Biology subjects

Silk, T. J.

Publications and source records attributed to Silk, T. J..

7 recordsLinked to original sources

bioRxiv2026

Genetic and environmental factors associated with DNA methylation across childhood and adolescence in individuals with and without attention-deficit/hyperactivity disorder

Background: Genetic and environmental factors both contribute risk to the development of childhood Attention-deficit/hyperactivity disorder (ADHD), yet the molecular mechanisms conferring this risk remain unclear. We investigated the genetic and environmental factors influencing DNA methylation (DNAm) at sites linked to ADHD symptom trajectories. Methods: We used two overlapping subsamples from a longitudinal paediatric cohort: (1) children with genetic and epigenetic data at first wave saliva sampling (Wave 3, n=113, 9.47-11.86 years) underwent methylation quantitative trait loci (meQTL) analysis; (2) children with environmental (Waves 1-3) and one or more waves of epigenetic data (n=126, 9.5-11.9 years) were analysed using LASSO regression to identify predictors of ADHD (Remitted ADHD/Persistent ADHD/Controls) and Wave 3 DNAm. In a subset with multiple DNAm timepoints (n=75), linear mixed models tested whether environmental predictors associated with longitudinal DNAm change, and whether ADHD moderated these associations. Analyses were conducted on 12 CpGs in which we previously identified change in DNAm according to the ADHD clinical outcome. Results: Nineteen meQTLs for 5 CpGs explained up to 40% of DNAm variance. We identified 17 environmental predictors of ADHD and wave 3 DNAm. Higher household income and school quality of life (QoL) were associated with reduced DNAm at cg02208776 (household) and cg11124426 (QoL) over time. Critically, higher income in Remitted ADHD showed greater DNAm declines than Controls, with opposite patterns in Persistent ADHD. Conclusion: DNAm patterns linked to ADHD outcomes were associated with genetic and environmental factors. Notably, household income and school functioning were associated with epigenetic change, with income effects varying by ADHD trajectories - characterising higher income as protective in remittent individuals.

genomics↗

bioRxiv2026

Diminished Stimulus-Evoked Activity During Sustained Attention Without Behavioural Cost in ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is often accompanied by attentional challenges, sleep difficulties and increased reports of daytime sleepiness, indicating potential links between attention and arousal mechanisms. Electroencephalographic (EEG) studies have shown that sleep-like wake slow wave (SW) activity during wakefulness, characterised by reduced cortical activity, corresponds with periods of inattention in both ADHD and neurotypical populations. However, it remains unclear whether group differences in waking SWs are consistent across different types of sustained attention tasks or may be context-dependent. The present study compared sustained attention performance and wake SW activity between adults with and without ADHD during a continuous visual target detection task. EEG data were collected while adults with (n = 52) and without ADHD (n = 49) completed a sustained attention paradigm. The task presented a continuous stream of rotating (anti-clockwise or clockwise) black-and-white checkerboard stimuli, and participants were required to detect infrequent targets that were marginally longer in duration than non-targets. Behavioural and neural measures (power spectra, steady-state visually evoked potentials (SSVEP), event-related potentials and SW density during wake) were analysed. No significant group differences were observed for task performance and wake SW activity. However, electrophysiological analyses revealed the ADHD group showed reduced P300, elevated beta-band power, and lower SSVEPs to target stimuli compared with the neurotypical group. These neural differences in the context of comparable performance suggest compensatory cortical recruitment in ADHD. The absence of SW differences further supports this, suggesting comparable performance and maintained arousal may reflect successful neural compensation in ADHD in this cognitive task. Significance StatementIndividuals with ADHD commonly experience attention differences, but emerging evidence suggests these difficulties may depend on task context. Using clinical diagnostic interviews, medication washout, and Bayesian statistics, we found strong evidence for comparable performance between ADHD and neurotypical adults on a sustained attention task. Notably, slow wave activity during wakefulness did not differ between groups, consistent with maintained arousal. Nevertheless, differences in brain activity, including altered target processing, increased cortical activation and reduced visual entrainment, suggested compensatory neural recruitment in ADHD. This context-dependent pattern has important theoretical and clinical implications: identifying task features that challenge or support performance in ADHD can reveal how individuals compensate neurally, and guide interventions that leverage task features to support attention in ADHD.

