Biology subjects

Mackey, A. P.

Publications and source records attributed to Mackey, A. P..

At least 19 recordsLinked to original sources

bioRxiv2026

Primary and higher-order thalamic nuclei make distinct contributions to cortical reorganization in congenital sensory loss

Early sensory loss transforms the functional organization of affected sensory systems, with regions that normally support vision or audition participating in noncanonical perceptual and cognitive functions. Such reorganization requires coordination across distributed networks. Higher-order thalamic nuclei are positioned to support these interactions through their widespread reciprocal cortical connectivity, yet studies of sensory-loss plasticity have focused primarily on cortex and first-order sensory pathways. Here, we combined structural and functional MRI in early blind and early deaf adults to test how reorganization after sensory loss is expressed across thalamocortical networks. In blindness, structural differences were concentrated along the primary input pathway, with reduced lateral geniculate nucleus volume that covaried with areal organization of primary visual cortex. Functional reorganization was more broadly distributed, with visual cortex showing greater similarity with higher-order (association) thalamic nuclei linked to cognitive control, paralleling a shift toward cognitive-control networks across cortex. This pattern was amplified during a nonvisual perceptual judgment task. Across visual cortex, cross-network functional differences were strongest in regions showing the largest structural effects. A related shift toward control-associated higher-order thalamus was observed in deafness, indicating that higher-order thalamic involvement generalizes across sensory modalities. Together, these results indicate that thalamocortical architecture shapes both the developmental consequences of early sensory loss and the capacity for distributed functional reorganization.

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

Developmental links between play behavior and brain network integration

Play is a fundamental aspect of childhood and plays a crucial role in the development of creativity, yet its neural mechanisms remain poorly understood. We tested the hypothesis that more frequent play is associated with stronger functional integration among the default mode network (DMN), executive control network (CN), and salience network (SAL), as these cortical networks have been implicated in creativity in adults. In a preregistered study of infants and toddlers (Study 1; N = 143, 10 months-3 years, 67 boys, Baby Connectome Project), parent-reported play and imitation behaviors increased sharply from 1 to 2 years, and were associated with stronger within-DMN connectivity and DMN-CN coupling, controlling for age, sex, and head motion. In middle childhood (Study 2; N = 108, ages 4-11 years, 52 boys), parent-reported play frequency declined with age, as did cross-network coupling involving SAL. However, children who engaged more frequently in play showed higher DMN-SAL and CN-SAL connectivity. Finally, in a quasi-experimental comparison (Study 3; N = 45; ages 4-12 years, 20 boys), children enrolled in a curriculum that includes guided play (Montessori) showed higher DMN-SAL and DMN-CN connectivity than peers in traditional schools, suggesting that pedagogies that center child-led exploration might enable protracted brain network integration. Across these three studies, play was consistently associated with greater integration among DMN, SAL, and CN, a pattern previously linked to creativity in adults. Our findings offer a potential mechanism linking childhood play to later creativity through its role in supporting brain integration during development. Public Significant StatementO_LIPlay is widely believed to nurture childrens creativity, yet the brain mechanisms behind this link are not well understood. C_LIO_LIAcross three studies from infancy to middle childhood, we found that more frequent play was associated with stronger integration among brain networks tied to imagination, attention, and control. C_LIO_LIThese findings suggest that play may help build the neural foundation for later creative thinking. C_LI

neuroscience↗

bioRxiv2026

Cascading periods of language-related brain plasticity across early childhood

Language is thought to have multiple sensitive periods in early childhood, but the neural basis of these sensitive periods is less understood. We leverage advances in in-vivo neuroimaging of plasticity, measuring the neural inhibition across the brain via Hurst exponent. Using two large datasets with children ages 10 months to 18 years (Baby Connectome Project: 10m-3y6m, 458 observations across n=222 children; Human Connectome Project-Development: 5-18y, n=437), we characterize the development of the Hurst exponent in language-related brain regions. In early childhood, Hurst increases in temporal and frontal language areas, and posterior regions develop earlier than anterior regions. In contrast, thalamic Hurst plateaus earlier, perhaps underlying the earliest language-related sensitive periods. Children with higher language-related skills show slower increases in cortical Hurst in early childhood, suggesting protracted plasticity. Later in childhood, cortical Hurst plateaus around age 9, suggesting a potential neural mechanism for age-related declines syntax learning. These results highlight a potential neural basis for cascading language-related sensitive periods. Research highlightsO_LILanguage has multiple, cascading sensitive periods, but the neural basis of these sensitive periods is not well-understood. C_LIO_LIWe leverage advances in in-vivo neuroimaging to quantify plasticity in language-related brain regions across childhood via Hurst, a measure of inhibition. C_LIO_LIWe find that Hurst increases (plasticity decreases) in a graded fashion, with posterior regions maturing before anterior regions. C_LIO_LIThalamic hurst plateaus in the first year of life, while cortical Hurst plateaus at age 9, suggesting a neural basis for distinct language-related sensitive periods. C_LI

developmental biology↗

bioRxiv2025

Anatomical White Matter Tracts Span the Cortical Hierarchy to Support Cognitive Diversity

