Biology subjects

Muir, A. M.

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

7 recordsLinked to original sources

bioRxiv2026

De novo missense variants in TRIM28 identified in individuals with neurodevelopmental delay show features of transposable element activation

TRIM28 is an epigenetic co-repressor protein that silences transposable elements (TEs). Although loss-of-function studies in mice led to neurodevelopmental defects, a functional link between TRIM28 and human neurodevelopment has yet to be established. In this study, we describe two patients with neurodevelopmental delay who carry de novo TRIM28 missense variants. Using CRISPR-edited induced pluripotent stem cell lines and differentiated neural organoids, we demonstrate that these variants result in the loss of the histone mark H3K9me3 over TEs. This releases the regulatory potential of TEs resulting in altered expression of nearby genes. These findings could be replicated using CRISPRi-based TRIM28 silencing, which suggests that the two variants result in a loss of function. Our results highlight the critical role of TRIM28 in regulating TEs during human brain development, establishing a link between TRIM28 variants and neurodevelopmental delay. One Sentence SummaryTRIM28 variants disrupt epigenetic control of transposable elements in the developing human brain, linking them to neurodevelopmental delay.

neuroscience↗

bioRxiv2021

Dissociating the effect of reward uncertainty and timing uncertainty on neural indices of reward prediction errors: A reward positivity (RewP) event-related potential (ERP) study

Accurate reward predictions include forecasting both what a reward will be and when a reward will occur. We tested how variations in the certainty of reward outcome and certainty in timing of feedback presentation modulate neural indices of reward prediction errors using the reward positivity (RewP) component of the scalp-recorded brain event-related potential (ERP). In a within-subjects design, seventy-three healthy individuals completed two versions of a cued doors task; one cued the probability of a reward outcome while the other cued the probability of a delay before feedback. Replicating previous results, RewP amplitude was larger for uncertain feedback compared to certain feedback. Additionally, RewP amplitude was differentially associated with uncertainty of presence/absence of reward, but not uncertainty of feedback timing. Findings suggest a dissociation in that RewP amplitude is modulated by reward prediction certainty but is less affected by certainty surrounding timing of feedback.

neuroscience↗

bioRxiv2020

The impact of exercise intensity on neurophysiological indices of food-related inhibitory control and cognitive control: A randomized crossover event-related potential (ERP) study

Food-related inhibitory control, the ability to withhold a dominant response towards highly palatable foods, influences dietary decisions. Food-related inhibitory control abilities may increase following a bout of aerobic exercise; however, the impact of exercise intensity on both food-related inhibitory control and broader cognitive control processes is currently unclear. We used a high-powered, within-subjects, crossover design to test how relative intensity of aerobic exercise influenced behavioral (response time, accuracy) and neural (N2 and P3 components of the scalp-recorded event-related potential [ERP]) measures of food-related inhibitory and cognitive control. Two hundred and thirteen participants completed three separate conditions separated by approximately one week in randomized order: two exercise conditions (35% [moderate] or 70% [vigorous] of VO2max) and seated rest. Directly following exercise or rest, participants completed a food-based go/no-go task and a flanker task while electroencephalogram data were recorded. Linear mixed models showed generally faster response times (RT) and improved accuracy following vigorous exercise compared to rest, but not moderate-intensity exercise; RTs and accuracy did not differ between moderate intensity exercise and rest conditions. N2 and P3 amplitudes were larger following vigorous exercise for the food-based go/no-go task compared to rest and moderate intensity exercise. There were no differences between exercise conditions for N2 amplitude during the flanker task; however, P3 amplitude was more positive following vigorous compared to rest, but not moderate exercise. Gender did not moderate exercise outcomes. Results suggest improved and more efficient food- related recruitment of later inhibitory control and cognitive control processes following vigorous exercise.

neuroscience↗

bioRxiv2020

Exogenous sex hormone effects on brain microstructure in women: a diffusion MRI study in the UK Biobank

Changes in estrogen levels in women have been associated with increased risk for age-related neurodegenerative diseases, including Alzheimers disease, but the impact of exogenous estrogen exposure on the brain is poorly understood. Oral contraceptives (OC) and hormone therapy (HT) and are both common sources of exogenous estrogen for women in reproductive and post-menopausal years, respectively. Here we examined the association of exogenous sex hormone exposure with the brains white matter (WM) aging trajectories in postmenopausal women using and not using OC and HT (HT users: n=3,033, non-users n=5,093; OC users: n=6,964; non-users n=1,156), while also investigating multiple dMRI models. Cross-sectional brain dMRI data was analyzed from the UK Biobank using conventional diffusion tensor imaging (DTI), the tensor distribution function (TDF), and neurite orientation dispersion and density imaging (NODDI). Mean skeletonized diffusivity measures were extracted across the whole brain, and fractional polynomial regressions were used to characterize age-related trajectories for WM microstructural measures. Advanced dMRI model NODDI revealed a steeper WM aging trajectory in HT users relative to non-users, and for those using unopposed estrogens relative to combined estrogens treatment. By contrast, no interaction was detected between OC status and age effects on the diffusivity measures we examined. Exogenous sex hormone exposure may negatively impact WM microstructure aging in postmenopausal women. We also present normative reference curves for white matter microarchitectural parameters in women, to help identify individuals with microstructural anomalies.

