Biology subjects

Keller, A. S.

Publications and source records attributed to Keller, A. S..

17 recordsLinked to original sources

bioRxiv2026

Generalizable sex differences in functional brain organization follow the cortical hierarchy in youth

It remains unknown if sex differences in human functional connectivity follow a generalizable overarching principle. Here, we tested whether sex differences in functional connectivity during childhood and adolescence are organized along the sensorimotor-association (S-A) axis, a cortical hierarchy spanning unimodal sensorimotor to transmodal association cortex. We analyzed four large-scale, independent datasets of youth ages 5-23 years (total N = 3,355). Across datasets, males showed greater connectivity between functional networks, whereas females showed greater connectivity within networks, most prominently within the default mode network. More broadly, the sensorimotor and association ends of the S-A axis were more segregated in females and more integrated in males. This difference extended to macroscale cortical organization: the cortical hierarchy was expanded in females relative to males along the principal gradient of functional connectivity. Together, these findings identify the S-A axis as a generalizable organizing principle of sex differences in functional brain organization during youth.

neuroscience↗

bioRxiv2026

White matter reflects the childhood exposome

The childhood environment is critical for brain development. However, most neuroimaging studies examine individual environmental measures (e.g., socioeconomic status) or a limited set of exposures, obscuring how the combination of complex, real-world exposures jointly influence brain development. Here we investigated how white matter shape and tissue properties are linked to the childhood exposome, a multidimensional measure capturing over 300 environmental exposures. Using multi-shell diffusion MRI from 8,183 children (ages 9-10) in the ABCD study, we quantified microstructural and macrostructural properties across 62 person-specific white matter tracts. The exposome showed widespread and highly replicable associations with both white matter microstructure and macrostructure: more advantaged environments were associated with larger tract macrostructure and lower orientation dispersion. Principal component analysis revealed that the dominant axis of exposome-white matter covariation aligns with the cortical sensorimotor-association hierarchy, such that tracts spanning this hierarchy exhibit the strongest associations with the exposome. Multivariate models demonstrated that patterns of white matter features explained 25% of the variance in the exposome in unseen individuals. Notably, white matter-based prediction of cognition was markedly reduced after accounting for the exposome ([~]82% reduction in explained variance), indicating that brain-cognition associations overlap substantially with variance captured by the exposome. These findings generalized to independent data from the Healthy Brain Network (n=869), which differs substantially from ABCD in MRI acquisition, participant selection, and childhood environments. Together, these results suggest that white matter architecture strongly reflects the childhood environment.

neuroscience↗

bioRxiv2026

Highly replicable multisite patterns of adolescent white matter maturation

The Adolescent Brain Cognitive Development (ABCD) Study is the largest U.S.-based neuroimaging initiative of adolescent brain maturation. Diffusion MRI (dMRI) provides unique insights into white matter organization, yet applying advanced processing pipelines and managing technical variability across scanning environments remains challenging at scale. To address these issues, we present ABCD-BIDS Community Collection (ABCC) release 3.1.0, including a curated resource of more than 24,000 fully processed ABCD dMRI datasets. ABCC provides fully processed images, nuanced image quality metrics, advanced microstructural measures, and person-specific bundle tractography. Evaluating these rich data revealed that measures of diffusion restriction and non-Gaussianity--in particular the intracellular volume fraction from NODDI and return-to-origin probability from MAP-MRI--were highly sensitive to neurodevelopment and robust to variation in image quality. Additionally, harmonization of microstructural features markedly improved the cross-vendor generalizability of developmental effects. Together, ABCC accelerates reproducible, rigorous research on adolescent white matter development.

neuroscience↗

bioRxiv2026

The PMADS Project: A Longitudinal Multimodal Cohort Study to Understand Risk for Perinatal Mood and Anxiety Disorders

