Biology subjects

Bellgrove, M. A.

Publications and source records attributed to Bellgrove, M. A..

25 records · Page 2Linked to original sources

bioRxiv2022

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample

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 sample 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 sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.

neuroscience↗

bioRxiv2022

An Efficient CRISPR-Cas9 DNA Editing Methodology Applicable for iPSC Disease Modelling

The capability to generate induced pluripotent stem cell (iPSC) lines, in tandem with CRISPR-Cas9 DNA editing, offers great promise to understand the underlying genetic mechanisms of human disease. The low efficiency of available methods for homogeneous expansion of singularised CRISPR-transfected iPSCs necessitates the coculture of transfected cells in mixed populations and/or on feeder layers. Consequently, edited cells must be purified using labour-intensive screening and selection, culminating in inefficient editing. Here, we provide a xeno-free method for single-cell cloning of CRISPRed iPSCs achieving a clonal survival of up to 70% within 7-10 days. This was accomplished through improved viability of the transfected cells, paralleled with provision of enriched environment for the robust establishment and proliferation of singularised iPSC clones. Enhanced cell survival was accompanied by a high transfection efficiency exceeding 97%, and editing efficiencies of 50-65% for NHEJ and 10% for HDR, indicative of the methods utility in stem cell disease modelling.

genetics↗

bioRxiv2022

Pharmacological manipulations of physiological arousal and sleep-like slow waves modulate sustained attention

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 behavioural consequences of sustained attention failures. In a double-blind, randomised-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 whilst participants completed a visual task requiring sustained attention. Methylphenidate, which increases wake-promoting dopamine and noradrenaline across cortical and subcortical areas, improved behavioural 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 to a classical marker of arousal such as alpha 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 StatementWe investigated whether the modulation of attention and arousal could not only share the same neuromodulatory pathways but also rely on similar neuronal mechanisms; for example, the intrusion of sleep-like activity within wakefulness. To do so, we pharmacologically manipulated noradrenaline, dopamine, and serotonin in a four-arm, randomised, placebo-controlled trial and examined the consequences on behavioural and EEG indices of attention and arousal. We showed that sleep-like slow waves can predict opposite behavioural 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.

neuroscience↗

bioRxiv2021

Age-related response speed deficits arise from specific impairments in sensory evidence accumulation rate

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 individual accumulates sensory evidence was a critical determinant of the extent to which RS was preserved in older adults. 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 individuals 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 STATEMENTResponse speed in older adults is closely linked with trajectories of cognitive ageing. Here, by recording brain activity while individuals 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.

neuroscience↗

bioRxiv2020

The efficacy of different preprocessing steps in reducing motion-related confounds in diffusion MRI connectomics

Head motion is a major confounding factor in neuroimaging studies. While numerous studies have investigated how motion impacts estimates of functional connectivity, the effects of motion on structural connectivity measured using diffusion MRI have not received the same level of attention, despite the fact that, like functional MRI, diffusion MRI relies on elaborate preprocessing pipelines that require multiple choices at each step. Here, we report a comprehensive analysis of how these choices influence motion-related contamination of structural connectivity estimates. Using a healthy adult sample (N = 252), we evaluated 240 different preprocessing pipelines, devised using plausible combinations of different choices related to explicit head motion correction, tractography propagation algorithms, track seeding methods, track termination constraints, quantitative metrics derived for each connectome edge, and parcellations. We found that an approach to motion correction that includes outlier replacement and within-slice volume correction led to a dramatic reduction in cross-subject correlations between head motion and structural connectivity strength, and that motion contamination is more severe when quantifying connectivity strength using mean tract fractional anisotropy rather than streamline count. We also show that the choice of preprocessing strategy can significantly influence subsequent inferences about network organization, with the location of network hubs varying considerably depending on the specific preprocessing steps applied. Our findings indicate that the impact of motion on structural connectivity can be successfully mitigated using recent motion-correction algorithms that include outlier replacement and within-slice motion correction. HighlightsO_LIWe assess how motion affects structural connectivity in 240 preprocessing pipelines C_LIO_LIMotion contamination of structural connectivity depends on preprocessing choices C_LIO_LIAdvanced motion correction tools reduce motion confounds C_LIO_LIFA edge weighting is more susceptible to motion effects than streamline count C_LI

neuroscience↗

bioRxiv2018

Behavioural and neural signatures of perceptual evidence accumulation are modulated by pupil-linked arousal

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.

neuroscience↗

bioRxiv2018

Generation of four iPSC lines from peripheral blood mononuclear cells (PBMCs) of an Attention Deficit Hyperactivity Disorder (ADHD) individual and a healthy sibling in an Australia-Caucasian family

Peripheral blood mononuclear cells were donated by a male teenager with clinically diagnosed Attention Deficit Hyperactivity Disorder 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 OCT, SOX2, KLF4, and c-MYC. All four iPSC lines displayed pluripotent cell morphology, pluripotency-associated factors at protein level, alkaline phosphatase enzymatic activity, male karyotype of 46, XY, and in vitro differentiation capacity into all the three germ layers and negative for Mycoplasma.

neuroscience↗