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Human brain mapping 43(1), 37-55 (2022). doi:10.1002/hbm.25029 special issue: "Special Issue: The ENIGMA Consortium: the first 10 years / Issue Edited by: P.M. Thompson, N. Jahanshad, L. Schmaal, J.A. Turner, A. Winkler, S.I. Thomopoulos, G.F. Egan, P. Kochunov", Published by Wiley-Liss, New York, NY

Objective: To determine the financial and non-financial costs of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan. Method: 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)). Results: 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). Conclusion: 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.

Atypical motor coordination and cognitive processes, such as response inhibition and working memory, have been extensively researched in individuals with attention deficit hyperactivity disorder (ADHD). Oculomotor neural circuits overlap extensively with regions involved in motor planning and cognition, therefore studies of oculomotor function may offer unique insights into motor and cognitive control in ADHD. We performed a series of pairwise meta-analyses based on data from 26 oculomotor studies in ADHD to examine whether there were differences in performance on visually-guided saccade, gap, antisaccade, memory-guided, pursuit eye movements and fixation tasks. These analyses revealed oculomotor disturbances in ADHD, particularly for difficulties relating to saccade inhibition, memorizing visual target locations and initiating antisaccades. There was no evidence for pursuit eye movement disturbances or saccade dysmetria. Investigating oculomotor abnormalities in ADHD may provide insight into top-down cognitive control processes and motor control, and may serve as a promising biomarker in ADHD research and clinical practice.

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 sample (N = 1,056), show test–retest reliability and between-subjects variability in a face-to-face community sample (N = 63), and replicate the results in a community and clinical sample (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. Existing measures of cognitive impulsivity have suboptimal reliability and validity. Here, the authors introduce a new online test battery featuring a gamified interface and show that it aids in the prediction of real-world, addiction-related problems.

Objective: This review aimed to understand the broader community’s attitudes toward ADHD, which could facilitate public health interventions to improve outcomes for individuals with ADHD. Methods: A standardized protocol identified peer-reviewed studies focusing on attitudes of broader community samples, published from January 2014 to February 2020 (inclusive). Results: A total of 1,318 articles were screened and 10 studies were included, examining attitudes of broader community samples from Australia, Sweden, Germany, Finland, Korea, Indonesia, and the United States. Findings revealed that broader community samples 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 individuals with ADHD. Conclusion: 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.

Smartphone-based cognitive assessment measures allow efficient, rapid, and convenient collection of cognitive datasets. Establishment of feasibility and validity is essential for the widespread use of this approach. We describe a novel smartphone application (HD-Mobile) that includes three performance-based cognitive tasks with four key outcome measures, for use with Huntington’s disease (HD) samples. We describe known groups and concurrent validity, test–retest reliability, sensitivity, and feasibility properties of the tasks. Forty-two HD CAG-expanded participants (20 manifest, 22 premanifest) and 28 healthy controls completed HD-Mobile cognitive tasks three times across an 8-day period, on days 1, 4, and 8. A subsample of participants had pen-and-paper cognitive task data available from their most recent assessment from their participation in a separate observational longitudinal study, Enroll-HD. Manifest-HD participants performed worse than healthy controls for three of four HD-Mobile cognitive measures, and worse than premanifest-HD participants for two of four measures. We found robust test–retest reliability for manifest-HD participants (ICC = 0.71–0.96) and with some exceptions, in premanifest-HD (ICC = 0.52–0.96) and healthy controls (0.54–0.96). Correlations between HD-Mobile and selected Enroll-HD cognitive tasks were mostly medium to strong (r = 0.36–0.68) as were correlations between HD-Mobile cognitive tasks and measures of expected disease progression and motor symptoms for the HD CAG-expanded participants (r = − 0.34 to − 0.54). Results indicated robust known-groups, test–retest, concurrent validity, and sensitivity of HD-Mobile cognitive tasks. The study demonstrates the feasibility and utility of HD-Mobile for conducting convenient, frequent, and potentially ongoing assessment of HD samples without the need for in-person assessment.

