Biology subjects

Ashworth, C.

Publications and source records attributed to Ashworth, C..

3 recordsLinked to original sources

bioRxiv2026

Short-Term Variability Reveals Early Neural Mechanisms of Pain Chronification

Moment-to-moment fluctuations in perceived pain are often dismissed as noise. However, across neural systems, rapid variability reflects fundamental network properties such as stability and flexibility, and in pain, reduced variability has been linked to chronic pain severity. Here, we tested whether alterations in such variability mark an early mechanistic transition from subacute to chronic pain. Using a longitudinal dataset of 120 individuals with subacute back pain followed over one year, we analysed continuous pain ratings alongside fMRI activity during spontaneous pain. We show that patients who develop persistent pain exhibit a marked decrease in moment-to-moment pain variability over the course of one year, in contrast to recovering individuals whose variability increases over time. Neural activity in thalamo-cortico-limbic and modulatory circuits associated with these fluctuations at pain onset predicts clinical outcomes one year later. Notably, similar predictive patterns are observed during the early post-onset, indicating that these neural signatures emerge early and remain stable during the initial phase of disease progression. These findings indicate that early loss of dynamical flexibility is a hallmark of pain chronification and identify moment-to-moment variability as a clinically accessible marker of the systems dynamical state.

neuroscience↗

bioRxiv2025

Multi-timescale Rhythmic Dynamics in Rostral Ventromedial Medulla Neurons

Effective pain therapies increasingly target neural circuits that regulate nociceptive processing; yet, how descending control systems regulate pain across time remains poorly understood. Because pain regulation must coordinate rapid defensive responses with slower fluctuations in physiological state, these neural circuits are likely to operate across multiple timescales. However, whether such dynamics exist in brainstem pain-control circuits remains largely unknown. Here, we investigated this question in populations of rostral ventromedial medullary (RVM) pain-modulating neurons. The RVM contains ON- and OFF-cells that exert descending control over spinal nociceptive transmission, regulating pain sensitivity and behaviors. By integrating neuronal recordings with probabilistic modeling, we show that unstimulated and stimulus-driven conditions give rise to distinct timescales of ON- and OFF-cell dynamics. During noxious stimulation, we find that population responses undergo rapid activation followed by superimposed slow and fast recovery dynamics over tens of seconds. In contrast, the same neurons exhibit quasi-periodic fluctuations in firing activity on the order of minutes in the absence of stimulation. Gaussian-process models show that these slow dynamics are statistically predictable from past activity, indicating structured temporal organization beyond stimulus-evoked responses. Taken together, these results indicate that descending pain-control circuits exhibit structured dynamics spanning rapid pain-related signaling and slower fluctuations associated with ongoing physiological state. SignificancePain regulation requires coordination between rapid defensive responses and slower changes in physiological state, yet how these processes are integrated in the brain remains unclear. We show that neurons in a key brainstem pain-control center, the rostral ventromedial medulla, operate across multiple timescales. Using neuronal recordings and computational modeling, we find that these neurons exhibit both fast responses to painful stimuli and slow, structured fluctuations in ongoing activity. These results demonstrate that descending pain control is temporally organized beyond immediate stimulus-evoked responses. This provides a framework for understanding how pain is regulated over time.

neuroscience↗

bioRxiv2025

Mapping Leukocyte Dynamics during Neuroinflammation Identifies Meningeal Monocyte-Derived Macrophages as Drivers of Progressive Disease

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by increasing disability. The cellular and molecular drivers of clinical transition towards progressive disease are poorly understood. Here, we combine single-cell profiling technologies with genetic and pharmacological perturbations across the course of murine CNS inflammation to dissect the role of the local immune landscape in disease progression. We uncover a chronic monocyte-to-phagocyte transition as a hallmark of progressive disease, characterized by the emergence of maladaptive, lipid-associated macrophages (LAMs) marked by lysosomal activation and fibrotic features. Spatial transcriptomics and multiplexed imaging revealed that these LAMs localized to the leptomeninges in close proximity to parenchymal colony-stimulating factor (CSF)-1 producing disease-associated microglia (DAMs) and meningeal granulocyte-macrophage (GM)-CSF-expressing T helper cells that license their differentiation. Interference with this local cytokine network revealed a protective role for resident microglia and implicated monocyte-derived phagocytes as key drivers of progressive neuroinflammation. Notably, LAM-like macrophages could also be identified in the meninges of people with MS, indicating a homology to human disease. By elucidating their ontogeny, spatial niche, and regulatory cytokine milieu, we provide a mechanistic framework for targeting harmful myeloid states while preserving reparative CNS immunity in progressive MS.

immunology↗