Long-range white matter (WM) tracts support cognition by enabling communication between distant cortical regions, which are organized along a hierarchy defined by the sensorimotor-to-association (S-A) axis. However, it remains unknown how WM tracts are positioned within the cortical hierarchy to support cognition. Here, we show that WM tracts are differentially positioned in the cortical hierarchy to support specific cognitive functions, and that tracts spanning the hierarchy connect regions with greater cognitive diversity. Moreover, tracts situated within the same hierarchical level connect biologically similar regions, while those crossing the hierarchy bridge distinct biological milieux to support diverse cognitive functions. The placement of tracts in the cortical hierarchy also reflects developmental variation in tract microstructure and individual differences in cognition. Together, these findings provide a framework that moves beyond conventional categories of association or projection tracts and links WM tract anatomy to cortical organization, cognitive function, cortical neurobiology, and neurodevelopment. We anticipate that this cortex-anchored framework for describing WM tracts may aid the interpretation of individual differences in WM structure related to development and behavior.

neuroscience↗

bioRxiv2025

Alcohol impacts an fMRI marker of neural inhibition in humans and rodents.

Acute alcohol consumption leads to cognitive and behavioral disinhibition that increase health and social risks, such as traffic fatalities and violence. Although rodent studies have shown that alcohol affects inhibitory neuronal activity, its relevance to humans remains largely unexplored. Here, we used the Hurst exponent--an fMRI-based marker of neural inhibition--to examine alcohols effects in both rats and humans. In rats, acute alcohol administration significantly reduced the cortical Hurst exponent, suggesting a decrease in inhibitory neuronal activity. This reduction was strongly correlated with the spatial distribution of GABAA receptor expression, highlighting the key role of these receptors in mediating alcohols effects. Similarly, in humans, acute alcohol consumption reduced the cortical Hurst exponent, especially in brain regions with high GABAA receptor expression. Our findings provide cross-species in vivo evidence that acute alcohol consumption modulates neural inhibition, offering new insights into the neural mechanisms underlying alcohol-induced behavioral modulation.

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↗

bioRxiv2025

Myelination across cortical hierarchies and depths in humans and macaques

Myelination is fundamental to brain function, enabling rapid neural communication and supporting neuroplasticity throughout the lifespan. While hierarchical patterns of myelin maturation across the cortical surface are well-documented in humans, it remains unclear which features reflect evolutionarily conserved developmental processes versus human-characteristic adaptations. Moreover, the laminar development of myelin across the primate cortical surface, which shapes hierarchies and supports functions ranging from sensory integration to network communication, has been largely unexplored. Using neuroimaging to measure the T1-weighted/T2-weighted ratio in tissue contrast as a proxy for myelin content, we systematically compared depth-dependent trajectories of myelination across the cortical surface in humans and macaques. We identified a conserved "inside-out" pattern, with deeper layers exhibiting steeper increases in myelination and earlier plateaus than superficial layers. This depth-dependent organization followed a hierarchical gradient across the cortical surface, progressing from early maturation in sensorimotor regions to prolonged development in association areas. Humans exhibited a markedly extended timeline of myelination across both cortical regions and depths compared to macaques, allowing for prolonged postnatal plasticity across the entire cortical hierarchy -- from sensory and motor processing to higher-order association networks. This extended potential for plasticity may facilitate the shaping of cortical circuits through postnatal experience in ways that support human-characteristic perceptual and cognitive capabilities.

developmental biology↗

bioRxiv2024

The Hurst exponent as a marker of inhibition in the developing brain

The maturation of inhibitory neurons is crucial for regulating plasticity in developing brains. Previous work using computational models has suggested that the Hurst exponent, the decay in power over frequency, reflects inhibition, but empirical data supporting this link is sparse. Here, we took a cross-species approach to validating the Hurst exponent of fMRI as a marker of inhibition, then characterized the development of the Hurst exponent in childhood. We found significant spatial correlations between the Hurst exponent and ex vivo parvalbumin mRNA expression in human children and adults, and between the Hurst exponent and parvalbumin-positive cell counts in mice. We identified a plateau in the mRNA expression by late childhood, aligning with the Hurst exponent plateau in both humans and rats. In sum, this work suggests that the Hurst exponent can be used to study the development of inhibition in vivo, and in the future, to understand individual differences in plasticity.

