Biology subjects

Muller, E. J.

Publications and source records attributed to Muller, E. J..

12 recordsLinked to original sources

bioRxiv2026

Dynamic Routing on a Static Structure: Noradrenergic Gatingof Cortical Wave Propagation

Stimulus-evoked cortical responses range from tightly localized activations to spatially extended traveling waves, yet the mechanisms through which these distinct regimes are flexibly recruited remain unclear. Based on neuroanatomical and neuroimaging evidence, we hypothesize that the noradrenergic (NA) arousal system, originating in the locus coeruleus (LC), dynamically modulates cortical gain to shape spatiotemporal propagation under a fixed anatomical backbone. To test this hypothesis, we extend an empirically grounded corticothalamic neural field model to incorporate an LC which delivers modulatory (gain-changing) rather than driving inputs to cortex. We then examine evoked responses under phasic versus tonic NA modulation, with geometry given by distance-dependent connectivity plus additional long-range fast-conducting non-local projections (FNPs). Phasic LC activation produces spatiotemporally sustained traveling waves of cortical activity, whereas tonic activation yields temporally prolonged but spatially localized responses; without modulation, waves are weak and dissipative. Timing and spatial pattern of LC engagement gate wave-onset latency and impose anisotropy, restricting propagation to modulated territories and halting it across unmodulated gaps. In the presence of long-range FNPs, modulation enables rapid non-local activation of distant cortical regions and sharply lowers the gain required for long-distance routing. These results identify NA phasic gain control as a parsimonious mechanism for variability in evoked dynamics and for context-dependent privileging of specific communication pathways over a largely static connectome. Author summaryThe brain doesnt always react to a stimulus in the same way: sometimes the response is local, while at other times it sweeps across the cortex as a wave. We propose that this flexibility can be controlled by the noradrenergic arousal signaling from the locus coeruleus (LC), which adjusts the gain of cortical circuits rather than directly driving them. Using an empirically grounded corticothalamic model augmented with an LC, we contrasted brief phasic bursts versus sustained tonic modulation. Phasic LC activity promoted robust traveling waves, while tonic activity produced longer-lasting but spatially confined responses. By further specifying when and where it engages, the LC can gate where waves start, which directions they travel, and where they stop--even across unmodulated gaps. When long-range connections are present, LC modulation also enables rapid, selective activation of distant targets and dramatically lowers the gain needed for long-distance routing. This neuromodulatory mechanism offers a simple, testable account of trial-to-trial variability in evoked dynamics, capturing a mechanism through which the brain can transiently privilege specific communication pathways through a static structural connectome.

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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.

neuroscience↗

bioRxiv2024

Thalamic Control Over Laminar Cortical Dynamics Across Conscious States

The human brain must support both stable and flexible neural dynamics in order to adapt to changing contexts that are inherently non-linear. The thalamus has been linked to the coordination of these opposing dynamical regimens in the cerebral cortex, however existing methodological approaches have not integrated sufficient neurobiological details with a sensitive measure of neural dynamics that permits sensitivity to time-series non-linearities. Inspired by the field of fluid dynamics, we use a novel approach to show that spontaneous fMRI data exhibits non-trivial fluctuations in predictability over time, akin to a river that has sections of smooth and predictable (laminar) versus rough and unpredictable (non-laminar) fluid flow. We use a combination of pharmacological fMRI, macaque electrophysiology and a large-scale biophysical model of the thalamocortical system to provide robust evidence that the thalamus provides versatile control over globally linear dynamics in the cerebral cortex that characterize conscious states.

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bioRxiv2024

Phylogenetically-Preserved Multiscale Neuronal Activity: Iterative Coarse-Graining Reconciles Scale-Dependent Theories of Brain Function

Brain recordings collected at different resolutions support statistically distinct signatures of information processing, leading to scale-dependent theories of brain function. Here, we demonstrate that these disparate neural-coding signatures emerge from the same multiscale functional organisation of neuronal activity across calcium-imaging recordings collected from the whole brains of zebrafish and nematode, as well as sensory regions of the fly, mouse, and macaque brain. Network simulations show that hierarchical-modular structural connectivity facilitates multiscale functional coordination, enhancing information processing benefits such as a maximal dynamic range. Finally, we demonstrate that this cross-scale organisation supports distinct behavioural states across species by reconfiguring functional affiliation and temporal dynamics at the mesoscale. Our findings suggest that self-similar scaling of neuronal activity is a universal principle that reconciles scale-dependent theories of brain function, facilitating both efficiency and resiliency while enabling significant reconfiguration of mesoscale cellular ensembles to accommodate behavioural demands.