BackgroundPerinatal mood and anxiety disorders (PMADs) are among the most common and consequential complications of pregnancy. The perinatal period is also characterized by profound hormonal fluctuations and large-scale brain plasticity. However, the mechanisms linking these neurobiological changes to psychiatric risk are poorly understood. Prospective, clinically informed studies are needed to identify quantitative biomarkers and clarify pathways linking perinatal neurobiology to PMADs risk. MethodsThis report describes the design of a prospective, longitudinal cohort study integrating multimodal neuroimaging, biofluid sampling, and deep clinical phenotyping to enable precision characterization of neurobiological trajectories of PMADs risk. Twenty-five individuals at elevated risk for PMADs will be recruited prior to conception and followed across six in-person timepoints spanning the menstrual cycle, pregnancy, and early postpartum, with additional remote follow-ups through the first postpartum year. Data collection includes high-resolution structural MRI, functional brain mapping using multi-echo resting-state fMRI, diffusion MRI, arterial spin labeling, ultra-high field MR-based techniques for measuring glutamate (GluCEST and 1HMRS), biofluid sampling, and comprehensive clinical, behavioral, and cognitive assessments. Structured clinical interviews assess categorical diagnoses while dimensional symptom measures capture heterogeneity and transdiagnostic features of perinatal psychopathology. Longitudinal analyses will model nonlinear trajectories of brain and symptom change across the perinatal period as well as evaluate whether preconception network features and menstrual cycle-related brain changes are associated with subsequent perinatal symptom emergence. DiscussionThis cohort study establishes a longitudinal, multimodal framework for investigating neurobiological changes across the transition to pregnancy in individuals at elevated risk for PMADs. By anchoring pregnancy-related brain changes to preconception and menstrual cycle-related variability within the same individuals, this study is designed to evaluate associations between preconception hormone sensitivity, pregnancy-induced neuroplasticity, and PMADs risk. The resulting dataset will provide a deeply phenotyped longitudinal resource for investigating brain-behavior relationships across the perinatal period. Findings are expected to inform future larger-scale studies aimed at advancing mechanistic understanding of PMADs, improving individualized risk stratification, and supporting development of personalized preventive and neuromodulatory interventions.

neuroscience↗

bioRxiv2026

Menarche onset is an inflection point for mental health and brain development

Menarche is a normative milestone of female puberty, yet its role in adolescent mental health and brain development remains poorly understood. Using longitudinal data from 5,016 females (7 annual visits, ages 10-16 years) in the Adolescent Brain Cognitive Development Study, we found that menarche onset functions as an inflection point for the development of internalizing symptoms and gross brain morphometry. The onset of menarche, largely independent of timing and socio-environmental factors, preceded a significant spike in internalizing symptoms, while altering the rate of ongoing structural brain development. Following menarche onset, individuals with faster declines in gray matter volume and surface area also had heightened internalizing symptoms. These findings suggest that menarche is not only a reproductive milestone but a neuroendocrine driver of adolescent brain and mental health trajectories. This normative and easily identifiable marker could define a critical window for mental health screenings with greater precision than current age-based guidelines.

neuroscience↗

bioRxiv2025

Multivariate environmental exposures are reflected in whole-brain functional connectivity and cognition in youth

Each individuals complex, multidimensional environment, known as their "exposome", plays an essential role in shaping cognitive neurodevelopment. Understanding the mechanisms whereby childrens exposome influences their development is crucial to facilitate the design of interventions to foster positive developmental trajectories for all youth. Recent work has identified a general exposome factor associated with socio-economic inequality that is strongly related to cognition and individual differences in the spatial organization of functional brain networks in youth. Building on these findings, the current study explores whether alterations in functional connectivity may represent a potential mechanism linking variation in the exposome to cognitive performance. We apply a data-driven, cross-validated, whole-brain machine learning approach, connectome-based statistical inference, to identify patterns of functional connectivity associated with exposome scores among early adolescents enrolled in the Adolescent Brain Cognitive Development (ABCD) Study using data collected during three cognitive tasks and during rest. Additionally, we investigate whether the identified patterns of functional connectivity relate to individual differences in cognitive performance across three domains: General Cognition, Executive Functioning, and Learning/Memory. Models incorporating 10-fold cross-validation over 100 iterations identified consistent functional connections associated with the exposome across task and rest conditions (model performance: ns = 6,137 - 8,391, rs = 0.34 - 0.44, ps <.001). Results were robust across data collection sites and functional connections common across all significant models were associated with cognitive performance across domains (ps < 0.0009). Collectively, these findings reveal that multidimensional environmental exposures are reflected in patterns of functional connectivity and relate to cognitive functioning among youth. HighlightsO_LIPatterns of functional connectivity reflect multivariate environmental exposures. C_LIO_LIConsistent exposome-related connectivity patterns were observed across brain states. C_LIO_LIThe identified general exposome network was associated with cognitive performance across domains. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/688261v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@b5cc3aorg.highwire.dtl.DTLVardef@172f954org.highwire.dtl.DTLVardef@14f0d01org.highwire.dtl.DTLVardef@deccb5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Two Axes of White Matter Development