neuroscience↗

bioRxiv2024

A sensorimotor-association axis of thalamocortical connection development

Human cortical development follows a sensorimotor-to-association sequence during childhood and adolescence1-6. The brains capacity to enact this sequence over decades indicates that it relies on intrinsic mechanisms to regulate inter-regional differences in the timing of cortical maturation, yet regulators of human developmental chronology are not well understood. Given evidence from animal models that thalamic axons modulate windows of cortical plasticity7-12, here we evaluate the overarching hypothesis that structural connections between the thalamus and cortex help to coordinate cortical maturational heterochronicity during youth. We first introduce, cortically annotate, and anatomically validate a new atlas of human thalamocortical connections using diffusion tractography. By applying this atlas to three independent youth datasets (ages 8-23 years; total N = 2,676), we reproducibly demonstrate that thalamocortical connections develop along a maturational gradient that aligns with the cortexs sensorimotor-association axis. Associative cortical regions with thalamic connections that take longest to mature exhibit protracted expression of neurochemical, structural, and functional markers indicative of higher circuit plasticity as well as heightened environmental sensitivity. This work highlights a central role for the thalamus in the orchestration of hierarchically organized and environmentally sensitive windows of cortical developmental malleability.

neuroscience↗

bioRxiv2023

Multilayer network associations between the exposome and childhood brain development

Growing up in a high poverty neighborhood is associated with elevated risk for academic challenges and health problems. Here, we take a data-driven approach to exploring how measures of childrens environments relate to the development of their brain structure and function in a community sample of children between the ages of 4 and 10 years. We constructed exposomes including measures of family socioeconomic status, childrens exposure to adversity, and geocoded measures of neighborhood socioeconomic status, crime, and environmental toxins. We connected the exposome to two structural measures (cortical thickness and surface area, n = 170) and two functional measures (participation coefficient and clustering coefficient, n = 130). We found dense connections within exposome and brain layers and sparse connections between exposome and brain layers. Lower family income was associated with thinner visual cortex, consistent with the theory that accelerated development is detectable in early-developing regions. Greater neighborhood incidence of high blood lead levels was associated with greater segregation of the default mode network, consistent with evidence that toxins are deposited into the brain along the midline. Our study demonstrates the utility of multilayer network analysis to bridge environmental and neural explanatory levels to better understand the complexity of child development.

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↗

bioRxiv2022

Intrinsic Activity Develops Along a Sensorimotor-Association Cortical Axis in Youth

Animal studies of neurodevelopmental plasticity have shown that intrinsic brain activity evolves from high amplitude and globally synchronized to suppressed and sparse as plasticity declines and the cortex matures. Leveraging resting-state functional MRI data from 1033 individuals (8-23 years), we reveal that this stereotyped refinement of intrinsic activity occurs during human development and provides evidence for a cortical gradient of neurodevelopmental plasticity during childhood and adolescence. Specifically, we demonstrate that declines in the amplitude of intrinsic activity are initiated heterochronously across regions, coupled to the maturation of a plasticity-restricting structural feature, and temporally staggered along a hierarchical sensorimotor-association axis from ages 8 to 18. Youth from disadvantaged environments exhibit reduced intrinsic activity in regions further up the sensorimotor-association axis, suggestive of a reduced level of plasticity in late-maturing cortices. Our results uncover a hierarchical axis of neurodevelopment and offer insight into the temporal sequence of protracted neurodevelopmental plasticity in humans.

neuroscience↗

bioRxiv2022

The age of reason: Functional brain network development during childhood

Human childhood is characterized by dramatic changes in the mind and brain. However, little is known about the large-scale intrinsic cortical network changes that occur during childhood due to methodological challenges in scanning young children. Here, we overcome this barrier by using sophisticated acquisition and analysis tools to investigate functional network development in children between the ages of 4 and 10 years (n = 92). At multiple spatial scales, age is positively associated with brain network segregation. At the system level, age was associated with segregation of systems involved in attention from those involved in abstract cognition, and with integration among attentional and perceptual systems. Associations between age and functional connectivity are most pronounced in visual and medial prefrontal cortex, the two ends of a gradient from perceptual, externally oriented cortex to abstract, internally oriented cortex. These findings suggest that both ends of the sensory-association gradient may develop early, in contrast to the classical theories that cortical maturation proceeds from back to front, with sensory areas developing first and association areas developing last. More mature patterns of brain network architecture, controlling for age, were associated with better visuospatial reasoning abilities. Our results suggest that as cortical architecture becomes more specialized, children become more able to reason about the world and their place in it. SignificanceAnthropologists have called the transition from early to middle childhood the "age of reason", when children across cultures become more independent. We employ cutting-edge neuroimaging acquisition and analysis approaches to investigate associations between age and functional brain architecture in childhood. Age was positively associated with segregation between cortical systems that process the external world, and those that process abstract phenomena like the past, future, and minds of others. Surprisingly, we observed pronounced development at both ends of the sensory-association gradient, challenging the theory that sensory areas develop first and association areas develop last. Our results open new directions for research into how brains reorganize to support rapid gains in cognitive and socioemotional skills as children reach the age of reason.