Animal neurophysiological studies have identified neural signals within dorsal frontoparietal areas that trace a perceptual decision by accumulating sensory evidence over time and trigger action upon reaching a threshold. Although analogous accumulation-to-bound signals are identifiable on extracranial human electroencephalography, their cortical origins remain unknown. Here neural metrics of human evidence accumulation, predictive of the speed of perceptual reports, were isolated using electroencephalography and related to dorsal frontoparietal network (dFPN) connectivity using diffusion and resting-state functional magnetic resonance imaging. The build-up rate of evidence accumulation mediated the relationship between the white matter macrostructure of dFPN pathways and the efficiency of perceptual reports. This association between steeper build-up rates of evidence accumulation and the dFPN was recapitulated in the resting-state networks. Stronger connectivity between dFPN regions is thus associated with faster evidence accumulation and speeded perceptual decisions. Our findings identify an integrated network for perceptual decisions that may be targeted for neurorehabilitation in cognitive disorders. How efficiently humans make perceptual decisions varies between people. Based on EEG and structural and functional MRI data, Brosnan et al. suggest a role for dorsal frontoparietal network connectivity in the speed of perceptual decisions.

The clinical heterogeneity of autism spectrum disorders majorly challenges their genetic study. Autism spectrum disorders symptoms occur in milder forms in the general population, as autistic-like traits, and share genetic factors with autism spectrum disorders. Here, we investigate the genetics of individual autistic-like traits to improve our understanding of autism spectrum disorders. We meta-analysed four population-based genome-wide association studies investigating four autistic-like traits – ‘attention-to-detail’, ‘imagination’, ‘rigidity’ and ‘social-skills’ ( n = 4600). Using autism spectrum disorder summary statistics from the Psychiatric Genomic Consortium ( N = 46,350), we applied polygenic risk score analyses to understand the genetic relationship between autism spectrum disorders and autistic-like traits. Using MAGMA, we performed gene-based and gene co-expression network analyses to delineate involved genes and pathways. We identified two novel genome-wide significant loci – rs6125844 and rs3731197 – associated with ‘attention-to-detail’. We demonstrated shared genetic aetiology between autism spectrum disorders and ‘rigidity’. Analysing top variants and genes, we demonstrated a role of the immune-related genes RNF114, CDKN2A, KAZN, SPATA2 and ZNF816A in autistic-like traits. Brain-based genetic expression analyses further linked autistic-like traits to genes involved in immune functioning, and neuronal and synaptic signalling. Overall, our findings highlight the potential of the autistic-like trait–based approach to address the challenges of genetic research in autism spectrum disorders. We provide novel insights showing a potential role of the immune system in specific autism spectrum disorder dimensions. Lay abstract Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients.

Objective: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD). Methods: 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). Results: 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. Conclusions: COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

Background Children with neurodevelopmental disorders share common phenotypes, support needs and comorbidities. Such overlap suggests the value of transdiagnostic assessment pathways that contribute to knowledge about research and clinical needs of these children and their families. Despite this, large transdiagnostic data collection networks for neurodevelopmental disorders are not well developed. This paper describes the development of a nationally supported transdiagnostic clinical and research assessment protocol across Australia. The vision is to establish a harmonised network for data collection and collaboration that promotes transdiagnostic clinical practice and research. Methods Clinicians, researchers and community groups across Australia were consulted using surveys and national summits to identify assessment instruments and unmet needs. A national research committee was formed and, using a consensus approach, selected assessment instruments according to pre‐determined criteria to form a harmonised transdiagnostic assessment protocol. Results Identified assessment instruments were clustered into domains of transdiagnostic assessment needs, which included child functioning/quality of life, child mental health, caregiver mental health, and family background information. From this, the research committee identified a core set of nine measures and an extended set of 14 measures that capture these domains with potential for further modifications as recommended by clinicians, researchers and community members. Conclusion The protocol proposed here was established through a strong partnership between clinicians, researchers and the community. It will enable (i) consensus driven transdiagnostic clinical assessments for children with neurodevelopmental disorders, and (ii) research studies that will inform large transdiagnostic datasets across neurodevelopmental disorders and that can be used to inform research and policy beyond narrow diagnostic groups. The long‐term vision is to use this framework to facilitate collaboration across clinics to enable large‐scale data collection and research. Ultimately, the transdiagnostic assessment data can be used to inform practice and improve the lives of children with neurodevelopmental disorders and their families.

