Biology subjects

Shine, J. M.

Publications and source records attributed to Shine, J. M..

At least 19 recordsLinked to original sources

bioRxiv2026

A Conserved Locus Coeruleus fMRI Signature of Brain-State Transitions across Sleep, Anesthesia, and Wakefulness

Neuromodulatory systems dynamically reconfigure large-scale brain networks to support adaptation across behavioral and cognitive states. The locus coeruleus (LC), which broadcasts noradrenaline throughout the forebrain, is a central regulator of arousal and state-dependent dynamics. However, how LC activity manifests in brain-wide organization across physiological contexts, and how it biases fMRI connectivity, remains poorly understood. Using an optogenetically informed cross-species framework, we identify a transient LC-derived spatiotemporal pattern of brain activity accompanying brain-state transitions under progressively naturalistic conditions: controlled LC stimulation and endogenous LC fluctuations in anesthetized mice, sleep-wake transitions in rodents and humans, and resting-state activity in awake humans. This LC-derived signature is conserved across species and contexts, leaving a robust and detectable imprint on the BOLD signal. Critically, the prevalence of LC events systematically biases functional connectivity metrics in human fMRI. These findings establish LC activity as a mechanistically interpretable source of variability in resting-state measurements, with direct implications for the interpretation of fMRI biomarkers in arousal-related disorders.

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bioRxiv2025

Compositional Recombination Relies on a Distributed Cortico-Cerebellar Network

Human cognition depends on the ability to flexibly recombine existing knowledge in new ways. Although this capacity for compositionality has traditionally been attributed to cortical networks, its broader neural basis remains unclear. Here, we combined dimensionality reduction of task-based fMRI with recurrent neural network modelling to dissociate two processes underlying compositional cognition: the recruitment of specialised components; and the more general process of recombination. Across 87 participants performing a well-established compositional task, component processes were supported by domain-selective cortical and anterior cerebellar regions, whereas recombination engaged a distributed cortico-cerebellar network that was low-dimensional, highly integrated, and generalised across contexts. Similar functional signatures were also observed in recurrent neural networks trained to perform multiple cognitive tasks, suggesting that low-dimensional recombination is a general solution for flexible compositional cognition. Our findings revise existing models of compositional cognition by highlighting cortico-cerebellar interactions as a mechanism for flexible, integrative task generalisation.

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bioRxiv2025

Mapping functional, structural, and transcriptomic correlates of homotopic connectivity

Homotopic functional connectivity (HoFC)--the synchronous activity between homologous regions of the left and right cortical hemispheres--is a hallmark of inter-hemispheric brain architecture, yet its biological underpinnings remain incompletely understood. Here, we characterize spatial variation in resting-state HoFC and its relation to dominant natural axes of anatomical, functional, and transcriptomic organization across the human cerebral cortex. We show that the regional distribution of HoFC, from the lowest in association areas (especially limbic) to the highest in primary sensorimotor regions, is preserved in neuropsychiatric disorders in a separate neuroimaging cohort (including schizophrenia, bipolar I disorder, and attention-deficit hyperactivity disorder) despite disease-associated perturbations in magnitude. Regional variation in HoFC is not fully explained by properties of physical embedding or vascular innervation in the brain, suggesting involvement of alternative physiological processes. Furthermore, we find that regions with stronger HoFC are more functionally connected within and across hemispheres at rest, suggesting that homotopic functional coupling is positively associated with brain-wide functional synchrony. Our results collectively suggest that HoFC is inherently aligned with a fundamental natural axis of macroscopic cortical organization and shared global signal--advancing our understanding of the biological correlates of cortical homotopy and suggesting potential mechanisms to investigate in the future.

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bioRxiv2025

A Minimal Physiological Model of Perceptual Suppression and Breakthrough in Visual Rivalry

Visual rivalry paradigms provide a powerful tool for probing the mechanisms of visual awareness and perceptual suppression. While the dynamics and determinants of perceptual switches in visual rivalry have been extensively studied and modeled, recent advances in experimental design - particularly those that quantify the depth and variability of perceptual suppression - have outpaced the development of computational models. Here we extend an existing dynamical model of binocular rivalry to encompass two novel experimental paradigms: a threshold detection variant of binocular rivalry, and tracking continuous flash suppression. Together, these tasks provide complementary measures of the dynamics and magnitude of perceptual suppression. Through numerical simulation we demonstrate that a single mechanism, competitive (hysteretic) inhibition between slowly adapting monocular populations, is sufficient to account for the suppression depth findings across both paradigms. This unified model offers a foundation for the development of a quantitative theory of perceptual suppression in visual rivalry.