Despite decades of neuroimaging research, how white matter develops along the length of major tracts in humans remains unknown. Here, we identify fundamental patterns of white matter maturation by examining developmental variation along major, long-range cortico-cortical tracts in youth ages 5-23 years using diffusion MRI from three large-scale, cross-sectional datasets (total N = 2,716). Across datasets, we delineate two replicable axes of human white matter development. First, we find a deep-to-superficial axis, in which superficial tract regions near the cortical surface exhibit greater age-related change than deep tract regions. Second, we demonstrate that the development of superficial tract regions aligns with the cortical hierarchy defined by the sensorimotor-association axis, with tract ends adjacent to sensorimotor cortices maturing earlier than those adjacent to association cortices. These results reveal developmental variation along tracts that conventional tract-average analyses have previously obscured, challenging the implicit assumption that white matter tracts mature uniformly along their length. Such developmental variation along tracts may have functional implications, including mitigating ephaptic coupling in densely packed deep tract regions and tuning neural synchrony through hierarchical development in superficial tract regions - ultimately refining neural transmission in youth.

neuroscience↗

bioRxiv2024

Reproducible Sex Differences in Personalized Functional Network Topography in Youth

BackgroundA key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex. AimsWe aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks. MethodWe leveraged person-specific atlases of functional brain networks defined using non-negative matrix factorization in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout ("topography") of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression. ResultsSex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons. ConclusionsSex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.

neuroscience↗

bioRxiv2023

XCP-D: A Robust Pipeline for the post-processing of fMRI data

Functional neuroimaging is an essential tool for neuroscience research. Pre-processing pipelines produce standardized, minimally pre-processed data to support a range of potential analyses. However, post-processing is not similarly standardized. While several options for post-processing exist, they tend not to support output from disparate pre-processing pipelines, may have limited documentation, and may not follow BIDS best practices. Here we present XCP-D, which presents a solution to these issues. XCP-D is a collaborative effort between PennLINC at the University of Pennsylvania and the DCAN lab at the University at Minnesota. XCP-D uses an open development model on GitHub and incorporates continuous integration testing; it is distributed as a Docker container or Singularity image. XCP-D generates denoised BOLD images and functional derivatives from resting-state data in either NifTI or CIFTI files, following pre-processing with fMRIPrep, HCP, and ABCD-BIDS pipelines. Even prior to its official release, XCP-D has been downloaded >3,000 times from DockerHub. Together, XCP-D facilitates robust, scalable, and reproducible post-processing of fMRI data.

neuroscience↗

bioRxiv2023

A general exposome factor explains individual differences in functional brain network topography and cognition in youth

Our minds and brains are highly unique. Despite the long-recognized importance of the environment in shaping individual differences in cognitive neurodevelopment, only with the combination of deep phenotyping approaches and the availability of large-scale datasets have we been able to more comprehensively characterize the many inter-connected features of an individuals environment and experience ("exposome"). Moreover, despite clear evidence that brain organization is highly individualized, most neuroimaging studies still rely on group atlases to define functional networks, smearing away inter-individual variation in the spatial layout of functional networks across the cortex ("functional topography"). Here, we leverage the largest longitudinal study of brain and behavior development in the United States to investigate how an individuals exposome may contribute to functional brain network organization leading to differences in cognitive functioning. To do so, we apply three previously-validated data driven computational models to characterize an individuals multidimensional exposome, define individual-specific maps of functional brain networks, and measure cognitive functioning across broad domains. In pre-registered analyses replicated across matched discovery (n=5,139, 48.5% female) and replication (n=5,137, 47.1% female) samples, we find that a childs exposome is associated with multiple domains of cognitive functioning both at baseline assessment and two years later - over and above associations with baseline cognition. Cross-validated ridge regression models reveal that the exposome is reflected in childrens unique patterns of functional topography. Finally, we uncover both shared and unique contributions of the exposome and functional topography to cognitive abilities, finding that models trained on a single variable capturing a childs exposome can more accurately and parsimoniously predict future cognitive performance than models trained on a wealth of personalized neuroimaging data. This study advances our understanding of how childhood environments contribute to unique patterns of functional brain organization and variability in cognitive abilities.

neuroscience↗

bioRxiv2023

Generalizable links between symptoms of borderline personality disorder and functional connectivity