neuroscience↗

bioRxiv2025

Longitudinal DNA methylation dynamics distinguish Persistent and Remitted ADHD in childhood and adolescence

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with symptoms that remit or persist over time. Biological mechanisms underlying symptom change remain poorly understood, though epigenetic processes, like DNA methylation (DNAm), may serve as dynamic biomarkers of clinical outcomes. We examined change in DNAm in children and adolescents with and without ADHD, including differences between remitted and persistent ADHD. MethodsWe analyzed 219 saliva samples from 94 participants (aged 9.5-14.5 years) attending 2 to 3 waves of NICAP. DNAm was profiled using the Infinium MethylationEPIC BeadChip. Linear mixed models adjusted for age, sex, medication, batch and cell-proportion assessed longitudinal change. Comparisons included (1) all ADHD cases versus controls, (2) persistent or remitted ADHD versus controls, and (3) persistent versus remitted ADHD. False discovery rate correction controlled for multiple testing (FDR p<0.05). ResultsNo CpGs were statistically different between ADHD and controls, after correction. Compared to controls, the average DNAm at 5 sites was statistically different in persistent or remitted ADHD, and methylation of 3 additional CpGs differentially changed over time in persistent ADHD. Remitted differed from persistent ADHD at four CpGs, including cg21443143 (ZFAT), which showed a unique decline over time. Gene enrichment links findings to brain structures and function, though these did not survive multiple testing. ConclusionOur study identified several epigenetic differences between remitted and persistent ADHD outcomes from typical development, and from each other. Given the early stage of this research, our findings warrant further prospective epigenome-wide studies into these diagnostic trajectories.

genomics↗

bioRxiv2024

Limbic System White Matter in Children and Adolescents with ADHD: A Longitudinal Diffusion MRI Analysis

Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a disorder linked to atypical white matter development across large-scale brain networks. However, current research predominantly focuses on cortical networks, leaving the developmental trajectories of many subcortical networks, including the limbic system, largely unexplored. The limbic system is crucial for emotion and cognition, making it a key area of interest in ADHD research. This study employed multi-shell high angular resolution diffusion magnetic resonance imaging to map the development of limbic system white matter in individuals with ADHD (n = 72) and controls (n = 97) across three time points between ages 9 and 14. Diffusion kurtosis imaging and graph theory metrics were used to characterize limbic system white matter, alongside assessments of emotional regulation and ADHD symptom severity. Compared to controls, individuals with ADHD exhibited significantly lower microstructural organization, particularly in kurtosis anisotropy, within the bilateral cingulum bundle from childhood to adolescence. Brain-behavior analyses further revealed that higher ADHD symptom severity was associated with a lower number of limbic system white matter connections, notably decreased routing efficiency and network density. These findings offer novel insights into the role of disrupted limbic system white matter in ADHD pathophysiology, broadening our understanding of the disorders neural mechanisms and opening promising avenues for future exploration of subcortical brain networks.

neuroscience↗

bioRxiv2023

Corticolimbic connectivity mediates the relationship between pubertal timing and mental health problems

BackgroundUndergoing puberty ahead of peers ("earlier pubertal timing") is an important risk factor for mental health problems during early adolescence. The current study examined pathways between pubertal timing and mental health via connectivity of neural systems implicated in emotional reactivity and regulation (specifically corticolimbic connections) in 9- to 14-year-olds. MethodResearch questions were examined in the Adolescent Brain Cognitive Development (ABCD) Study, a large population representative sample in the United States. Linear mixed models examined associations between pubertal timing and resting-state corticolimbic connectivity. Significant connections were examined as potential mediators of the relationship between pubertal timing and mental health (withdrawn depressed and rule-breaking delinquency) problems. Exploratory analyses interrogated whether the family environment moderated neural risk patterns in those undergoing puberty earlier than their peers. ResultsEarlier pubertal timing was related to decreased connectivity between limbic structures (bilateral amygdala and right hippocampus) and the cingulo-opercular network (CON), as well as between the left hippocampus and ventral attention network (VAN). Corticolimbic connections also mediated the relationship between earlier pubertal timing and increased withdrawn depressed problems (but not rule-breaking delinquency). Finally, parental acceptance buffered against limbic-CON connectivity patterns that were implicated in withdrawn depressed problems in those undergoing puberty earlier than their peers. ConclusionFindings highlight the role of decreased corticolimbic connectivity in mediating pathways between earlier pubertal timing and withdrawn depressed problems, and we present preliminary evidence that the family environment may buffer against these neural risk patterns during early adolescence.

