Dynamic Configuration of Large-Scale Cortical Networks: A Useful Framework for Clarifying the Heterogeneity Found in Attention-Deficit/Hyperactivity Disorder

The heterogeneity of attention-deficit/hyperactivity disorder(ADHD) traits (inattention vs. hyperactivity/impulsivity) complicates diagnosis and intervention. Identifying how the configuration of large-scale functional brain networks during cognitive processing correlate with this heterogeneity could help us understand the neural mechanisms altered across ADHD presentations. Here, we recorded high-density EEG while 62 non-clinical participants (ages 18-24; 32 male) underwent an inhibitory control task (Go/No-Go). Functional EEG networks were created using sensors as nodes and across-trial phase-lag index values as edges. Using cross-validated LASSO regression, we examined whether graph-theory metrics applied to both static networks (averaged across time-windows: -500–0ms, 0–500ms) and dynamic networks (temporally layered with 2ms intervals), were associated with hyperactive/impulsive and inattentive traits. Network configuration during response execution/inhibition was associated with hyperactive/impulsive (mean R2across test sets = .20, SE = .02), but not inattentive traits. Post-stimulus results at higher frequencies (Beta, 14-29Hz; Gamma, 30-90Hz) showed the strongest association with hyperactive/impulsive traits, and predominantly reflected less burst-like integration between modules in oscillatory beta networks during execution, and increased integration/small-worldness in oscillatory gamma networks during inhibition. We interpret the beta network results as reflecting weaker integration between specialized pre-frontal and motor systems during motor response preparation, and the gamma results as reflecting a compensatory mechanism used to integrate processing between less functionally specialized networks. This research demonstrates that the neural network mechanisms underlying response execution/inhibition might be associated with hyperactive/impulsive traits, and that dynamic, task-related changes in EEG functional networks may be useful in disentangling ADHD heterogeneity

Dynamic functional brain network connectivity during pseudoword processing relates to children’s reading skill

Learning to read requires children to link print (orthography) with its corresponding speech sounds (phonology). Yet, most EEG studies of reading development focus on emerging functional specialization (e.g., developing increasingly refined orthographic representations), rather than directly measuring the functional connectivity that links orthography and phonology in real time. In this proof-of-concept study we relate children's reading skill to both orthographic specialization for print (via the N170, also called the N1, event related potential, ERP) and orthographic-phonological integration (via dynamic/event-related EEG phase synchronization – an index of functional brain network connectivity). Typically developing English speaking children (n = 24; 4–14 years) and control adults (n = 20; 18–35 years) viewed pseudowords, consonants and unfamiliar false fonts during a 1-back memory task while 64-channel EEG was recorded. Orthographic specialization (larger N170 for pseudowords vs. false fonts) became more left-lateralized with age, but not with reading skill. Conversely, children's reading skill correlated with functional brain network connectivity during pseudoword processing that requires orthography-phonology linking. This was seen during two periods of simultaneous low frequency synchronization/high frequency desynchronization of posterior-occipital brain network activity. Specifically, in stronger readers, left posterior-occipital activity showed more delta (1–3Hz) synchronization around 300–500 ms (simultaneous with gamma 30–80 Hz desynchronization) and more gamma desynchronization around 600–1000 ms (simultaneous with theta 3–7Hz synchronization) during pseudoword vs. false font processing. These effects were significant even when controlling for age (moderate – large effect sizes). Dynamic functional brain network connectivity measures the brain's real-time sound-print linking. It may offer an under-explored, yet sensitive, index of the neural plasticity associated with reading development. Reading requires us to link visual print with speech sound processing. Yet, most EEG reading research explores functional specialization not integration. While children's age relates to ERPs (N170) associated with print specialization. Children's reading skill relates to real-time functional brain network connectivity. EEG phase synchrony = sensitive index of functional integration during reading

Transcriptomic signatures across human tissues identify functional rare genetic variation

