Biology subjects

Mancini, F.

Publications and source records attributed to Mancini, F..

11 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↗

bioRxiv2024

Enhanced behavioural and neural sensitivity to punishments in chronic pain and fatigue

Chronic pain and fatigue in musculoskeletal disease contribute significantly to disability, and recent studies suggest an association with reduced motivation and excessive fear avoidance. In this behavioural neuroimaging study in chronic inflammatory arthritis participants and healthy controls, we aimed to identify the specific behavioral and neural changes associated pain and fatigue during reward and loss decision-making. Computational modeling of behaviour identified a parametric signature, characterized most notably by increased punishment sensitivity. This signature is distinct from patterns previously reported in psychiatric conditions and it aligns with predictions of mechanistic models of chronic pain such as the fear avoidance model. Neural activity associated with the punishment prediction error was enhanced in the right posterior insular cortex, putamen, pallidum, and dorsolateral prefrontal cortex. Functional network connectivity analysis showed that insula centrality correlated with subjective reports of fatigue and pain. Overall, the findings show that pain and fatigue in chronic pain relate to objective behavioural changes, and can be mapped to a specific pattern of activity in brain circuits of motivation and decision-making.

neuroscience↗

bioRxiv2022

Confidence of probabilistic predictions modulates the cortical response to pain

Pain typically evolves over time and the brain needs to learn this temporal evolution to predict how pain is likely to change in the future and orient behavior. This process is termed temporal statistical learning (TSL). Recently, it has been shown that TSL for pain sequences can be achieved using optimal Bayesian inference, which is encoded in somatosensory processing regions. Here, we investigate whether the confidence of these probabilistic predictions modulates the EEG response to noxious stimuli, using a TSL task. Confidence measures the uncertainty about the probabilistic prediction, irrespective of its actual outcome. Bayesian models dictate that the confidence about probabilistic predictions should be integrated with incoming inputs and weight learning, such that it modulates the early components of the EEG responses to noxious stimuli, and this should be captured by a negative correlation: when confidence is higher, the early neural responses are smaller as the brain relies more on expectations/predictions and less on sensory inputs (and vice versa). We show that participants were able to predict the sequence transition probabilities using Bayesian inference, with some forgetting. Then, we find that the confidence of these probabilistic predictions was negatively associated with the amplitude of the N2 and P2 components of the Vertex Potential: the more confident were participants about their predictions, the smaller was the Vertex Potential. These results confirm key predictions of a Bayesian learning model and clarify the functional significance of the early EEG responses to nociceptive stimuli, as being implicated in confidence-weighted statistical learning. SIGNIFICANCEThe functional significance of EEG responses to pain has long been debated because of their dramatic variability. This study indicates that such variability can be partly related to the confidence of probabilistic predictions emerging from sequences of pain inputs. The confidence of pain predictions is negatively associated with the cortical EEG responses to pain. This indicates that the brain relies less on sensory inputs when confidence is higher and shows us that confidence-weighted statistical learning modulates the cortical response to pain.

neuroscience↗

bioRxiv2021

Learning the statistics of pain: computational and neural mechanisms

Pain invariably changes over time, and these temporal fluctuations are riddled with uncertainty about body safety. In theory, statistical regularities of pain through time contain useful information that can be learned, allowing the brain to generate expectations and inform behaviour. To investigate this, we exposed healthy participants to probabilistic sequences of low and high-intensity electrical stimuli to the left hand, containing sudden changes in stimulus frequencies. We demonstrate that humans can learn to extract these regularities, and explicitly predict the likelihood of forthcoming pain intensities in a manner consistent with optimal Bayesian models with dynamic update of beliefs. We studied brain activity using functional MRI whilst subjects performed the task, which allowed us to dissect the underlying neural correlates of these statistical inferences from their uncertainty and update. We found that the inferred frequency (posterior probability) of high intensity pain correlated with activity in bilateral sensorimotor cortex, secondary somatosensory cortex and right caudate. The uncertainty of statistical inferences of pain was encoded in the right superior parietal cortex. An intrinsic part of this hierarchical Bayesian model is the way that unexpected changes in frequency lead to shift beliefs and update the internal model. This is reflected by the KL divergence between consecutive posterior distributions and associated with brain responses in the premotor cortex, dorsolateral prefrontal cortex, and posterior parietal cortex. In conclusion, this study extends what is conventionally considered a sensory pain pathway dedicated to process pain intensity, to include the generation of Bayesian internal models of temporal statistics of pain intensity levels in sensorimotor regions, which are updated dynamically through the engagement of premotor, prefrontal and parietal regions.

neuroscience↗

bioRxiv2021

Directed differentiation of hPSCs through lateral plate mesoderm for generation of articular cartilage progenitors

Developmentally the articular joints are derived from lateral plate (LP) mesoderm. However, no study has produced LP derived prechondrocytes or preosteoblasts from human pluripotent stem cells (hPSC) in a chemically defined manner. Differentiation of hPSCs through the authentic route, via an LP-osteochondral progenitor (OCP), may aid understanding of human cartilage development and the generation of effective cell therapies for osteoarthritis. We refined our existing chondrogenic protocol, incorporating knowledge from development and other studies to produce a LP-OCP from which prechondrocytes- and preosteoblast-like cells can be produced. Results show the formation of an OCP, which can be further driven to prechondrocytes and preosteoblasts. Prechondrocytes cultured in pellets produced cartilage like matrix with lacunae and superficial flattened cells expressing lubricin. Additionally, preosteoblasts were able to generate a mineralised structure. This protocol can therefore be used to further investigate cartilage development and in the development of joint cartilage for potential treatments.

