Biology subjects

Brown, C. A.

Publications and source records attributed to Brown, C. A..

15 recordsLinked to original sources

bioRxiv2026

Intelligible distracting speech disrupts early auditory attention

Intelligible speech disrupts selective auditory attention more than an unintelligible stream. However, low-level acoustic features of intelligible speech are relatively similar to target speech, confounding results. While controlling acoustic similarity and limiting energetic masking, we examined how masker intelligibility affects behavior and electroencephalography (EEG). Normal hearing listeners detected color words within a target stream of randomly timed words while ignoring an ongoing masker. Maskers were either spoken by the same or a different talker and comprised either isochronous sequences of intelligible words or temporally scrambled versions. Scrambled maskers either lacked broadband energy changes over time (Experiment 1) or were amplitude modulated to have the same energy profiles as intelligible, isochronous maskers (Experiment 2). In both experiments, scrambled maskers yielded better performance than intelligible maskers. For intelligible maskers, performance was better for different compared to identical talkers. EEG responses paralleled behavior: target-evoked onset responses were larger for scrambled than for intelligible maskers, particularly for identical talkers. Later target recognition responses were larger for color than other target words but unaffected by masker type or talker. Even when low-level acoustic features were carefully matched, intelligible maskers impaired auditory attention and reduced target-evoked neural responses more than scrambled maskers, implicating early sensory filtering.

neuroscience↗

bioRxiv2025

Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neuropathology patterns

Structured AbstractO_ST_ABSIntroductionC_ST_ABSThe impact of different neuropathologies on deep brain structures remains to be understood. We examine subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, -synuclein and TDP-43. MethodsWe acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimers disease (AD), Lewy body disease (LBD), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP) and FTLD-Tau. ResultsLBD had the least subcortical, limbic and cortical atrophy compared to AD, FTLD-TDP and FTLD-Tau. In donors with both AD and LBD pathologies, primary LBD was associated with less atrophy than primary AD. While AD had cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical while FTLD-Tau had cortico-subcortical and cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with p-tau burden, neuron loss and gliosis. In LBD, thalamic -synuclein severity was associated with subcortical/limbic volumes. DiscussionPostmortem neuroimaging reveals disease- and region-specific structure-pathology relationships.

neuroscience↗

bioRxiv2025

Distinct talkers combat catastrophic failures of spatial attention due to interruption

Task-irrelevant features can impact formation of auditory objects and influence the effectiveness of selective attention, including the buildup of attention over time. Using a previously established paradigm exploring the effects of random interruptions on spatial selective attention, this study explores how the task-irrelevant feature of talker identity impacts the buildup of spatial attention and whether it alters the impact of interruptions. Participants performed a sequence recall task in which participants were presented with two competing syllable sequences coming from different spatial directions and were asked to report the syllable sequence coming from the target direction. On half of the trials, an unpredictable, novel interrupting sound occurred, disrupting attentional focus. Two experiments explored how talker influenced performance, specifically, whether 1) making the two streams come from different talkers facilitates task performance and reduces the impact of interruption compared to when the streams are spoken by the same talker, and 2) talker discontinuity interferes with attention buildup and harms syllable recall performance compared to when the talker is the same from one syllable to the next. Our results showed that distinct talker features, though task-irrelevant in this spatial task, significantly improved syllable recall performance and reduced the impact of interrupters. Further, irrelevant talker discontinuities damaged attention buildup and reduced syllable recall performance.

neuroscience↗

bioRxiv2025

Interaural time and level differences contribute differently to source segregation and spatial selection

Interaural time and level differences are crucial in sound localization, yet their contributions to sound source segregation and spatial selection remain underspecified. Here, participants completed a spatial auditory selective attention task while we measured hemodynamic activity in the prefrontal cortex and superior temporal gyrus using functional near-infrared spectroscopy. Participants listened to a target sound stream and a simultaneous spatially separated speech stream or white noise masker. Sound streams were spatialized with either 50 s interaural time differences (ITDs), 500 s ITDs, naturally occurring interaural level differences (ILDs) from a non-individualized head-related transfer function (HRTF), or broadband 10 dB ILDs. Behavioral results revealed a stronger effect of spatial cues when the masker was speech. Error patterns differed in the two difficult conditions, small ITDs and natural ILDs: Small ITDs produced lower hit rates, while naturally occurring ILDs produced higher false alarm rates. Small ITDs led to greater activity in prefrontal cortex and activity in superior temporal gyrus that was lateralized, greater in the hemisphere contralateral to attentional focus, consistent with previous reports. These results suggest that natural ILDs alone support source segregation even if they are insufficient to cause large shifts in perceived lateralization, explaining high false alarm rates (confusions between target and distractor words). In contrast, small ITDs alone may be insufficient to segregate competing sources, leading to low hit and false alarm rates. Together, these results reveal differences in how ITDs and ILDs contribute to auditory scene analysis and spatial attention.