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 individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (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, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = −0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, pspin = 0.006), BD (rho = −0.672, pspin = 0.009), and MDD (rho = −0.692, pspin = 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.

Objective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods 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 sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results 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. Conclusion 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., Journal of Child Psychology and Psychiatry, 62 (10), ISSN:0021-9630, ISSN:1469-7610

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 amplitude 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.

Objective: This study aimed to investigate how sleep and physical activity habits related to cognitive functioning, in naturalistic settings, in early Huntington's disease (HD). Method: Forty-two participants with the expanded HD repeat (20 manifest, 22 premanifest) and 29 healthy controls wore Fitbit One sleep and activity monitors for 7 days and 7 nights. They used a smartphone application to complete daily sleep and activity diaries, sleep and mood inventories, and a brief battery of cognitive tests, which were completed on Day 8 of the study. All data were collected in naturalistic home and community settings. Results: Amongst participants with the expanded HD repeat, greater time spent in bed, measured by Fitbit, was associated with poorer accuracy and response speed on a test of visual memory, whereas lower levels of physical activity, measured by Fitbit, were associated with poorer accuracy on a test involving a working memory component. Neither time in bed nor physical activity is associated with a test of psychomotor speed. Groups were mostly similar across a range of Fitbit and self-report measures of sleep and physical activity, although the Manifest-HD group spent more time in bed than the Premanifest-HD and Healthy Control groups and had better self-reported sleep quality and more self-reported time spent sitting than the Healthy Control group and the Premanifest-HD group, respectively. Conclusions: Sleep timing and physical activity relate to cognitive functioning in HD and may be important targets for management in behavioral intervention studies aimed at improving cognition in HD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Food homeostatic states (hunger and satiety) influence the cognitive systems regulating impulsive responses, but the direction and specific mechanisms involved in this effect remain elusive. We examined how fasting, and satiety, affect cognitive mechanisms underpinning disinhibition using a novel framework and a gamified test-battery. Thirty-four participants completed the test-battery measuring three cognitive facets of disinhibition: attentional control, information gathering and monitoring of feedback, across two experimental sessions: one after overnight fasting and another after a standardised meal. Homeostatic state was assessed using subjective self-reports and biological markers (i.e., blood-derived liver-expressed antimicrobial protein 2 (LEAP-2), insulin and leptin). We found that participants who experienced greater subjective hunger during the satiety session were more impulsive in the information gathering task, results were not confounded by changes in mood or anxiety. Homeostatic state did not significantly influence disinhibition mechanisms linked to attentional control or feedback monitoring. However, we found a significant interaction between homeostatic state and LEAP-2 on attentional control, with higher LEAP-2 associated with faster reaction times in the fasted condition only. Our findings indicate lingering hunger after eating increases impulsive behaviour via reduced information gathering. These findings identify a novel mechanism that may underpin the tendency to overeat and/or engage in broader impulsive behaviours.

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.

Recent behavioural modelling 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 randomised, 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 (MPH) and atomoxetine (ATM) and their effects were compared to those of citalopram (CIT), and placebo (PLA). Participants performed a classic EEG oddball paradigm which 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 MPH and ATM administration shortened RTs to the oddball targets. The neural basis of this behavioural effect was an earlier P3b peak latency, driven specifically by an increase in its build-up rate without any change in its time of onset or peak amplitude. This study provides neurophysiological evidence for the catecholaminergic enhancement of a discrete aspect of human decision making, i.e. evidence accumulation. Our results also support theoretical accounts suggesting that catecholamines may enhance cognition via increases in neural gain.