BackgroundSymptoms of borderline personality disorder (BPD) often manifest in adolescence, yet the underlying relationship between these debilitating symptoms and the development of functional brain networks is not well understood. Here we aimed to investigate how multivariate patterns of functional connectivity are associated with symptoms of BPD in a large sample of young adults and adolescents. MethodsWe used high-quality functional Magnetic Resonance Imaging (fMRI) data from young adults from the Human Connectome Project: Young Adults (HCP-YA; N = 870, ages 22-37 years, 457 female) and youth from the Human Connectome Project: Development (HCP-D; N = 223, age range 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five Factor Inventory (NEO-FFI). A ridge regression model with 10-fold cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity, while controlling for in-scanner motion, age, and sex. The trained model was further tested on data from HCP-D without further tuning. Finally, we tested how the connectivity patterns associated with BPD aligned with agerelated changes in connectivity. ResultsMultivariate functional connectivity patterns significantly predicted out-of-sample BPD proxy scores in unseen data in both young adults (HCP-YA; pperm = 0.001) and older adolescents (HCP-D; pperm = 0.001). Predictive capacity of regions was heterogeneous; the most predictive regions were found in functional systems relevant for emotion regulation and executive function, including the ventral attention network. Finally, regional functional connectivity patterns that predicted BPD proxy scores aligned with those associated with development in youth. ConclusionIndividual differences in functional connectivity in developmentally-sensitive regions are associated with the symptoms of BPD.

neuroscience↗

bioRxiv2023

Functional Connectivity Development along the Sensorimotor-Association Axis Enhances the Cortical Hierarchy

Human cortical maturation has been posited to be organized along the sensorimotor-association (S-A) axis, a hierarchical axis of brain organization that spans from unimodal sensorimotor cortices to transmodal association cortices. Here, we investigate the hypothesis that the development of functional connectivity during childhood through adolescence conforms to the cortical hierarchy defined by the S-A axis. We tested this pre-registered hypothesis in four large-scale, independent datasets (total n = 3,355; ages 5-23 years): the Philadelphia Neurodevelopmental Cohort (n = 1,207), Nathan Kline Institute-Rockland Sample (n = 397), Human Connectome Project: Development (n = 625), and Healthy Brain Network (n = 1,126). In each dataset, the development of functional connectivity systematically varied along the S-A axis. Connectivity in sensorimotor regions increased, whereas connectivity in association cortices declined, refining and reinforcing the cortical hierarchy. These robust and generalizable results establish that the sensorimotor-association axis of cortical organization encodes the dominant pattern of functional connectivity development.

neuroscience↗

bioRxiv2022

Personalized Functional Brain Network Topography Predicts Individual Differences in Youth Cognition

Individual differences in cognition during childhood are associated with important social, physical, and mental health outcomes in adolescence and adulthood. Given that cortical surface arealization during development reflects the brains functional prioritization, quantifying variation in the topography of functional brain networks across the developing cortex may provide insight regarding individual differences in cognition. We test this idea by defining personalized functional networks (PFNs) that account for interindividual heterogeneity in functional brain network topography in 9-10 year olds from the Adolescent Brain Cognitive DevelopmentSM Study. Across matched discovery (n=3,525) and replication (n=3,447) samples, the total cortical representation of fronto-parietal PFNs positively correlated with general cognition. Cross-validated ridge regressions trained on PFN topography predicted cognition across domains, with prediction accuracy increasing along the cortexs sensorimotor-association organizational axis. These results establish that functional network topography heterogeneity is associated with individual differences in cognition before the critical transition into adolescence.

neuroscience↗

bioRxiv2022

Development of Top-Down Cortical Propagations in Youth

Hierarchical processing requires activity propagating between higher and lower-order cortical areas. However, studies of brain development have chiefly quantified fluctuations within regions over time rather than propagations occurring over space. Here, we leveraged advances in neuroimaging and computer vision to track cortical activity propagations in a large sample of youth (n=388). We found that propagations robustly ascend and descend the cortical hierarchy, and that top-down propagations become both more prevalent with cognitive control demands and with development in youth.

neuroscience↗

bioRxiv2021

Attention enhances category representations across the brain with strengthened residual correlations to ventral temporal cortex