neuroscience↗

bioRxiv2025

PERINATAL ORGANOPHOSPHATE FLAME RETARDANT EXPOSURE ALTERS ADULT HPA AXIS FUNCTION AND AVOIDANCE BEHAVIOR IN A SEX-SPECIFIC MANNER IN MICE

Organophosphate flame retardants (OPFRs) are ubiquitous flame-retardant additives with endocrine-disrupting properties. Despite increasing evidence that OPFRs impact neurodevelopment, their effects on the neuroendocrine stress response remain poorly understood. To examine their long-term impact on stress regulation, we treated pregnant C57Bl/6J dams to a mixture of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP; 1 mg/kg each) from gestational day (GD) 7 through postnatal day (PND) 14. Adult offspring (8-9 weeks of age) were then challenged with acute stressors, including 1 h restraint or a 6-day acute variable stress (AVS) paradigm. Perinatal OPFR exposure produced persistent, sex-specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis and stress-related neurocircuitry. Following 1 h restraint, OPFR-treated females showed heightened serum corticosterone. In addition, gene expression analysis revealed sex-dependent disruptions in key stress-regulatory pathways after OPFR treatment and 1 h restraint in the hypothalamus (Crhr1, Crhr2, Ptpn5) and pituitary (Crhr1, Pomc, Nr3c1). Females demonstrated more differences in adrenal gene expression related to steroidogenesis (Mc2r, Cyp11b2) and catecholamine biosynthesis (Dbh, Pnmt), with OPFR-treated groups having blunted responses. OPFR AVS females displayed reduced corticosterone and Crh mRNA in the hypothalamus, and downregulated Pacap/Pac1r expression in the bed nucleus of the stria terminalis (BNST), accompanied by increased behavioral avoidance and immobility. In males, OPFR exposure led to increased BNST Pacap and Pac1r, expression, along with hyperactivity and avoidance behaviors. Together, these findings demonstrate that early-life OPFR exposure induces lasting, sex-specific dysregulation of the HPA axis and associated stress circuits, highlighting OPFRs as developmental neuroendocrine disruptors with implications for mood and stress-related disorders.

neuroscience↗

bioRxiv2025

A GCN1-independent activator of the kinase GCN2

Mutations of EIF2AK4, which encodes the eIF2 kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP-pocket binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP-pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.

cell biology↗

bioRxiv2024

Magnified interaural level differences enhance spatial release from masking in bilateral cochlear implant users

Bilateral cochlear implant (BiCI) usage makes binaural benefits a possibility for implant users. Yet for BiCI users, limited access to interaural time difference (ITD) cues and reduced saliency of interaural level difference (ILD) cues restricts perceptual benefits of spatially separating a target from masker sounds. The present study explored whether magnifying ILD cues improves intelligibility of masked speech for BiCI listeners in a "symmetrical-masker" configuration, which ensures that neither ear benefits from a long-term positive target-to-masker ratio (TMR) due to naturally occurring ILD cues. ILD magnification estimates moment-to-moment ITDs in octave-wide frequency bands, and applies corresponding ILDs to the target-masker mixtures reaching the two ears at each specific time and frequency band. ILD magnification significantly improved intelligibility in two experiments: one with NH listeners using vocoded stimuli and one with BiCI users. BiCI listeners showed no benefit of spatial separation between target and maskers with natural ILDs, even for the largest target-masker separation. Because ILD magnification relies on and manipulates only the mixed signals at each ear, the strategy never alters the monaural TMR in either ear at any time. Thus, the observed improvements to masked speech intelligibility come from binaural effects, likely from increased perceptual separation of the competing sources.

neuroscience↗

bioRxiv2024

Automatic segmentation of medial temporal lobe subregions in multi-scanner, multi-modality MRI of variable quality

ObjectivesVolumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimers disease. However, poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images. MethodMRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimers Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. ResultsThe multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. ConclusionThe multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.

