waves may be a candidate mechanism for the occurrence of attentional lapses since the relationship between slow-wave occurrence and performance is region-specific and the consequences of these local sleep intrusions are in line with the cognitive functions carried by the underlying brain regions.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2009.07.018
Abstract: This study examined the developmental trajectories associated with response inhibition and error processing as exemplar executive processes. We present fMRI data showing developmental changes to the functional networks underlying response inhibition and error-monitoring, comparing activation between adults and young adolescents performing the sustained attention to response task (SART). During successful inhibitions, we observed greater activation for the young adolescents than for the adults, in a widely distributed network including frontal, parietal and medial regions. When inhibition failed, however, adults showed increased activation compared to young adolescents in a number of regions, including bilateral parahippoc al gyrus, left and right lingual gyri, the right insula, and cerebellar regions. These differences largely remained even when the two groups were matched for performance, suggesting that performance differences are unlikely to be the driving factor behind these developmental differences. Instead, the neurodevelopmental trajectory of these important executive functions may reveal the basis for the immature executive functioning of the young adolescent.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.SCHRES.2007.02.020
Abstract: Visuospatial memory encoding deficits have been reported in adults with schizophrenia, while adolescents with schizophrenia have not been specifically investigated with visuospatial memory encoding and retrieval paradigms. A cross sectional study of delayed matching-to-s le performance in 19 right handed, male, anti-psychotic medication naïve adolescents with undifferentiated schizophrenia and 28 age, gender, IQ and handedness matched healthy participants was completed. The adolescent-onset schizophrenia group demonstrated significant impairment in visuospatial memory, independent of the degree of delay, consistent with an encoding impairment. The impaired encoding phase of visuospatial memory in the adolescent-onset schizophrenia group is consistent with findings in adult onset schizophrenia s les, suggesting a developmental stage-independent deficit.
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S0278-2626(02)00509-2
Abstract: In this study we report the results of two experiments on visual attention conducted with patients with early-onset schizophrenia. These experiments investigated the effect of irrelevant spatial-scale information upon the processing of relevant spatial-scale information, and the ability to shift the spatial scale of attention, across consecutive trials, between different levels of the hierarchical stimulus. Twelve patients with early-onset schizophrenia and matched controls performed local-global tasks under: (1) directed attention conditions with a consistency manipulation and (2) ided-attention conditions. In the directed-attention paradigm, the early-onset patients exhibited the normal patterns of global advantage and interference, and were not unduly affected by the consistency manipulation. Under ided-attention conditions, however, the early-onset patients exhibited a local-processing deficit. The source of this local processing deficit lay in the prolonged reaction time to local targets, when these had been preceded by a global target, but not when preceded by a local target. These findings suggest an impaired ability to shift the spatial scale of attention from a global to a local spatial scale in early-onset schizophrenia.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.CORTEX.2016.05.012
Abstract: Although lower brain volume is a consistent neuroimaging finding in attention deficit hyperactivity disorder (ADHD), we lack an understanding of whether this effect is driven by changes in cortical thickness or surface area, which are governed by distinct neurodevelopmental processes. This study examined ADHD-control differences in cortical thickness, surface area and volume, and tests whether thickness and surface area mediates any observed volume differences. Magnetic resonance imaging (MRI) data was collected from 35 males with ADHD-combined type and 35 typically developing control participants aged 9-17 years. Morphometric measures were examined for between group differences and the specific contribution of surface area and thickness to group differences in volume tested using mediation analysis. In iduals with ADHD had smaller total cortical volume (7.3%), surface area (4.3%), and mean cortical thickness (2.8%) compared to controls. Differences were pronounced in frontal and parietal lobes. Variance in volume as a function of ADHD diagnosis was accounted for at least in part by the relationship between diagnosis and each of cortical thickness and surface area, with regional variation in the relative contributions of these measures. The surface area of the precuneus was a major driver of volume differences, attesting to the potential relevance of this region for neurodevelopment in ADHD. Both surface area and cortical thickness play a significant mediating role in determining diagnostic differences in volume, with regional variation in the contribution of thickness and surface area to those volume differences, highlighting the importance of examining both cortical thickness and surface area in examining ADHD.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 28-11-2007
Abstract: Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (3' untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 3'-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-05-2023
Abstract: Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 s les from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality.