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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

Personalized stimulation therapies for disorders of consciousness: A computational approach to inducing healthy-like brain activity based on neural field theory

Disorders of consciousness (DoC) pose significant challenges in neurology. Conventional neuromodulation therapies for DoC have exhibited limited success, with varying effectiveness among patients. In this study, we introduce a computational approach for constructing personalized stimulus signals capable of inducing healthy-like neural activity patterns in DoC patients. Leveraging a simplified brain model based on neural field theory, we fit this model to the power spectrum of a patient with DoC and derive a personalized stimulus time series to induce a healthy-like power spectrum. By applying this stimulus to brain regions typically targeted by stimulation therapies such as deep brain stimulation and repetitive transcranial magnetic stimulation, we demonstrate in silico the ability of our method to elicit EEG power spectra resembling those of healthy individuals. We speculate that in the course of a long-term treatment, when the brain produces healthy-like activity, it may trigger intrinsic plasticity mechanisms, potentially leading to sustained improvements in the patients condition. While further clinical adjustments and validation are needed, this novel approach offers promise in tailoring brain stimulation therapies for DoC patients. Moreover, it presents potential extensions to other conditions that could also benefit from brain stimulation therapies. Author summaryIn this research, we tackled a challenging issue in the field of neurology - disorders of consciousness (DoC). These conditions, which include states like coma and the minimally consciousness state, have been difficult to treat effectively. While traditional brain stimulation treatments have been tried, they do not always work well, and their effects can vary greatly from one person to another. Thus, we set out to find a new way to help these patients. Our approach involves using computer models of the brain to design personalized treatments. We designed a method to generate stimulation signals tailored to individual DoC patients. These signals aim to trigger healthier brain activity patterns, similar to those found in individuals without consciousness disorders. What is exciting is that if the brain begins to produce these healthy-like patterns, it could potentially lead to lasting improvements in the patients consciousness level. We show that this approach works in different simulations, and can be applied in multiple neuromodulation techniques like deep brain stimulation and transcranial magnetic stimulation. This research opens up new possibilities for more effective treatments for people dealing with these challenging disorders. Plus, it might work for other conditions treated with similar brain stimulation therapies.

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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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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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bioRxiv2021

Extracting dynamical understanding from neural-mass models of mouse cortex

New brain atlases with high spatial resolution and whole-brain coverage have rapidly advanced our knowledge of the brains neural architecture, including the systematic variation of excitatory and inhibitory cell densities across the mammalian cortex. But understanding how the brains microscale physiology shapes brain dynamics at the macroscale has remained a challenge. While physiologically based mathematical models of brain dynamics are well placed to bridge this explanatory gap, their complexity can form a barrier to providing clear mechanistic interpretation of the dynamics they generate. In this work we develop a neural-mass model of the mouse cortex and show how bifurcation diagrams, which capture local dynamical responses to inputs and their variation across brain regions, can be used to understand the resulting whole-brain dynamics. We show that strong fits to resting-state functional magnetic resonance imaging (fMRI) data can be found in surprisingly simple dynamical regimes--including where all brain regions are confined to a stable fixed point--in which regions are able to respond strongly to variations in their inputs, consistent with direct structural connections providing a strong constraint on functional connectivity in the anesthetized mouse. We also use bifurcation diagrams to show how perturbations to local excitatory and inhibitory coupling strengths across the cortex, constrained by cell-density data, provide spatially dependent constraints on resulting cortical activity, and support a greater diversity of coincident dynamical regimes. Our work illustrates methods for visualizing and interpreting model performance in terms of underlying dynamical mechanisms, an approach that is crucial for building explanatory and physiologically grounded models of the dynamical principles that underpin large-scale brain activity.

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bioRxiv2021

The ascending arousal system shapes low-dimensional brain dynamics to mediate awareness of changes in intrinsic cognitive states

Models of cognitive function typically focus on the cerebral cortex and hence overlook functional links to subcortical structures. This view neglects the highly-conserved ascending arousal systems role and the computational capacities it provides the brain. In this study, we test the hypothesis that the ascending arousal system modulates cortical neural gain to alter the low-dimensional energy landscape of cortical dynamics. Our analyses of spontaneous functional magnetic resonance imaging data and phasic bursts in both locus coeruleus and basal forebrain demonstrate precise time-locked relationships between brainstem activity, low-dimensional energy landscapes, network topology, and spatiotemporal travelling waves. We extend our analysis to a cohort of experienced meditators and demonstrate locus coeruleus-mediated network dynamics were associated with internal shifts in conscious awareness. Together, these results present a novel view of brain organization that highlights the ascending arousal systems role in shaping both the dynamics of the cerebral cortex and conscious awareness.

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bioRxiv2020

Core and Matrix Thalamic Sub-Populations Relate to Spatio-Temporal Cortical Connectivity Gradients

Recent neuroimaging experiments have defined low-dimensional gradients of functional connectivity in the cerebral cortex that subserve a spectrum of capacities that span from sensation to cognition. Despite well-known anatomical connections to the cortex, the subcortical areas that support cortical functional organization have been relatively overlooked. One such structure is the thalamus, which maintains extensive anatomical and functional connections with the cerebral cortex across the cortical mantle. The thalamus has a heterogeneous cytoarchitecture, with at least two distinct cell classes that send differential projections to the cortex: granular-projecting Core cells and supragranular-projecting Matrix cells. Here we use high-resolution 7T resting-state fMRI data and the relative amount of two calcium-binding proteins, parvalbumin and calbindin, to infer the relative distribution of these two cell-types (Core and Matrix, respectively) in the thalamus. First, we demonstrate that thalamocortical connectivity recapitulates large-scale, low-dimensional connectivity gradients within the cerebral cortex. Next, we show that diffusely-projecting Matrix regions preferentially correlate with cortical regions with longer intrinsic fMRI timescales. We then show that the Core-Matrix architecture of the thalamus is important for understanding network topology in a manner that supports dynamic integration of signals distributed across the brain. Finally, we replicate our main results in a distinct 3T resting-state fMRI dataset. Linking molecular and functional neuroimaging data, our findings highlight the importance of the thalamic organization for understanding low-dimensional gradients of cortical connectivity.

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