EEG Source Imaging Indices of Cognitive Control Show Associations with Dopamine System Genes.

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness

Phosphorylation of Cdc5 regulates its accumulation

<p>Abstract</p> <p>Background</p> <p>Cdc5 (polo kinase/Plk1) is a highly conserved key regulator of the <it>S. cerevisiae </it>cell cycle from S-phase until cytokinesis. However, much of the regulatory mechanisms that govern Cdc5 remain to be determined. Cdc5 is phosphorylated on up to 10 sites during mitosis. In this study, we investigated the function of phosphorylation site T23, the only full consensus Cdk1 (Cdc28) phosphorylation site present.</p> <p>Findings</p> <p><it>Cdc5^T23A</it>introduces a degron that reduces its cellular amount to undetectable levels, which are nevertheless sufficient for normal cell proliferation. The degron acts <it>in cis </it>and is reversed by N-terminal GFP-tagging. Cdk1 kinase activity is required to maintain Cdc5 levels during G2. This, Cdk1 inhibited, Cdc5 degradation is APC/C^Cdh1independent and requires new protein synthesis. Cdc5^T23Eis hyperactive, and reduces the levels of Cdc5 (<it>in trans</it>) and drastically reduces Clb2 levels.</p> <p>Conclusions</p> <p>Phosphorylation of Cdc5 by Cdk1 is required to maintain Cdc5 levels during G2. However, phosphorylation of T23 (probably by Cdk1) caps Cdc5 and other <it>CLB2 </it>cluster protein accumulation, preventing potential protein toxicity, which may arise from their overexpression or from APC/C^Cdh1inactivation.</p

Early neurophysiological stimulus processing during a performance-monitoring task differentiates women with bipolar disorder from women with ADHD

Adults with attention-deficit/hyperactivity disorder (ADHD) or bipolar disorder (BD) may display similar cognitive impairments and clinical symptoms, which might reflect shared mechanisms. Initial evidence indicates disorder-specific and overlapping neurophysiological alterations using event-related potentials (ERPs) in individuals with BD or ADHD during attentional tasks, but it is unknown whether impairments generalize across other processes and tasks. We conduct the first comparison between women with ADHD (n = 20), women with BD (n = 20) and control women (n = 20) on ERPs from a performance-monitoring flanker task. The BD group showed a significantly attenuated frontal ERP of conflict monitoring (N2) compared to the ADHD group across both low-conflict (congruent) and high-conflict (incongruent) task conditions, and compared to controls in the high-conflict condition. However, when controlling for an earlier attentional ERP (frontal N1), which was significantly reduced in participants with BD compared to participants with ADHD and controls, N2 group differences were no longer significant. These results indicate that ERP differences in conflict monitoring may be attributable to differences in earlier attentional processes. These findings identify neural differences in early attention between BD and ADHD which precede conflict monitoring processes, potentially pointing to distinct neural mechanisms implicated in the two disorders

Self-report of ADHD shows limited agreement with objective markers of persistence and remittance

Objective A controversial issue is whether self-report of symptoms and impairment is sufficient for diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adolescents and adults in the absence of other informants, such as parents. The present study investigated how well self-report is reflected by cognitive-neurophysiological and actigraph measures, which we have previously shown to discriminate between ADHD persisters, remitters and controls using parent-report (Cheung et al., 2015; Brit J Psychiat http://dx.doi.org/10.1192/bjp.bp.114.145185). Method Parent- and self-reported ADHD symptoms and impairment, together with cognitive, electroencephalogram (EEG) frequency, event-related potential (ERP) and actigraph measures were obtained from 108 adolescents and young adults with childhood ADHD and 167 controls. Results Participants reported lower levels of ADHD symptoms and impairments than parents (p < 0.05) and the ADHD persistence rate based on self-report was low at 44%, compared to the persistence rate of 79% previously reported based on parent-report. Regression analyses showed that the objective measures distinguished poorly between ADHD persistent and remittent groups based on self-report, in contrast to findings based on parent-report (Cheung et al., 2015), although the measures differentiated well between ADHD persisters and controls. Correlation analyses revealed that self-reported impairment significantly correlated with fewer of the objective measures, despite parent- and self-reported symptoms showing similar correlations with the measures. Conclusions The findings show that self-reported ADHD outcome is not as well reflected by cognitive-neurophysiological and movement correlates as we previously found for parent-reported ADHD

EEG Source Imaging Indices of Cognitive Control Show Associations with Dopamine System Genes

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness

Autism Is Associated With Interindividual Variations of Gray and White Matter Morphology

BACKGROUND Although many studies have explored atypicalities in gray matter (GM) and white matter (WM) morphology of autism, most of them relied on unimodal analyses that did not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish brain patterns of modalities that differentiate between individuals with and without autism and explore associations between these brain patterns and clinical measures in the autism group. METHODS We studied 183 individuals with autism and 157 nonautistic individuals (age range, 6-30 years) in a large, deeply phenotyped autism dataset (EU-AIMS LEAP [European Autism Interventions-A Multicentre Study for Developing New Medications Longitudinal European Autism Project]). Linked independent component analysis was used to link all participants' GM volume and WM diffusion tensor images, and group comparisons of modality shared variances were examined. Subsequently, we performed univariate and multivariate brain-behavior correlation analyses to separately explore the relationships between brain patterns and clinical profiles. RESULTS One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM volume in bilateral insula and frontal, precentral and postcentral, cingulate, and caudate areas and co-occurred with altered WM features in the superior longitudinal fasciculus. The brain-behavior correlation analyses showed a significant multivariate association primarily between brain patterns that involved variation of WM and symptoms of restricted and repetitive behavior in the autism group. CONCLUSIONS Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism and show that the complex clinical autism phenotype can be interpreted by brain covariation patterns that are spread across the brain involving both cortical and subcortical areas