bioengineering↗

bioRxiv2024

AutoGDC: A Python Package for DNA Methylation and Transcription Meta-Analyses

AO_SCPLOWBSTRACTC_SCPLOW0.1 MotivationThe Genomic Data Commons is a powerful resource which facilitates the exploration of molecular alterations across various diseases. However, utilizing this resource for meta-analysis requires many different tools to query, download, organize, and analyze the data. In order to facilitate a more rapid, simple means of analyzing DNA methylation and RNA sequencing datasets from the GDC we developed autogdc, a python package that integrates data curation and preprocessing with meta-analysis functionality into one simplified bioinformatic pipeline. 0.2 Availability and ImplementationThe autogdc python package is available under the GPLv3 license at along with several examples of typical use-case scenarios in the form of a jupyter notebook. The data is all originally provided by the GDC, and is therefore available under the NIH Genomic Data Sharing (GDS) and NCI GDS policies.

bioinformatics↗

bioRxiv2024

Persistent homology centrality improves link prediction performance in PubMed co-occurrence networks

AO_SCPLOWBSTRACTC_SCPLOWThis paper provides a novel approach to understanding the nature of innovation and scientific progress by analyzing large-scale datasets of scientific literature. A new measure of novelty potential or disruptiveness for a set of scientific entities is proposed, based in the mathematical formalism of algebraic topology via a method called persistent homology. In this framework, understanding where academic ideas depart from the existing body of knowledge to fill knowledge gaps is key to scoring a set of entities and their potential for filling future knowledge gaps. This framework is motivated by the assumption that scientific discovery has underlying regularities that can be modeled and predicted. Our method uses a filtration, which is a type of ranking of hypergraph components along a chosen parameter. In this work two different axes are used, which constructs a growing grid of sub-hypergraphs. The axes of time (scientific knowledge evolution) and normalized point-wise mutual information (network structure) affords the ability to succinctly represent the entire dynamic structure of the scientific literature network. We then find that using very simple and interpretable measures of centrality derived from this crude bifiltration or vineyard affords the ability to predict links within the dynamic scientific network. While several different methods of link prediction have been proposed in the past, the method presented here extends the notion of link prediction to a higher dimension, as the boundary of the knowledge gap may be more than just 0-dimensional nodes. The system presented here not only suggests a mathematical basis, consistent with observations in cognitive neurosciences regarding early childhood language acquisition, but additionally provides useful applications for the scientific community in predicting and ranking hypothesis for scientific discovery.

bioinformatics↗

bioRxiv2023

Methylation Array Signals are Predictive of Chronological Age Without Bisulfite Conversion

DNA methylation data has been used to make "epigenetic clocks" which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. Here, we demonstrate how another hallmark of aging, genomic instability, influences methylation measurements in both bisulfite sequencing and methylation arrays. We found that non-methylation factors lead to "pseudomethylation" signals that are both confounding of epigenetic clocks and uniquely age predictive. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

molecular biology↗

bioRxiv2021

Online tests yield robust thresholds with the right auditory hygiene

Most human auditory psychophysics research has historically been conducted in carefully controlled environments with calibrated audio equipment, and over potentially hours of repetitive testing with expert listeners. Here, we operationally define such conditions as having high auditory hygiene. From this perspective, conducting auditory psychophysical paradigms online presents a serious challenge, in that results may hinge on absolute sound presentation level, reliably estimated perceptual thresholds, low and controlled background noise levels, and sustained motivation and attention. We introduce a set of procedures that address these challenges and facilitate auditory hygiene for online auditory psychophysics. First, we establish a simple means of setting sound presentation levels. Across a set of four level-setting conditions conducted in person, we demonstrate the stability and robustness of this level setting procedure in open air and controlled settings. Second, we test participants tone-in-noise thresholds using widely adopted online experiment platforms and demonstrate that reliable threshold estimates can be derived online in approximately one minute of testing. Third, using these level and threshold setting procedures to establish participant-specific stimulus conditions, we show that an online implementation of the classic probe-signal paradigm can be used to demonstrate frequency-selective attention on an individual-participant basis, using a third of the trials used in recent in-lab experiments. Finally, we show how threshold and attentional measures relate to well-validated assays of online participants in-task motivation, fatigue, and confidence. This demonstrates the promise of online auditory psychophysics for addressing new auditory perception and neuroscience questions quickly, efficiently, and with more diverse samples. Code for the tests is publicly available through Pavlovia and Gorilla.

neuroscience↗

bioRxiv2020

Entraining alpha activity using visual stimulation in patients with chronic musculoskeletal pain. A feasibility study.