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bioRxiv2025

Cerebellar and Subcortical Contributions to Working Memory Manipulation

Working memory enables us to temporarily store and manipulate information, a crucial function for problem-solving. However, most working memory models emphasize cortical interactions ignoring contributions from subcortical and cerebellar regions. Given the dense connectivity between the cerebellum, subcortex, and cortex, we hypothesize that these regions provide unique contributions during working memory manipulation. We tested this hypothesis using functional Magnetic Resonance Imaging (fMRI) to measure blood oxygen-level dependent (BOLD) activity during a mental rotation task, where participants judged whether rotated pairs of three-dimensional stimuli were identical. Our results revealed a distributed network spanning the cortex, subcortex, and cerebellum that differentiates rotated from non-rotated stimuli and correct from incorrect responses. BOLD recruitment in these regions increased with larger angles of rotation. We observed delayed responses in premotor, subcortical, and cerebellar regions during incorrect trials. These findings suggest that cerebellar and subcortical regions support working memory manipulation, highlighting a broader mechanism by which distributed brain regions interact to coordinate higher cognitive functions.

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bioRxiv2024

Targeted Time-Varying Functional Connectivity

To elucidate the neurobiological basis of cognition, which is dynamic and evolving, various methods have emerged to characterise time-varying functional connectivity (FC) and track the temporal evolution of functional networks. However, given a selection of regions, many of these methods are based on modelling all possible pairwise connections, diluting a potential focus of interest on individual connections. This is the case with the hidden Markov model (HMM), which relies on region-by-region covariance matrices across all pairs of selected regions, assuming that fluctuations in FC occur across all investigated connections; that is, that all connections are locked to the same temporal pattern. To address this limitation, we introduce Targeted Time-Varying FC (T-TVFC), a variant of the HMM that explicitly models the temporal fluctuations between two sets of regions in a targeted fashion, rather than across the entire connectivity matrix. In this study, we apply T-TVFC to both simulated and real-world data. Specifically, we investigate thalamocortical connectivity, hypothesizing distinct temporal signatures compared to corticocortical networks. Given the thalamuss role as a critical hub, thalamocortical connections might contain unique information about cognitive processing that could be overlooked in a coarser representation. We tested these hypotheses on high-field functional magnetic resonance data from 60 participants engaged in a reasoning task with varying complexity levels. Our findings demonstrate that the time-varying interactions captured by T-TVFC contain task-related information not detected by more traditional decompositions.

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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.

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bioRxiv2024

Cardiometabolic state links neurovascular burden with brain structure and function across age: evidence from EEG and MRI

Aging affects brain structure and function alongside metabolic and vascular processes leading to energetic impairments. While local neurometabolic dysfunction in aging is well-documented, the influence of systemic cardiometabolic and vascular markers on brain structure and function remains less understood. We examine the link between cardiometabolic dysfunction (measured by an allostatic load index) and neurovascular burden (measured by white matter hyperintensities) with brain changes, including ventricular and hippocampal volume, as well as EEG activity, across age. Analyzing data from 196 healthy individuals across age (20-75 years), we found a significant positive correlation between allostatic load index and white-matter hyperintensities, irrespective of age. White-matter hyperintensities are also positively linked with ventricular enlargement, but not hippocampal atrophy. The allostatic load index mediated the relationship between white-matter hyperintensities and ventricular volume. Regarding brain function, changes in the spectral aperiodic exponent but not periodic alpha power were linked to white-matter hyperintensities and the allostatic load index. Such index mediated the relationship between spectral aperiodic exponent and white-matter hyperintensities. Thus, findings suggest that the cardiometabolic state, as measured by an allostatic load index, plays a crucial role in brain health across age, particularly influencing ventricular enlargement and increased aperiodic activity.