© 2020 American Association for the Advancement of Science. All rights reserved. INTRODUCTION: The human genome contains tens of thousands of rare (minor allele frequency 800 genomes matched with transcriptomes across 49 tissues, we were able to study RVs that underlie extreme changes in the transcriptome. To capture the diversity of these extreme changes, we developed and integrated approaches to identify expression, allele-specific expression, and alternative splicing outliers, and characterized the RV landscape underlying each outlier signal. We demonstrate that personal genome interpretation and RV discovery is enhanced by using these signals. This approach provides a new means to integrate a richer set of functional RVs into models of genetic burden, improve disease gene identification, and enable the delivery of precision genomics

Resting-state EEG dynamics help explain differences in response control in ADHD: Insight into electrophysiological mechanisms and sex differences.

Reductions in response control (greater reaction time variability and commission error rate) are consistently observed in those diagnosed with attention-deficit/hyperactivity disorder (ADHD). Previous research suggests these reductions arise from a dysregulation of large-scale cortical networks. Here, we extended our understanding of this cortical-network/response-control pathway important to the neurobiology of ADHD. First, we assessed how dynamic changes in three resting-state EEG network properties thought to be relevant to ADHD (phase-synchronization, modularity, oscillatory power) related with response control during a simple perceptual decision-making task in 112 children/adolescents (aged 8-16) with and without ADHD. Second, we tested whether these associations differed in males and females who were matched in age, ADHD-status and ADHD- subtype. We found that changes in oscillatory power (as opposed to phase-synchrony and modularity) are most related with response control, and that this relationship is stronger in ADHD compared to controls. Specifically, a tendency to dwell in an electrophysiological state characterized by high alpha/beta power (8-12/13-30Hz) and low delta/theta power (1-3/4-7Hz) supported response control, particularly in those with ADHD. Time in this state might reflect an increased initiation of alpha-suppression mechanisms, recruited by those with ADHD to suppress processing unfavourable to response control. We also found marginally significant evidence that this relationship is stronger in males compared to females, suggesting a distinct etiology for response control in the female presentation of ADHD

Sex differences in the correlation between HMM-power dwell-times and RT-variability.

Scatterplots showing bivariate correlations between dwell-times and RT-variability, for both males and females.</p

Descriptive statistics.

Reductions in response control (greater reaction time variability and commission error rate) are consistently observed in those diagnosed with attention-deficit/hyperactivity disorder (ADHD). Previous research suggests these reductions arise from a dysregulation of large-scale cortical networks. Here, we extended our understanding of this cortical-network/response-control pathway important to the neurobiology of ADHD. First, we assessed how dynamic changes in three resting-state EEG network properties thought to be relevant to ADHD (phase-synchronization, modularity, oscillatory power) related with response control during a simple perceptual decision-making task in 112 children/adolescents (aged 8–16) with and without ADHD. Second, we tested whether these associations differed in males and females who were matched in age, ADHD-status and ADHD- subtype. We found that changes in oscillatory power (as opposed to phase-synchrony and modularity) are most related with response control, and that this relationship is stronger in ADHD compared to controls. Specifically, a tendency to dwell in an electrophysiological state characterized by high alpha/beta power (8-12/13-30Hz) and low delta/theta power (1-3/4-7Hz) supported response control, particularly in those with ADHD. Time in this state might reflect an increased initiation of alpha-suppression mechanisms, recruited by those with ADHD to suppress processing unfavourable to response control. We also found marginally significant evidence that this relationship is stronger in males compared to females, suggesting a distinct etiology for response control in the female presentation of ADHD.</div

Correlations between HMM-power dwell-times and RT-variability.

Scatterplots showing bivariate correlations between dwell-times and RT-variability.</p

Cortex-wide dynamics identified by HMM-power model.

(A) Portion of participants in each state at a given time-point throughout the resting state paradigm. (B) μ coefficients from the HMM-power model, showing the specific electrophysiological profile of each state.</p

Correlations between dwell-times and attention problems/age.

Scatterplots showing bivariate correlations between dwell-times and attention problems/age.</p

Validation of HMM-power models across a variable number of states.

Validation of HMM-power models across a variable number of states.</p