Entraining alpha activity with rhythmic visual, auditory, and electrical stimulation can reduce experimentally induced pain. However, evidence for alpha entrainment and pain reduction in patients with chronic pain is limited. This feasibility study investigated whether visual alpha stimulation can increase alpha power in patients with chronic musculoskeletal pain and secondarily, if chronic pain was reduced following stimulation. In a within-subject design, 22 patients underwent 4-minute periods of stimulation at 10 Hz (alpha), 7 Hz (high-theta, control), and 1 Hz (control) in a pseudo-randomized order. Patients underwent stimulation both sitting and standing and verbally rated their pain before and after each stimulation block on a 0-10 numerical rating scale. Global alpha power was significantly higher during 10 Hz compared to 1 Hz stimulation when patients were standing (t = -6.08, p <.001). On a more regional level, a significant increase of alpha power was found in the right-middle and left-posterior region when patients were sitting. With respect to our secondary aim, no significant reduction of pain intensity and unpleasantness was found. However, only the alpha stimulation resulted in a minimal clinically important difference in at least 50% of participants for pain intensity (50%) and unpleasantness ratings (65%) in the sitting condition. This study provides initial evidence for the potential of visual stimulation as a means to enhance alpha activity in patients with chronic musculoskeletal pain. The brief period of stimulation was insufficient to reduce chronic pain. This study is the first to provide evidence that a brief period of visual stimulation at alpha frequency can significantly increase alpha power in patients with chronic musculoskeletal pain. Further study is warranted to investigate optimal dose and individual stimulation parameters to achieve pain relief in these patients.

neuroscience↗

bioRxiv2019

Skeletal and Dental Development Preserve Evidence of Energetic Stress in the Moose of Isle Royale

Food shortages can leave diagnostic, and in the case of the dentition, irreversible changes in mineralized tissue that persist into historical and fossil records. Consequently, developmental defects of tooth enamel might be used to track ungulate population irruption but dental tissues capacity for preserving historical population density changes has yet to be investigated in wild populations. We test the ability of enamel defects, mandible and metapodial lengths to track changes in the well-known fluctuating moose population of Isle Royale National Park. Our study demonstrates that 1) a moose density threshold exists on the island above which there is a significant decrease in mandible and metatarsus length and a concomitant increase in enamel hypoplasias, 2) food limitation has a more pronounced effect on male than female skeletal growth, and 3) combined data from tooth enamel hypoplasias and bone lengths reflect the relative density of this ungulate population, and should be broadly applicable to other ungulate osteological samples. Developmental defects in dental enamel were among the highest recorded in a wild population, and even during low-density intervals the population density of Isle Royale moose has been high enough to negatively impact skeletal and dental growth, indicating the comparatively poor health of this century-old ecosystem

ecology↗

bioRxiv2019

Sub-Optimal Learning of Tactile-Spatial Predictions in Patients with Complex Regional Pain Syndrome

In Complex Regional Pain Syndrome (CRPS), tactile sensory deficits have motivated the therapeutic use of sensory discrimination training. However, the hierarchical organisation of the brain is such that low-level sensory processing can be dynamically influenced by higher-level knowledge, e.g. knowledge learnt from statistical regularities in the environment. It is unknown whether the learning of such statistical regularities is impaired in CRPS. Here, we employed a hierarchical Bayesian model of predictive coding to investigate statistical learning of tactile-spatial predictions in CRPS. Using a sensory change-detection task, we manipulated bottom-up (spatial displacement of a tactile stimulus) and top-down (probabilistic structure of occurrence) factors to estimate hierarchies of prediction and prediction error signals, as well as their respective precisions or reliability. Behavioural responses to spatial changes were influenced by both the magnitude of spatial displacement (bottom-up) and learnt probabilities of change (top-down). The Bayesian model revealed that patients predictions (of spatial displacements) were found to be less precise, deviating further from the ideal (statistical optimality) compared to healthy controls. This imprecision was less context-dependent, i.e. more enduring across changes in probabilistic context and less finely-tuned to statistics of the environment. This caused greater precision on prediction errors, resulting in predictions that were driven more by momentary spatial changes and less by the history of spatial changes. These results suggest inefficiencies in higher-order statistical learning in CRPS. This may have implications for therapies based on sensory re-training whose effects may be more short-lived if success depends on higher-order learning.

neuroscience↗