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bioRxiv2024

Brain-wide impacts of sedation on spontaneous activity and auditory processing in larval zebrafish

Despite their widespread use, we have limited knowledge of the mechanisms by which sedatives mediate their effects on brain-wide networks. This is, in part, due to the technical challenge of observing activity across large populations of neurons in normal and sedated brains. In this study, we examined the effects of the sedative dexmedetomidine, and its antagonist atipamezole, on spontaneous brain dynamics and auditory processing in zebrafish larvae. Our brain-wide, cellular-resolution calcium imaging reveals, for the first time, the brain regions involved in these network-scale dynamics and the individual neurons that are affected within those regions. Further analysis reveals a variety of dynamic changes in the brain at baseline, including marked reductions in spontaneous activity, correlation, and variance. The reductions in activity and variance represent a "quieter" brain state during sedation, an effect that causes highly correlated evoked activity in the auditory system to stand out more than it does in un-sedated brains. We also observe a reduction in auditory response latencies across the brain during sedation, suggesting that the removal of spontaneous activity leaves the core auditory pathway free of impingement from other non-auditory information. Finally, we describe a less dynamic brain-wide network during sedation, with a higher energy barrier and a lower probability of brain state transitions during sedation. In total, our brain-wide, cellular-resolution analysis shows that sedation leads to quieter, more stable, and less dynamic brain, and that against this background, responses across the auditory processing pathway become sharper and more prominent. Significance StatementAnimals brain states constantly fluctuate in response to their environment and context, leading to changes in perception and behavioral choices. Alterations in perception, sensorimotor gating, and behavioral selection are hallmarks of numerous neuropsychiatric disorders, but the circuit- and network-level underpinnings of these alterations are poorly understood. Pharmacological sedation alters perception and responsiveness and provides a controlled and repeatable manipulation for studying brain states and their underlying circuitry. Here, we show that sedation of larval zebrafish with dexmedetomidine reduces brain-wide spontaneous activity and locomotion but leaves portions of brain-wide auditory processing and behavior intact. We describe and computationally model changes at the levels of individual neurons, local circuits, and brain-wide networks that lead to altered brain states and sensory processing during sedation.

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bioRxiv2023

Simultaneously-recorded cholinergic axons and cortical acetylcholine are highly correlated with pupil size and locomotion under spontaneous conditions

Even under spontaneous conditions and in the absence of changing environmental demands, awake animals alternate between increased or decreased periods of alertness. These changes in brain state can occur rapidly, on a timescale of seconds, and neuromodulators such as acetylcholine (ACh) are thought to play an important role in driving these spontaneous state transitions. Here, we perform the first simultaneous imaging of ACh sensors and GCaMP-expressing axons in vivo, to examine the spatiotemporal properties of cortical ACh activity and release during spontaneous changes in behavioral state. We observed a high correlation between simultaneously recorded basal forebrain axon activity and neuromodulator sensor fluorescence around periods of locomotion and pupil dilation. Consistent with volume transmission of ACh, increases in axon activity were accompanied by increases in local ACh levels that fell off with the distance from the nearest axon. GRAB-ACh fluorescence could be accurately predicted from axonal activity alone, providing the first validation that neuromodulator axon activity is a reliable proxy for nearby neuromodulator levels. Deconvolution of fluorescence traces allowed us to account for the kinetics of the GRAB-ACh sensor and emphasized the rapid clearance of ACh for smaller transients outside of running periods. Finally, we trained a predictive model of ACh fluctuations from the combination of pupil size and running speed; this model performed better than using either variable alone, and generalized well to unseen data. Overall, these results contribute to a growing understanding of the precise timing and spatial characteristics of cortical ACh during fast brain state transitions.

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bioRxiv2023

Integrating brainstem and cortical functional architectures

The brainstem is a fundamental component of the central nervous system yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.

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bioRxiv2023

Translating electrophysiological signatures of awareness into thalamocortical mechanisms by inverting systems-level computational models across arousal states

While consciousness never fades during wakefulness, there is a paradoxical coexistence of consciousness during dreaming states. Its also possible for sensory awareness to be either present or absent when awakened from seemingly-identical states of sedation and anaesthesia. Traditionally, these states have been characterised in terms of their electroencephalographic neural correlates, however, without clear underlying neurobiological mechanisms. To bridge this gap, we invert a validated neural mass model of the corticothalamic system using scalp EEG collected during nonlinear transitions in conscious experience and sensory awareness across varying depths of dexmedetomidine sedation. We found that a decline in conscious experience and sensory awareness with dexmedetomidine was associated with a decrease in the engagement of excitatory thalamocortical loop resonances, along with an increase in inhibitory intrathalamic loop gains. These findings shed light into the neural mechanisms of conscious experience and sensory awareness, and explain how it fades across arousal states, bridging the gap between the neural correlates of consciousness and its underlying systems-level thalamocortical mechanisms.