BackgroundASD 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 hampered 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.MethodsThe 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.ConclusionThe 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.

Visual processing deficits have been widely reported in developmental dyslexia however the locus of cognitive dysfunction remains unclear. Here, we examined the neural correlates of perceptual decision-making using a dot-motion task and electroencephalography (EEG) and investigated whether presenting deficits were unique to children with dyslexia or if they were also evident in other, typically developing children with equally immature reading systems. Sixty-eight children participated: 32 with dyslexia (DD; 16 females); 21 age-matched controls (AM; 11 females) and 15 reading-matched controls (RM; 9 females). All participants completed a bilaterally presented random-dot-motion task while EEG was recorded. Neural signatures of low level sensory processing (steady state visual evoked potentials; SSVEPs), pre-target attentional bias (posterior α power), attentional orienting (N2), evidence accumulation (centro-parietal positive decision signal; CPP) and execution of a motor response (β) were obtained to dissect the temporal sequence of perceptual decision-making. Reading profile provided a score of relative lexical and sublexical skills for each participant. Although all groups performed comparably in terms of task accuracy and false alarm rate, the DD group were slower and demonstrated an earlier peak latency, reduced slope and lower amplitude of the CPP compared with both AM and RM controls. Reading profile was found to moderate the relationship between word reading ability, reaction time as well as CPP indices showing that lexical dyslexics responded more slowly and had a shallower slope, reduced amplitude and earlier latency of CPP waveforms than sublexical dyslexics. These findings suggest that children with dyslexia, particularly those with relatively poorer lexical abilities, have a reduced rate and peak of evidence accumulation as denoted by CPP markers yet remain slow in their overt response. This is in keeping with hypotheses that children with dyslexia have impairment in effectively sampling and processing evidence about visual motion stimuli.

Impulsive behaviours are a major contributor to global burden of disease. Recent research has criticised measures of cognitive impulsivity for poor reliability and inability to predict real-world behaviours. We address this concern via the development of the Cognitive Impulsivity Suite (CIS), comprising three computerised/online tasks delivered within a harmonised gamified interface. We conceptualise impulsive behaviour as arising from the failure of three distinct mechanisms: attentional control, information gathering, and shifting. Utilising the CIS, we aimed to examine: (1) construct and criterion-related validity in an online sample (N = 1056), (2) test-retest reliability and between-subjects variability in a face-to-face sample (n = 63). Results supported the theoretical architecture of the attentional control, information gathering, and shifting constructs. The three factors were differentially associated with trait-impulsivity facets, and the strength of these associations were substantially higher than previously reported. Furthermore, the CIS demonstrated incremental criterion-related validity for prediction of real-world, addiction-related problems.

Objectives: Previous studies have postulated that the error-related negativity (ERN) may reflect individual differences in impulsivity; however, none have used a longitudinal framework or evaluated impulsivity as a multidimensional construct. The current study evaluated whether ERN amplitude, measured in childhood and adolescence, is predictive of impulsiveness during adolescence. Methods: Seventy-five children participated in this study, initially at ages 7–9 years and again at 12–18 years. The interval between testing sessions ranged from 5 to 9 years. The ERN was extracted in response to behavioural errors produced during a modified visual flanker task at both time points (i.e. childhood and adolescence). Participants also completed the Barratt Impulsiveness Scale − a measure that considers impulsiveness to comprise three core sub-traits − during adolescence. Results: At adolescence, the ERN amplitude was significantly larger than during childhood. Additionally, ERN amplitude during adolescence significantly predicted motor impulsiveness at that time point, after controlling for age, gender, and the number of trials included in the ERN. In contrast, ERN amplitude during childhood did not uniquely predict impulsiveness during adolescence. Conclusions: These findings provide preliminary evidence that ERN amplitude is an electrophysiological marker of self-reported motor impulsiveness (i.e. acting without thinking) during adolescence. Keywords: Error-related negativity, ERN, Impulsivity, BIS, Development, Adolescence