neuroscience↗

bioRxiv2020

Childhood conduct problems are associated with reduced white matter fibre density and morphology

Childhood conduct problems are an important public health issue as these children are at-risk of adverse outcomes. Studies using diffusion Magnetic Resonance Imaging (dMRI) have found that conduct problems in adults are characterised by abnormal white-matter microstructure within a range of white matter pathways underpinning socio-emotional processing, while evidence within children and adolescents has been less conclusive based on non-specific diffusion tensor imaging metrics. Fixel-based analysis (FBA) provides measures of fibre density and morphology that are more sensitive to developmental changes in white matter microstructure. The current study used FBA to investigate whether childhood conduct problems were related both cross-sectionally and longitudinally to microstructural alterations within the fornix, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and the uncinate fasciculus (UF). dMRI data was obtained for 130 children across two time-points in a community sample with high levels of externalising difficulties (age: time-point 1 = 9.47 - 11.86 years, time-point 2 = 10.67 -13.45 years). Conduct problems were indexed at each time-point using the Conduct Problems subscale of the parent-informant Strengths and Difficulties Questionnaire (SDQ). Conduct problems were related to lower fibre density in the fornix at both time-points, and in the ILF at time-point 2. We also observed lower fibre cross-section in the UF at time-point 1. The change in conduct problems did not predict longitudinal changes in white-matter microstructure across time-points. The current study suggests that childhood conduct problems are related to reduced fibre-specific microstructure within white matter fibre pathways implicated in socio-emotional functioning.

neuroscience↗

bioRxiv2018

Development of white matter fibre density and morphology over childhood: a longitudinal fixel-based analysis

PurposeWhite matter fibre development in childhood involves dynamic changes to microstructural organisation driven by increasing axon diameter, density, and myelination. However, there is a lack of longitudinal studies that have quantified advanced diffusion metrics to identify regions of accelerated fibre maturation, particularly across the early pubertal period. We applied a novel longitudinal fixel-based analysis (FBA) framework, in order to estimate microscopic and macroscopic white matter changes over time.\n\nMethodsDiffusion-weighted imaging (DWI) data were acquired for 59 typically developing children (27 female) aged 9 - 13 years at two time-points approximately 16 months apart (time-point 1: 10.4 {+/-} 0.4 years, time-point 2: 11.7 {+/-} 0.5 years). Whole brain FBA was performed using the connectivity-based fixel enhancement method, to assess longitudinal changes in fibre microscopic density and macroscopic morphological measures, and how these changes are affected by sex, pubertal stage, and pubertal progression. Follow-up analyses were performed in sub-regions of the corpus callosum to confirm the main findings using a Bayesian repeated measures approach.\n\nResultsThere was a statistically significant increase in fibre density over time localised to medial and posterior commissural and association fibres, including the forceps major and bilateral superior longitudinal fasciculus. Increases in fibre cross-section were substantially more widespread. The rate of fibre development was not associated with age or sex. In addition, there was no significant relationship between pubertal stage or progression and longitudinal fibre development over time. Follow-up Bayesian analyses were performed to confirm the findings, which supported the null effect of the longitudinal pubertal comparison.\n\nConclusionUsing a novel longitudinal fixel-based analysis framework, we demonstrate that white matter fibre density and fibre cross-section increased within a 16-month scan rescan period in specific regions. The observed increases might reflect increasing axonal diameter or axon count. Pubertal stage or progression did not influence the rate of fibre development in the early stages of puberty. Future work should focus on quantifying these measures across a wider age range to capture the full spectrum of fibre development across the pubertal period.

neuroscience↗