Publisher: Wiley
Date: 18-01-2023
DOI: 10.1111/JCPP.13752
Abstract: Understanding the unmet needs of healthcare consumers with attention‐deficit/hyperactivity disorder (ADHD) (in iduals with ADHD and their caregivers) provides critical insight into gaps in services, education and research that require focus and funding to improve outcomes. This review examines the unmet needs of ADHD consumers from a consumer perspective. A standardised search protocol identified peer‐reviewed studies published between December 2011 and December 2021 focusing on consumer‐identified needs relating to ADHD clinical care or research priorities. 1,624 articles were screened with 23 studies that reviewed examining the needs of ADHD consumers from Europe, the U.K., Hong Kong, Iran, Australia, the U.S.A. and Canada. Consumer‐identified needs related to: treatment that goes beyond medication (12 studies) improved ADHD‐related education/training (17 studies) improved access to clinical services, carer support and financial assistance (14 studies) school accommodations/support (6 studies) and ongoing treatment efficacy research (1 study). ADHD consumers have substantial unmet needs in clinical, psychosocial and research contexts. Recommendations to address these needs include: improving access to and quality of multimodal care provision incorporating recovery principles into care provision fostering ADHD health literacy and increasing consumer participation in research, service development and ADHD‐related training/education.
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/S0010-9452(08)70426-X
Abstract: Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2022
DOI: 10.1007/S10578-022-01338-3
Abstract: The COVID-19 pandemic has markedly impacted functioning for children and adolescents including those with attention-deficit/hyperactivity disorder (ADHD). We explored home learning difficulties (HLD) during COVID-19 restrictions in Australian children (aged 5–17) with ADHD, aiming to: (1) describe home learning experiences, and (2) examine associations between child anxiety (i.e., concurrent anxiety symptoms and pre-existing anxiety disorder status) and HLD. Baseline data from the longitudinal ADHD COVID-19 Survey were used ( n = 122). Parents reported on school factors and HLD pre-existing anxiety and co-occurring difficulties anxiety, ADHD, and oppositional symptoms demographics and medications. Parents retrospectively reported more children often looked forward to school pre-pandemic, than during the pandemic. Anxiety symptoms, but not pre-existing anxiety disorder status, were associated with HLD after accounting for covariates. ADHD inattention symptoms were also associated with HLD. Results support recommendations to continue pre-pandemic supports to assist with ADHD symptoms during home learning, and strategies/supports for families are discussed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1097/00001756-200411150-00021
Abstract: Research into attention deficit hyperactivity disorder (ADHD) has indicated abnormalities in electrodermal system activity (EDA) and separately, deficits in sustained attention. Here we asked whether reduced EDA in ADHD was consequential for the attention problems associated with this disorder. On a sustained attention task ADHD participants had higher overall error rates and exhibited a marked decrease in skin conductance responses (SCRs) to errors, relative to control children. Further, sustained attention errors were predicted by SCR litudes. Evidence of post-error slowing in both groups suggested comparable error awareness. It is proposed that attenuation of the normal autonomic response to errors reflects impairment in ADHD participants' psychological response to error significance and results in decreased behavioural correction and hence poorer sustained attention.
Publisher: Oxford University Press (OUP)
Date: 15-09-2010
Abstract: Recent behavioral studies suggest that asymmetries in visuospatial orienting are modulated by changes in the demand on nonspatial components of attention, but the brain correlates of this modulation are unknown. We used scalp-recorded event-related potentials to examine the influence of central attentional load on neural responses to lateralized visual targets. Forty-five participants were required to detect transient, unilateral visual targets while monitoring a stream of alphanumeric stimuli at fixation, in which the target was defined either by a unique feature (low load) or by a conjunction of features (high load). The earliest effect of load on spatial orienting was seen at the latency of the posterior N1 (190-240 ms). The commonly observed N1 enhancement with contralateral visual stimulation was attenuated over the right hemisphere under high load. Source analysis localized this effect to occipital and inferior parietal regions of the right hemisphere. In addition, we observed perceptual enhancement with increasing load within the focus of attention (fixation) at an earlier stage (P1, 90-140 ms) than has previously been reported. These data support the view that spatial asymmetries in visual orienting are modulated by nonspatial attention due to overlapping neural circuits within the right hemisphere.