How does attention enhance neural representations of goal-relevant stimuli while suppressing representations of ignored stimuli across regions of the brain? While prior studies have shown that attention enhances visual responses, we lack a cohesive understanding of how selective attention modulates visual representations across the brain. Here, we used functional magnetic resonance imaging (fMRI) while participants performed a selective attention task on superimposed stimuli from multiple categories and used a data-driven approach to test how attention affects both decodability of category information and residual correlations (after regressing out stimulus-driven variance) with category-selective regions of ventral temporal cortex (VTC). Our data reveal three main findings. First, when two objects are simultaneously viewed, the category of the attended object can be decoded more readily than the category of the ignored object, with the greatest attentional enhancements observed in occipital and temporal lobes. Second, after accounting for the response to the stimulus, the correlation in the residual brain activity between a cortical region and a category-selective region of VTC was elevated when that regions preferred category was attended vs. ignored, and more so in the right occipital, parietal, and frontal cortices. Third, we found that the stronger the residual correlations between a given region of cortex and VTC, the better visual category information could be decoded from that region. These findings suggest that heightened residual correlations by selective attention may reflect the sharing of information between sensory regions and higher-order cortical regions to provide attentional enhancement of goal-relevant information.

neuroscience↗

bioRxiv2021

Endothelial alpha globin is a nitrite reductase

Small artery vasodilation in response to hypoxia is essential for matching oxygen supply to tissue oxygen demand. One source of hypoxic dilation via nitric oxide (NO) signaling is nitrite reduction by erythrocytic hemoglobin (2{beta}2). However, the alpha subunit of hemoglobin is also expressed in resistance artery endothelium and localized to myoendothelial junctions, a subcellular domain that contacts underlying vascular smooth muscle cells. We hypothesized that nitrite reduction mediated by endothelial alpha globin may occur at myoendothelial junctions to regulate hypoxic vasodilation. To test this concept, we created two novel mouse strains: one lacking alpha globin specifically in endothelium (EC Hba1{Delta}/{Delta}) and one where alpha globin is mutated such that its inhibitory association with endothelial NO synthase (eNOS) is prevented (Hba1WT/{Delta}36-39). In EC Hba1{Delta}/{Delta} or Hba1WT/{Delta}36-39 mice hemoglobin levels, hematocrit and erythrocyte counts were unchanged from littermate controls. Loss of the full alpha globin protein from the endothelium in the EC Hba1{Delta}/{Delta} model was associated with decreased exercise capacity and decreased intracellular nitrite utilization in hypoxic conditions. These effects were not seen in Hba1WT/{Delta}36-39 animals. Hypoxia induced vasodilation was decreased by 60% in isolated thoracodorsal arteries from EC Hba1{Delta}/{Delta}, while infusion of erythrocytes only partially rescued the dilatory response. Lastly, unlike other models where blood pressure is decreased, EC Hba1{Delta}/{Delta} blood pressure was not altered in response to hypoxia. Overall, we conclude that alpha globin in the resistance artery endothelium can act as a nitrite reductase to provide a local vasodilatory response to hypoxia.

physiology↗

bioRxiv2019

Vascular Expression of Hemoglobin Alpha in Antarctic Icefish Supports Iron Limitation as Novel Evolutionary Driver

Frigid temperatures of the Southern Ocean are known to be an evolutionary driver in Antarctic fish. For example, many fish have reduced red blood cell (RBC) concentration to minimize vascular resistance. Via the oxygen-carrying protein hemoglobin, RBCs contain the vast majority of the bodys iron, which is known to be a limiting nutrient in marine ecosystems. Since lower RBC levels also lead to reduced iron requirements, we hypothesized that low iron availability was an additional evolutionary driver of Antarctic fish speciation. Antarctic Icefish of the family Channichthyidae are known to have extreme alteration of iron metabolism due to loss of two iron-binding proteins, hemoglobin and myoglobin, and no RBCs. Loss of hemoglobin is considered a maladaptive trait allowed by relaxation of predator selection, since extreme adaptations are required to compensate for the loss of oxygen-carrying capacity. However, iron dependency minimization may have driven hemoglobin loss instead of a random evolutionary event. Given the variety of functions that hemoglobin serves in the endothelium, we suspected the protein corresponding to the 3 truncated Hb fragment (Hb-3f) that was not genetically excluded by icefish, may still be expressed as a protein. Using whole mount confocal microscopy, we show that Hb-3f is expressed in the vascular endothelium of icefish retina, suggesting this Hb fragment may still serve an important role in the endothelium. These observations support a novel hypothesis that iron minimization could have influenced icefish speciation with the loss of the iron-binding portion of Hb in Hb-3f, as well as hemoglobin {beta} and myoglobin.

physiology↗