Sleep has been classically described as an all-or-nothing global phenomenon. However, recent research suggests that this view requires tempering. Invasive and non-invasive recordings in animals and humans show that neural activity typically associated with sleep can locally occur during wakefulness. Although local sleep is defined neuronally, it has been associated with impaired performance during cognitive tasks. Comparatively, the phenomenology of local sleep (i.e. what it feels like when your brain is partially asleep) has been less explored. Taking into account the literature on the neuronal and behavioural profile of local sleep intrusions in wakefulness, we propose that occurrences of local sleep could represent the neural mechanism underlying many attentional lapses. In particular, we argue that a unique physiological event such as local sleep could account for a diversity of behavioural outcomes from sluggish to impulsive responses. We further propose that local sleep intrusions could impact individuals’ subjective experience. Specifically, we propose that the timing and anatomical sources of local sleep intrusions could be responsible for both the behavioural consequences and subjective content of attentional lapses and may underlie the difference between subjective experiences such as mind wandering and mind blanking. Our framework aims to build a parallel between spontaneous experiences in sleep and wakefulness by integrating evidence across neuronal, behavioural and experiential levels. We use the example of attention deficit hyperactivity disorder (ADHD) to illustrate how local sleep could explain complex cognitive profiles which include inattention, impulsivity, mind-wandering and mind-blanking.

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 individuals with relative lexical reading deficits, rather than being a unique contributor to reading dysfunction.

BackgroundPsychotic 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 individuals, is associated with the severity of subclinical PLEs.MethodsA community sample 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.ResultsPCA 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.ConclusionsConsistent with past findings in patients and high-risk individuals, 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.

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.

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 samples.

Background Cognitive assessment tools developed for use on personal electronic devices can allow convenient collection of large amounts of cognitive data. This methodology is novel in HD and validation must proceed before large scale implementation. Aims We aim to demonstrate discriminant and concurrent validity of our cognitive assessment methodology that involves participants utilising a smartphone app to self-administer cognitive tasks in their home environment. Methods We developed a smartphone app for iOS and Android, which includes informed consent, prompts through study procedures, and two cognitive tasks. We are using the app in a HD study, with currently, n=21; pre-symptomatic=17, symptomatic=4, HD participants, and n=18 control participants, across an eight-day period including self-administration of cognitive tasks (speeded tapping and a visual memory task) on day 1, 4, and 8. ENROLL-HD cognitive data are available for a subset of HD participants (n=11; pre-symptomatic=7, symptomatic=4). Groups were compared on app-based cognitive tasks to assess discriminant validity. For our HD subsample with ENROLL data, app-based and ENROLL cognitive tasks were compared to assess concurrent validity. Results Tapping speed of the HD group was significantly slower than the control group (p=0.013, d=0.83) as was their response time on the visual memory task (p=0.018, d=0.82). Visual memory performance was similar between the two groups. Greater speeded tapping performance and visual memory performance correlated significantly with greater ENROLL HD Symbol Digit Modality Test and verbal fluency performance (Pearson’s r values ranged from.61 – 0.88, p-values from 0.001 to 0.046). Conclusions Current results with a HD sample indicate both promising concurrent and discriminant validity properties of our remote-phone-based cognitive assessment methodology. All participants have completed all tasks, indicating sound usability and acceptability of the app.

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 individuals' 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.

Limited resources for the in-depth processing of external stimuli make it necessary to select only relevant information from our surroundings and to ignore irrelevant stimuli. Attentional mechanisms facilitate this selection via top-down modulation of stimulus representations in the brain. Previous research has indicated that acetylcholine (ACh) modulates this influence of attention on stimulus processing. However, the role of muscarinic receptors as well as the specific mechanism of cholinergic modulation remains unclear. Here we investigated the influence of ACh on feature-based, top-down control of stimulus processing via muscarinic receptors by using a contingent capture paradigm which specifically tests attentional shifts toward uninformative cue stimuli which display one of the target defining features In a double-blind, placebo controlled study we measured the impact of the muscarinic receptor antagonist scopolamine on behavioral and electrophysiological measures of contingent attentional capture. The results demonstrated all the signs of functional contingent capture, i.e., attentional shifts toward cued locations reflected in increased amplitudes of N1 and N2Pc components, under placebo conditions. However, scopolamine did not affect behavioral or electrophysiological measures of contingent capture. Instead, scopolamine reduced the amplitude of the distractor-evoked Pd component which has recently been associated with active suppression of irrelevant distractor information. The findings suggest a general cholinergic modulation of top-down control during distractor processing.