Publisher: Mary Ann Liebert Inc
Date: 12-2013
Abstract: A naturalistic, prospective study of the influence of genetic variation on dose prescribed, clinical response, and side effects related to stimulant medication in 77 children with attention-deficit/hyperactivity disorder (ADHD) was undertaken. The influence of genetic variation of the CES1 gene coding for carboxylesterase 1A1 (CES1A1), the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate, was investigated. Parent- and teacher-rated behavioral questionnaires were collected at baseline when the children were medication naïve, and again at 6 weeks while they were on medication. Medication dose, prescribed at the discretion of the treating clinician, and side effects, were recorded at week 6. Blood and saliva s les were collected for genotyping. Single nucleotide polymorphisms (SNPs) were selected in the coding, non-coding and the 3' flanking region of the CES1 gene. Genetic association between CES1 variants and ADHD was investigated in an expanded s le of 265 Irish ADHD families. Analyses were conducted using analysis of covariance (ANCOVA) and logistic regression models. None of the CES1 gene variants were associated with the dose of methylphenidate provided or the clinical response recorded at the 6 week time point. An association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate was found. The two associated CES1 markers were in linkage disequilibrium and were significantly associated with ADHD in a larger s le of ADHD trios. The associated CES1 markers were also in linkage disequilibrium with two SNP markers of the noradrenaline transporter gene (SLC6A2). This study found an association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate. These markers were in linkage disequilibrium together and with two SNP markers of the noradrenaline transporter gene.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2014.01.015
Abstract: Atypical asymmetries of spatial attention have been reported in children with attention deficit hyperactivity disorder (ADHD) and may be exacerbated by non-spatial factors such as attentional capacity. Although preliminary evidence suggests that asymmetries of attention in ADHD may be modifiable by the psychostimulant, methylphenidate, further placebo-controlled studies are required. This study first aimed to confirm recent evidence that increasing non-spatial processing load at fixation can unmask a spatial gradient of target detection in children with ADHD but not Controls. Second, we used placebo-controlled randomised trial methodology to ask whether 20mg of methylphenidate (MPH) could remediate any load-dependent asymmetry of spatial attention in adolescents with ADHD. Twelve male adolescents with ADHD were assessed twice in a double-blind, randomized design, under either placebo or an acute dose of methylphenidate. Thirteen typically developing adolescent Controls completed a single session under placebo. Participants completed a computer-based task in which they monitored a centrally presented rapid serial visual presentation stream for a probe stimulus, while also responding to brief peripheral events. The attentional load of the central task was manipulated by varying the target instructions but not the physical stimuli or the frequency of targets. Between-group analyses under placebo conditions indicated that increased attentional load induced a spatial gradient for target detection in the ADHD but not Controls, such that load slowed response times for left, but not, right hemi-field targets. This load-dependent spatial asymmetry in the adolescents with ADHD was abolished by administration of methylphenidate. Methylphenidate may "normalise" target detection between the hemi-fields in ADHD via enhancement of the right-lateralised ventral attention networks that support non-spatial attention.
Publisher: American Psychological Association (APA)
Date: 09-2021
DOI: 10.1037/NEU0000757
Publisher: Elsevier BV
Date: 2021
Publisher: Oxford University Press (OUP)
Date: 28-06-2011
Publisher: SAGE Publications
Date: 17-12-2020
Abstract: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD). Parents of 213 Australian children (5–17 years) with ADHD completed a survey in May 2020 when COVID-19 restrictions were in place (i.e., requiring citizens to stay at home except for essential reasons). Compared to pre-pandemic, children had less exercise (Odds Ratio (OR) = 0.4 95% CI 0.3–0.6), less outdoor time (OR = 0.4 95% 0.3–0.6), and less enjoyment in activities (OR = 6.5 95% CI 4.0–10.4), while television (OR = 4.0 95% CI 2.5–6.5), social media (OR = 2.4 95% CI 1.3–4.5), gaming (OR = 2.0 95% CI 1.3–3.0), sad/depressed mood (OR = 1.8 95% CI 1.2–2.8), and loneliness (OR = 3.6 95% CI 2.3–5.5) were increased. Child stress about COVID-19 restrictions was associated with poorer functioning across most domains. Most parents (64%) reported positive changes for their child including more family time. COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2022
DOI: 10.1038/S41588-022-01203-Y
Abstract: The canonical paradigm for converting genetic association to mechanism involves iteratively mapping in idual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of in idual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.
Publisher: SAGE Publications
Date: 26-03-2021
DOI: 10.1177/10870547211003671
Abstract: This review aimed to understand the broader community’s attitudes toward ADHD, which could facilitate public health interventions to improve outcomes for in iduals with ADHD. A standardized protocol identified peer-reviewed studies focusing on attitudes of broader community s les, published from January 2014 to February 2020 (inclusive). A total of 1,318 articles were screened and 10 studies were included, examining attitudes of broader community s les from Australia, Sweden, Germany, Finland, Korea, Indonesia, and the United States. Findings revealed that broader community s les displayed varying degrees of ADHD-related knowledge, negative attitudes (that ADHD is over-diagnosed that pharmacological treatment is not acceptable that those with ADHD are more likely to exhibit poor behavior), and a desire for maintaining social distance from in iduals with ADHD. Findings suggest that community attitudes are generally negative toward those with ADHD. Targeted mental health literacy could provide an important avenue for improving the broader community’s attitudes toward those with ADHD.