Association of preterm birth with ADHD-like cognitive impairments and additional subtle impairments in attention and arousal malleability

BACKGROUND: Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce. METHODS: We directly compared preterm-born adolescents (n = 186) to term-born adolescents with ADHD (n = 69), and term-born controls (n = 135), aged 11-23, on cognitive-performance, event-related potential and skin conductance level (SCL) measures associated with attention and arousal. The measures are from baseline and fast-incentive conditions of a four-choice reaction time task, previously shown to discriminate between the individuals with ADHD and controls. We aimed to establish whether preterm-born adolescents show: (a) identical cognitive-neurophysiological impairments to term-born adolescents with ADHD (b) possible additional impairments, and whether (c) the observed impairments correlate with ADHD symptom scores. RESULTS: The preterm group, like the term-born ADHD group, showed increased mean reaction time (MRT) and reaction time variability (RTV) in the baseline condition, and attenuated contingent negative variation (CNV) amplitude (response preparation) in the fast-incentive condition. The preterm group, only, did not show significant within-group adjustments in P3 amplitude (attention allocation) and SCL (peripheral arousal). Dimensional analyses showed that ADHD symptoms scores correlated significantly with MRT, RTV and CNV amplitude only. CONCLUSIONS: We find impairments in cognition and brain function in preterm-born adolescents that are linked to increased ADHD symptoms, as well as further impairments, in lack of malleability in neurophysiological processes. Our findings indicate that such impairments extend at least to adolescence. Future studies should extend these investigations into adulthood

Impairments in error processing and their association with ADHD symptoms in individuals born preterm

<p>(<b>A</b>) Grand average response-locked event-related potentials (ERPs) of the error-related positivity (Pe) at the Cz electrode between 150 and 450 ms for the preterm group (represented by dotted lines), the ADHD group (attention-deficit/hyperactivity disorder represented by dashed lines) and the control group (shown in solid lines), and (<b>B</b>) topographic maps for each group.</p

Does Greater Low Frequency EEG Activity in Normal Immaturity and in Children with Epilepsy Arise in the Same Neuronal Network?

Greater low frequency power (<8Hz) in the electroencephalogram (EEG) at rest is normal in the immature developing brain of children when compared to adults. Children with epilepsy also have greater low frequency interictal resting EEG activity. Whether these power elevations reflect brain immaturity due to a developmental lag or the underlying epileptic pathophysiology is unclear. The present study addresses this question by analyzing spectral EEG topographies and sources for normally developing children and children with epilepsy. We first compared the resting EEG of healthy children to that of healthy adults to isolate effects related to normal brain immaturity. Next, we compared the EEG from 10 children with generalized cryptogenic epilepsy to the EEG of 24 healthy children to isolate effects related to epilepsy. Spectral analysis revealed that global low (delta: 1-3Hz, theta: 4-7Hz), medium (alpha: 8-12Hz) and high (beta: 13-25Hz) frequency EEG activity was greater in children without epilepsy compared to adults, and even further elevated for children with epilepsy. Topographical and tomographic EEG analyses showed that normal immaturity corresponded to greater delta and theta activity at fronto-central scalp and brain regions, respectively. In contrast, the epilepsy-related activity elevations were predominantly in the alpha band at parieto-occipital electrodes and brain regions, respectively. We conclude that lower frequency activity can be a sign of normal brain immaturity or brain pathology depending on the specific topography and frequency of the oscillating neuronal networ

Is association of preterm birth with cognitive-neurophysiological impairments and ADHD symptoms consistent with a causal inference or due to familial confounds?

BACKGROUND: Preterm birth is associated with an increased risk for cognitive-neurophysiological impairments and attention-deficit/hyperactivity disorder (ADHD). Whether the associations are due to the preterm birth insult per se, or due to other risk factors that characterise families with preterm-born children, is largely unknown. METHODS: We employed a within-sibling comparison design, using cognitive-performance and event-related potential (ERP) measures from 104 preterm-born adolescents and 104 of their term-born siblings. Analyses focused on ADHD symptoms and cognitive and ERP measures from a cued continuous performance test, an arrow flanker task and a reaction time task. RESULTS: Within-sibling analyses showed that preterm birth was significantly associated with increased ADHD symptoms (β = 0.32, p = 0.01, 95% CI 0.05 to 0.58) and specific cognitive-ERP impairments, such as IQ (β = -0.20, p = 0.02, 95% CI -0.40 to -0.01), preparation-vigilance measures and measures of error processing (ranging from β = 0.71, -0.35). There was a negligible within-sibling association between preterm birth with executive control measures of inhibition (NoGo-P3, β = -0.07, p = 0.45, 95% CI -0.33 to 0.15) or verbal working memory (digit span backward, β = -0.05, p = 0.63, 95% CI -0.30 to 0.18). CONCLUSIONS: Our results suggest that the relationship between preterm birth with ADHD symptoms and specific cognitive-neurophysiological impairments (IQ, preparation-vigilance and error processing) is independent of family-level risk and consistent with a causal inference. In contrast, our results suggest that previously observed associations between preterm birth with executive control processes of inhibition and working memory are instead linked to background characteristics of families with a preterm-born child rather than preterm birth insult per se. These findings suggest that interventions need to target both preterm-birth specific and family-level risk factors