neuroscience↗

bioRxiv2020

Advanced diffusion-weighted MRI metrics detect sex differences in aging among 15,000 adults in the UK Biobank

A comprehensive characterization of the brains white matter is critical for improving our understanding of healthy and diseased aging. Here we used diffusion-weighted magnetic resonance imaging (dMRI) to estimate age and sex effects on white matter microstructure in a cross-sectional sample of 15,628 adults aged 45-80 years old (47.6% male, 52.4% female). Microstructure was assessed using the following four models: a conventional single-shell model, diffusion tensor imaging (DTI); a more advanced single-shell model, the tensor distribution function (TDF); an advanced multi-shell model, neurite orientation dispersion and density imaging (NODDI); and another advanced multi-shell model, mean apparent propagator MRI (MAPMRI). Age was modeled using a data-driven statistical approach, and normative centile curves were created to provide sex-stratified white matter reference charts. Participant age and sex substantially impacted many aspects of white matter microstructure across the brain, with the advanced dMRI models TDF and NODDI detecting such effects the most sensitively. These findings and the normative reference curves provide an important foundation for the study of healthy and diseased brain aging.

neuroscience↗

bioRxiv2019

Dimensions of anxiety and depression and neurophysiological indicators of error-monitoring: Relationship with delta and theta oscillatory power and error-related negativity amplitude

Error-monitoring processes may be affected by transdiagnostic dimensions of psychopathology symptoms including trait anxiety, worry, and severity of depressive symptoms. We tested the relationship between continuous measures of anxiety and depressive symptomology and neural correlates of error-monitoring as measured by time-frequency domain delta and theta oscillatory power and time domain error-related negativity (ERN) amplitude extracted from the electroencephalogram (EEG). Secondary analyses tested for diagnostic group differences in error-related neural responses in individuals with generalized anxiety disorder (GAD), major depressive disorder (MDD), and comorbid psychiatric disorders. 178 participants (104 female, M[SD]age = 21.7[4.6]) with a wide range of psychopathology symptoms completed a modified version of the Eriksen flanker task and symptom questionnaires. Residualized difference values between correct and error trials for delta/theta power and error/correct ERN amplitude were dependent variables. Linear regression analyses adjusted for age and sex showed nonsignificant associations of symptom dimension measures with error-related residualized delta/theta power or residualized ERN amplitude. Subset analyses on those with confirmed psychopathology diagnoses also did not predict residualized error-related delta/theta power nor ERN amplitude. Exploratory analyses with only error trial delta/theta power and ERN amplitude also revealed nonsignificant relationships. Taken in the context of previous literature, results suggest a heterogeneous relationship between depressive and anxiety symptom dimensions and neurophysiological indices of error-monitoring. Impact StatementIn line with the RDoC framework, we tested the relationship between anxiety and depressive symptom dimensions and neural indices of error-processing (delta and theta power, error-related negativity ERP amplitude) in 178 participants with a range of pathology symptoms. A non-significant relationship emerged between neural and symptom measures suggesting anxiety and depressive symptomology have a nuanced relationship with error-monitoring in a large sample across a range of anxiety and depression symptoms.

neuroscience↗

bioRxiv2019

Differentiating electrophysiological indices of internal and external performance monitoring: Relationship with perfectionism and locus of control

The impact of individual differences on performance monitoring and psychopathology is a question of active debate. Personality traits associated with psychopathology may be related to poor internal performance monitoring (as measured by the error-related negativity [ERN]) but intact external performance monitoring (as measured by the reward positivity [RewP]), suggesting that there are underlying neural differences between internal and external performance monitoring processes. We tested the relationships between individual difference measures of perfectionism, locus of control, and ERN, Pe, and RewP component difference amplitude in a healthy undergraduate sample. A total of 128 participants (69 female, M(SD)age= 20.6(2.0) years) completed two tasks: a modified version of the Eriksen Flanker and a doors gambling task along with the Frost Multidimensional Perfectionism scale, the Rotter Locus of Control scale, and the Levenson Multidimensional Locus of Control scale to quantify perfectionism and locus of control traits, respectively. Linear regressions adjusting for age and gender showed that neither {Delta}ERN nor {Delta}RewP amplitude were significantly moderated by perfectionism or locus of control scores. Findings suggest that, in psychiatrically-healthy individuals, there is not a strong link between perfectionism, locus of control, and ERN or RewP amplitude. Future research on individual difference measures in people with psychopathology may provide further insight into how these personality traits affect performance monitoring.

neuroscience↗