Within-subject, or intra-individual, 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-individual 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-individual 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.

Healthy subjects typically exhibit a subtle bias of visuospatial attention favouring left space that is commonly termed ‘pseudoneglect’. This bias is attenuated, or shifted rightwards, with decreasing alertness over time, consistent with theoretical models proposing that pseudoneglect is a result of the right hemisphere׳s dominance in regulating attention. Although this ‘time-on-task effect’ for spatial bias is observed when averaging across whole samples of healthy participants, Benwell, C. S. Y., Thut, G., Learmonth, G., & Harvey, M. (2013b). Spatial attention: differential shifts in pseudoneglect direction with time-on-task and initial bias support the idea of observer subtypes. Neuropsychologia, 51(13), 2747–2756 recently presented evidence that the direction and magnitude of bias exhibited by the participant early in the task (left biased, no bias, or right biased) were stable traits that predicted the direction of the subsequent time-on-task shift in spatial bias. That is, the spatial bias of participants who were initially left biased shifted in a rightward direction with time, whereas that of participants who were initially right biased shifted in a leftward direction. If valid, the data of Benwell et al. are potentially important and may demand a re-evaluation of current models of the neural networks governing spatial attention. Here we use two novel spatial attention tasks in an attempt to confirm the results of Benwell et al. We show that rather than being indicative of true participant subtypes, these data patterns are likely driven, at least in part, by ‘regression towards the mean’ arising from the analysis method employed. Although evidence supports the contention that trait-like individual differences in spatial bias exist within the healthy population, no clear evidence is yet available for participant/observer subtypes in the direction of time-on-task shift in spatial biases.

This work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) (APP1065677). 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 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. Postprint

Healthy subjects tend to exhibit a bias of visual attention whereby left hemifield stimuli are processed more quickly and accurately than stimuli appearing in the right hemifield. It has long been held that this phenomenon arises from the dominant role of the right cerebral hemisphere in regulating attention. However, methods that would enable more precise understanding of the mechanisms underpinning visuospatial bias have remained elusive. We sought to finely trace the temporal evolution of spatial biases by leveraging a novel bilateral dot motion detection paradigm. In combination with electroencephalography, this paradigm enables researchers to isolate discrete neural signals reflecting the key neural processes needed for making these detection decisions. These include signals for spatial attention, early target selection, evidence accumulation, and motor preparation. Using this method, we established that three key neural markers accounted for unique between-subject variation in visuospatial bias: hemispheric asymmetry in posterior α power measured before target onset, which is related to the distribution of preparatory attention across the visual field; asymmetry in the peak latency of the early N2c target-selection signal; and, finally, asymmetry in the onset time of the subsequent neural evidence-accumulation process with earlier onsets for left hemifield targets. Our development of a single paradigm to dissociate distinct processing components that track the temporal evolution of spatial biases not only advances our understanding of the neural mechanisms underpinning normal visuospatial attention bias, but may also in the future aid differential diagnoses in disorders of spatial attention.SIGNIFICANCE STATEMENTThe significance of this research is twofold. First, it shows that individual differences in how humans direct their attention between left and right space reflects physiological differences in how early the brain starts to accumulate evidence for the existence of a visual target. Second, the novel methods developed here may have particular relevance to disorders of attention, such as unilateral spatial neglect. In the case of spatial neglect, pathological inattention to left space could have multiple underlying causes, including biased attention, impaired decision formation, or a motor deficit related to one side of space. Our development of a single paradigm to dissociate each of these components may aid in supporting more precise differential diagnosis in such heterogeneous disorders.