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bioRxiv2023

A Biophysical Model of Visual Rivalry Links Cellular Mechanisms to Signatures of Conscious Perception

Contemporary models of perceptual awareness lack tractable neurobiological constraints. Inspired by recent cellular recordings in a mouse model of tactile threshold detection, we constructed a biophysical model of perceptual awareness that incorporated essential features of thalamocortical anatomy and cellular physiology. Our model reproduced, and mechanistically explains, the key in vivo neural and behavioural signatures of perceptual awareness in the mouse model, as well as the response to a set of causal perturbations. We generalised the same model (with identical parameters) to a more complex task - visual rivalry - and found that the same thalamic-mediated mechanism of perceptual awareness determined perceptual dominance. This led to the generation of a set of novel, and directly testable, electrophysiological predictions. Analyses of the model based on dynamical systems theory show that perceptual awareness in simulations of both threshold detection and visual rivalry arises from the emergent systems-level dynamics of thalamocortical loops.

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bioRxiv2023

Criticality supports cross-frequency cortical-thalamic information transfer during conscious states

Consciousness is thought to be regulated by bidirectional information transfer between the cortex and thalamus, but the nature of this bidirectional communication - and its possible disruption in unconsciousness - remains poorly understood. Here, we present two main findings elucidating mechanisms of corticothalamic information transfer during conscious states. First, we identify a highly preserved spectral channel of cortical-thalamic communication which is present during conscious states but which is diminished during the loss of consciousness and enhanced during psychedelic states. Specifically, we show that in humans, mice, and rats, information sent from either the cortex or thalamus via{delta} /{theta}/ waves (~1.5-13 Hz) is consistently encoded by the other brain region by high{gamma} waves (~50-100 Hz); moroever, unconsciousness induced by propofol anesthesia or generalized spike-and-wave seizures diminishes this cross-frequency communication, whereas the psychedelic 5-methoxy-N,N/-dimethyltryptamine (5-MeO-DMT) enhances this interregional communication. Second, we leverage numerical simulations and neural electrophysiology recordings from the thalamus and cortex of human patients, rats, and mice to show that these changes in cross-frequency cortical-thalamic information transfer are mediated by excursions of low-frequency thalamocortical electrodynamics toward/away from edge-of-chaos criticality, or the phase transition from stability to chaos. Overall, our findings link thalamic-cortical communication to consciousness, and further offer a novel, mathematically well-defined framework to explain the disruption to thalamic-cortical information transfer during unconscious states.

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bioRxiv2022

Parallel processing relies on a distributed, low-dimensional cortico-cerebellar architecture

A characteristic feature of human cognition is our ability to multi-task - performing two or more tasks in parallel - particularly when one task is well-learned. How the brain supports this capacity remains poorly understood. Most past studies have focussed on identifying the areas of the brain - typically the dorsolateral prefrontal cortex - that are required to navigate information processing bottlenecks. In contrast, we take a systems neuroscience approach to test the hypothesis that the capacity to conduct effective parallel processing relies on a distributed architecture that interconnects the cerebral cortex with the cerebellum. The latter structure contains over half of the neurons in the adult human brain, and is well-suited to support the fast, effective, dynamic sequences required to perform tasks relatively automatically. By delegating stereotyped within-task computations to the cerebellum, the cerebral cortex can be freed up to focus on the more challenging aspects of performing the tasks in parallel. To test this hypothesis, we analysed task-based fMRI data from 50 participants who performed a task in which they either balanced an avatar on a screen ( Balance), performed serial-7 subtractions ( Calculation) or performed both in parallel ( Dual-Task). Using a set of approaches that include dimensionality reduction, structure-function coupling and time-varying functional connectivity, we provide robust evidence in support of our hypothesis. We conclude that distributed interactions between the cerebral cortex and cerebellum are crucially involved in parallel processing in the human brain.