neuroscience↗

bioRxiv2021

Individual differences in frontoparietal plasticity in humans

Neuroplasticity, defined as the brains potential to change in response to its environment, has been extensively studied at the cellular and molecular levels. Work in animal models suggests that stimulation to the ventral tegmental area (VTA) enhances plasticity, and that myelination constrains plasticity. Little is known, however, about whether proxy measures of these properties in the human brain are associated with learning. Here, we investigated the plasticity of the frontoparietal system by asking whether VTA resting-state functional connectivity and myelin map values (T1w/T2w ratios) predicted learning after short-term training on the adaptive n-back (n = 46, ages 18-25). We found that stronger baseline connectivity between VTA and lateral prefrontal cortex predicted greater improvements in accuracy. Lower myelin map values predicted improvements in response times, but not accuracy. Our findings suggest that proxy markers of neural plasticity can predict learning in humans.

neuroscience↗

bioRxiv2021

Association between Neighborhood Socioeconomic Status and Executive System Activation in Youth

Low socioeconomic status has been shown to have detrimental effects on cognitive performance, including working memory (WM). As executive systems that support WM undergo functional neurodevelopment during adolescence, environmental stressors at both individual and community levels may have a particularly strong impact on cognitive outcomes. Here, we sought to examine how neighborhood socioeconomic status (SES) impacts task-related activation of the executive system during adolescence, and to determine whether this effect mediates the relationship between neighborhood SES and WM performance. To address these questions, we studied 1,158 youths (age 8-22) that completed a fractal n-back WM task during fMRI at 3T as part of the Philadelphia Neurodevelopmental Cohort. We found that higher neighborhood SES was associated with greater activation of the executive system to WM load, including the bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and precuneus. These associations remained significant when controlling for related factors like parental education and exposure to traumatic events. Furthermore, high dimensional multivariate mediation analysis identified two distinct patterns of brain activity within the executive system that significantly mediated the relationship between neighborhood SES and task performance. Together, these findings underscore the importance of the neighborhood environment in shaping executive system function and WM in youth.

neuroscience↗

bioRxiv2021

Early life stress is associated with earlier emergence of permanent molars

Exposure to adversity can accelerate biological aging. However, existing biomarkers of early aging are either difficult to detect in individuals at scale, like epigenetic signatures, or cannot be detected until late childhood, like pubertal onset. We evaluated the hypothesis that early adversity is associated with earlier molar eruption, an easily assessed measure that has been used to track the length of childhood across primates. In a pre-registered analysis (N = 117, ages 4-7), we demonstrate that lower family income and exposure to adverse childhood experiences (ACEs) are significantly associated with earlier eruption of the first permanent molars, as rated in T2-weighted magnetic resonance images (MRI). We replicate relationships between income and molar eruption in a population-representative dataset (NHANES; N = 1,973). These findings suggest that the impact of stress on the pace of biological development is evident in early childhood, and detectable in the timing of molar eruption.

neuroscience↗

bioRxiv2021

Functional brain network community structure in childhood: Unfinished territories and fuzzy boundaries

Adult cortex is organized into distributed functional communities. Yet, little is known about community architecture of childrens brains. Here, we uncovered the community structure of cortex in childhood using fMRI data from 670 children aged 9-11 years from the Adolescent Brain and Cognitive Development study. Children showed similar community structure to adults in early-developing sensory and motor communities, but differences emerged in transmodal areas. Children have more cortical territory in the limbic community, which is involved in emotion processing, than adults. Regions of association cortex interact more flexibly across communities, creating uncertainty for the model-based assignment algorithm, and perhaps reflecting cortical boundaries that are not yet solidified. Uncertainty was highest for cingulo-opercular areas involved in flexible deployment of cognitive control. Collectively, our findings suggest that community boundaries are not solidified by middle childhood, an instability that provides important context for childrens thoughts and behaviors.

neuroscience↗