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 20 mg 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.

Objective: 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. Methods: 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 functio...

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.

It is known that the parahippocampal 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 parahippocampal 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.

Objectives: Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie individual 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. Results: 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. Conclusions: These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses.

Intra-individual variability in response time has been proposed as an important endophenotype for attention deficit hyperactivity disorder (ADHD). Here we asked whether intra-individual variability is predicted by common variation in catecholamine genes and whether it mediates the relationship between these gene variants and self-reported ADHD symptoms. A total of 402 non-clinical Australian adults of European descent completed a battery of five cognitive tasks and the Conners' Adult ADHD Rating Scale. Exclusion criteria included the presence of major psychiatric or neurologic illnesses and substance dependency. A total of 21 subjects were excluded due to incomplete data or poor quality cognitive or genotyping data. The final sample comprised 381 subjects (201 males; mean age=21.2 years, s.d.=5.1 years). Principal components analysis on variability measures yielded two factors (response selection variability vs selective attention variability). Association of these factors with catecholamine gene variants was tested using single-step linear regressions, with multiple comparisons controlled using permutation analysis. The response selection variability factor was associated with two ADRA2A single-nucleotide polymorphisms (SNPs) (rs1800544, rs602618), p corrected=0.004, 0.012, respectively, whereas the selective attention variability factor was associated with a TH SNP (rs3842727), p corrected=0.024. A bootstrapping analysis indicated that the response selection variability factor mediated the relationship between the ADRA2A SNP rs1800544 and self-reported ADHD symptoms. Thus this study finds evidence that DNA variation in the ADRA2A gene may be causally related to ADHD-like behaviors, in part through its influence on intra-individual variability. Evidence was also found for a novel association between a TH gene variant and intra-individual variability.

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 amplitude of an early electrophysiological index of error processing, the ERN. Citalopram increased the amplitude 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.

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.

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.

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.

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 individuals 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.

Attention deficit/hyperactivity disorder (ADHD) is increasingly being viewed as a dysfunction of distributed brain networks rather than focal abnormalities. Here we investigated the structural brain network differences in children and adolescents with ADHD and healthy controls, using graph theory metrics to describe the anatomic networks and connectivity patterns, and the Network Based Statistic (NBS) to isolate the network components that differ between the two groups. Using DWI high-angular resolution diffusion imaging ('HARDI'), whole brain tractography was conducted on 21 ADHD-combined type boys (m 13.3 ± 1.9 yrs) and 21 typically developing boys (m 14.8 ± 2.1 yrs). This study presents a comprehensive structural network investigation in ADHD covering a range of commonly used methodologies, including both streamline and probabilistic tractography, tensor and constrained spherical deconvolution (CSD) models, as well as different edge weighting methods at a range of densities and t-thresholds. Using graph metrics, ADHD was associated with local neighbourhoods that were more modular and interconnected than controls, where there was a decrease in the global, long-range connections, indicating reduced communication between local, specialised networks in ADHD. ADHD presented with a sub-network of stronger connectivity encompassing bilateral frontostriatal connections as well as left occipital, temporal, and parietal regions, of which the white matter microstructure was associated with ADHD symptom severity. Probabilistic tractography using CSD and the Hagmann weighting method produced that highest stability and most robust network differences across t-thresholds. It demonstrates topological organisation disruption in distributed neural networks in ADHD, supportive of the theory of maturation delay in ADHD.

Brain networks subserving alertness in humans interact with those for spatial attention orienting. We employed blue-enriched light to directly manipulate alertness in healthy volunteers. We show for the first time that prior exposure to higher, relative to lower, intensities of blue-enriched light speeds response times to left, but not right, hemifield visual stimuli, via an asymmetric effect on right-hemisphere parieto-occipital α-power. Our data give rise to the tantalising possibility of light-based interventions for right hemisphere disorders of spatial attention.