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bioRxiv2022

Thalamocortical contribution to cognitive task activity

Thalamocortical interaction is a ubiquitous functional motif in the mammalian brain. Previously (Hwang et al., 2021), we reported that lesions to network hubs in the human thalamus are associated with multi-domain behavioral impairments in language, memory, and executive functions. Here we show how task-evoked thalamic activity and thalamocortical interactions are organized to support these broad cognitive abilities. To address this question, we analyzed functional MRI data from human subjects that performed 127 tasks encompassing a broad range of cognitive representations. We first investigated the spatial organization of task-evoked activity and found that multi-task thalamic activity converged onto a low-dimensional structure, through which a basis set of activity patterns are evoked to support processing needs of each task. Specifically, the anterior, medial, and posterior-medial thalamus exhibit hub-like activity profiles that are suggestive of broad functional participation. These thalamic task hubs overlapped with network hubs interlinking cortical systems. To further determine the cognitive relevance of thalamocortical interactions, we built a data-driven thalamocortical interaction model to test whether thalamocortical functional connectivity transformed thalamic activity to cortical task activity. The thalamocortical model predicted task-specific cortical activity patterns, and outperformed comparison models built on cortical, hippocampal, and striatal regions. Simulated lesions to low-dimensional, multi-task thalamic hub regions impaired task activity prediction. This simulation result was further supported by profiles of neuropsychological impairments in human patients with focal thalamic lesions. In summary, our results suggest a general organizational principle of how thalamocortical interactions support cognitive task activity. Impact StatementHuman thalamic activity transformed via thalamocortical functional connectivity to support task representations across functional domains.

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bioRxiv2021

Precision dynamical mapping using topological data analysis reveals a unique hub-like transition state at rest

Even in the absence of external stimuli, neural activity is both highly dynamic and organized across multiple spatiotemporal scales. The continuous evolution of brain activity patterns during rest is believed to help maintain a rich repertoire of possible functional configurations that relate to typical and atypical cognitive phenomena. Whether these transitions or "explorations" follow some underlying arrangement or instead lack a predictable ordered plan remains to be determined. Here, using a precision dynamics approach, we aimed at revealing the rules that govern transitions in brain activity at rest at the single participant level. We hypothesized that by revealing and characterizing the overall landscape of whole brain configurations (or states) we could interpret the rules (if any) that govern transitions in brain activity at rest. To generate the landscape of whole-brain configurations we used Topological Data Analysis based Mapper approach. Across all participants, we consistently observed a rich topographic landscape in which the transition of activity from one state to the next involved a central hub-like "transition state." The hub topography was characterized as a shared attractor-like basin where all canonical resting-state networks were represented equally. The surrounding periphery of the landscape had distinct network configurations. The intermediate transition state and traversal through it via a topographic gradient seemed to provide the underlying structure for the continuous evolution of brain activity patterns at rest. In addition, differences in the landscape architecture were more consistent within than between subjects, providing evidence of idiosyncratic dynamics and potential utility in precision medicine.

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bioRxiv2021

Intracranial electrical stimulation alters meso-scale network integration as a function of network topology

Human brain dynamics are organized into a multi-scale network structure that contains multiple tight-knit, meso-scale communities. Recent work has demonstrated that many psychological capacities, as well as impairments in cognitive function secondary to damage, can be mapped onto organizing principles at this mesoscopic scale. However, we still dont know the rules that govern the dynamic interactions between regions that are constrained by the topology of the broader network. In this preregistered study, we utilized a unique human dataset in which whole brain BOLD-fMRI activity was recorded simultaneously with intracranial electrical stimulation, to characterize the effects of direct neural stimulation on the dynamic reconfiguration of the broader network. Direct neural stimulation increased the extent to which the stimulation sites own mesoscale community integrated with the rest of the brain. Further, we found that these network changes depended on the topological role of the stimulation site itself: stimulating regions with high participation coefficients led to global integration, whereas stimulating sites with low participation coefficients integrated that regions own community with the rest of the brain. These findings provide direct causal evidence for how network topology shapes and constrains inter-regional coordination, and suggest applications for targeted therapeutic interventions in patients with deep-brain stimulation.

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