Publisher: MIT Press - Journals
Date: 07-2019
DOI: 10.1162/JOCN_A_01393
Abstract: Recent behavioral modeling and pupillometry studies suggest that neuromodulatory arousal systems play a role in regulating decision formation but neurophysiological support for these observations is lacking. We employed a randomized, double-blinded, placebo-controlled, crossover design to probe the impact of pharmacological enhancement of catecholamine levels on perceptual decision-making. Catecholamine levels were manipulated using the clinically relevant drugs methylphenidate and atomoxetine, and their effects were compared with those of citalopram and placebo. Participants performed a classic EEG oddball paradigm that elicits the P3b, a centro-parietal potential that has been shown to trace evidence accumulation, under each of the four drug conditions. We found that methylphenidate and atomoxetine administration shortened RTs to the oddball targets. The neural basis of this behavioral effect was an earlier P3b peak latency, driven specifically by an increase in its buildup rate without any change in its time of onset or peak litude. This study provides neurophysiological evidence for the catecholaminergic enhancement of a discrete aspect of human decision-making, that is, evidence accumulation. Our results also support theoretical accounts suggesting that catecholamines may enhance cognition via increases in neural gain.
Publisher: BMJ
Date: 11-2022
DOI: 10.1136/BMJOPEN-2022-064920
Abstract: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder which affects 5% of children globally. In Australia, it is estimated that 4.1% of children and adolescents have ADHD. While research has examined the treatment and outcomes of children with ADHD attending public mental health services during their time in the public system in Australia, it is not known what treatment they received before and after these treatment episodes, which will provide a more complete understanding of these children’s treatment journey. We will link clinical data from cohorts of children and adolescents treated in the public child and youth mental health and/or child development services in Brisbane, Melbourne and Sydney to the Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS) and National Death Index. MBS data will demonstrate the treatment journey with respect to clinicians seen, and treatment episodes from the public health service data sets will be examined to assess if the type and intensity of treatment are related to treatment outcomes. PBS data will reveal all psychotropic medications prescribed, allowing an examination of not just ADHD medications, but also other psychotropics which may indicate co-occurring conditions (eg, anxiety and mood disorders). Statistical analyses will include descriptive statistics to describe the rates of specific medications and clinician specialties seen. Linear and logistic regression will be used to model how treatment and sociodemographic variables relate to routinely collected outcome measures in the public health system while controlling for covarying factors. This study has been approved by the following institutional ethics committees: (1) Children’s Health Queensland Hospital and Health Service (HREC/21/QCHQ/76260), (2) The University of Queensland (2021/HE002143) and (3) The Australian Institute of Health and Welfare (EO2021/4/1300). Findings will be disseminated through peer-reviewed journals, conferences, professional associations and to public mental health services that treat ADHD.
Publisher: MIT Press - Journals
Date: 2014
DOI: 10.1162/JOCN_A_00468
Abstract: It is known that the parahippoc al cortex is involved in object–place associations in spatial learning, but it remains unknown whether activity within this region is modulated by affective signals during navigation. Here we used fMRI to measure the neural consequences of emotional experiences on place memory during navigation. A day before scanning, participants undertook an active object location memory task within a virtual house in which each room was associated with a different schedule of task-irrelevant emotional events. The events varied in valence (positive, negative, or neutral) and in their rate of occurrence (intermittent vs. constant). On a subsequent day, we measured neural activity while participants were shown static images of the previously learned virtual environment, now in the absence of any affective stimuli. Our results showed that parahippoc al activity was significantly enhanced bilaterally when participants viewed images of a room in which they had previously encountered negatively arousing events. We conclude that such automatic enhancement of place representations by aversive emotional events serves as an important adaptive mechanism for avoiding future threats.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2006
Start Date: 2015
End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2008
End Date: 2010
Funder: Brain and Behavior Research Foundation
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Tatts Group Limited
View Funded ActivityStart Date: 2006
End Date: 2006
Funder: Murdoch Children's Research Institute
View Funded ActivityStart Date: 2004
End Date: 2004
Funder: Enterprise Ireland
View Funded ActivityStart Date: 2003
End Date: 2006
Funder: Wellcome Trust
View Funded ActivityStart Date: 2016
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Australian Research Council
View Funded Activity