developmental biology↗

bioRxiv2020

Prefrontal responses during proactive and reactive inhibition are differentially impacted by stress in anorexia and bulimia nervosa

BackgroundBinge-eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in fronto-striatal regions implicated in self-regulatory control. However, it remains unknown if negative affective states, including stress, impair self-regulation, and, if so, whether such self-regulatory deficits generalize to binge-eating in underweight individuals (i.e., the bingeing/purging subtype of anorexia nervosa; AN-BP). MethodsWe determined the effect of acute stress on inhibitory control in 85 women (33 BN, 22 AN-BP, 30 matched controls). Participants underwent repeated functional MRI scanning, during performance of the stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses to induced, psychological stress and a control task were evaluated on two separate days. ResultsWomen with BN had reduced proactive inhibition while prefrontal responses were increased in both AN-BP and BN. Reactive inhibition was neurally and behaviorally intact in both diagnostic groups. Both AN-BP and BN groups showed distinct, stress-induced changes in prefrontal activity during both proactive and reactive inhibition. However, task performance was not significantly affected by stress. ConclusionsThese findings offer novel evidence of reduced proactive inhibition in BN, yet inhibitory control deficits did not generalize to AN-BP. While both groups showed altered neural responses during inhibition following stress, neither group demonstrated stress-induced performance deficits. As such, our findings counsel against a simplistic, stress-induced failure of regulation as a holistic explanation for binge-eating in these conditions.

neuroscience↗

bioRxiv2019

Within-finger maps of tactile and nociceptive input in the human parietal cortex

The spatial representation of nociceptive input in the human parietal cortex is not fully understood. For instance, it is known that the primary somatosensory cortex (S1) contains a representation of nociceptive-selective input to different fingers, but it is unclear whether S1 subdivisions contain finer-grained, within-finger maps of nociceptive input. It is also unknown whether within-finger maps of somatosensory input exist in intraparietal regions. Therefore, we used high-field 7T functional MRI to reveal within-finger maps of nociceptive and tactile inputs in the human parietal cortex. Although we replicated the previous findings of between-finger maps of nociceptive input spanning S1 subdivisions, we found weak and inconsistent evidence for within-finger maps of nociceptive input in S1 subdivisions. In the same subjects, we found mirrored, within-finger maps of tactile input in areas 3a, 3b, and 1. Importantly, we discovered a within-finger map of nociceptive input, but not of tactile input, in the human intraparietal area 1 (hIP1). In conclusion, our study indicates that the spatial representation of nociceptive input in the parietal cortex partly differs from that of tactile input and reports the discovery of a within-finger map of nociceptive input in hIP1.\n\nNew & NoteworthyWe report the discovery of a fine-grained map of nociceptive input to finger segments in the human intraparietal area 1.

neuroscience↗

bioRxiv2018

Preserved cortical maps of the body in Complex Regional Pain Syndrome

Chronic pain can be associated with functional and morphological changes in the brain. It has long been thought that some severe chronic pain conditions, such as Complex Regional Pain Syndrome (CRPS), are not only associated with, but even maintained by a reorganisation of the somatotopic representation of the affected limb in the primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used functional MRI to characterize the S1 representation of the affected and unaffected hand in patients with unilateral CRPS of one hand. Our study demonstrates that the cortical area, location, and geometry of the S1 representation of the CRPS hand are comparable to those of the healthy hand, as well as to those of controls. Given that S1 representations are largely preserved in CPRS patients, it is compelling to reconsider not only the cortical mechanisms that underlie the disorder, but also the rationale for interventions that aim to \"restore\" somatotopic representations.

neuroscience↗

bioRxiv2017

Characterising the short-term habituation of event-related evoked potentials

Fast-rising sensory events evoke a series of functionally heterogeneous event-related potentials (ERPs). Stimulus repetition at 1 Hz is known to induce a strong habituation of the largest ERP responses, the vertex waves, which are elicited by stimuli regardless of their modality7, provided that they are salient and behaviourally-relevant. In contrast, the effect of stimulus repetition on the earlier sensor)7 components of ERls has been less explored, and the few existing results are inconsistent. To characterize how the different ERP waves habituate over time, we recorded the responses elicited by 60 identical somatosensory stimuli (activating either non-nociceptive A {beta} or nociceptive A5 afferents), delivered at 1 Hz to healthy human participants. We show that the well-described spatiotemporal sequence of lateralised and vertex ERP components elicited by the first stimulus of the series is largely preserved in the smaller-amplitude, habituated response elicited by the last stimuli of the series. We also found that the earlier lateralised sensory waves habituate across the 60 trials following the same decay function of the vertex waves: this decay function is characterised by a large drop at the first stimulus repetition followed by smaller decreases at subsequent repetitions. Interestingly, the same decay functions described the habituation of ERPs elicited by repeated non-nociceptive and nociceptive stimuli. This study provides a neurophysiological characterization of the effect of prolonged and repeated stimulation on the main components of somatosensory ERPs. It also demonstrates that both lateralised waves and vertex waves are obligator}7 components of ERPs elicited by non-nociceptive and nociceptive stimuli.\n\nSignificance statementOur results provide a functional characterization of the decay of the different ERP components when identical somatosensory (nociceptive and non-nociceptive) stimuli are repeated at 1Hz. East-rising stimuli elicit ERPs obligator)7 contributed by both early lateralised components and late vertex components, even when stimulus repetition minimizes stimulus relevance. This challenges the view that lateralised waves are not obligatorily elicited by nociceptive stimuli. Furthermore, the lateralised and vertex waves habituate to stimulus repetition following similar decay functions, which are unlikely explained in terms of fatigue or adaptation of skin receptors.

neuroscience↗

bioRxiv2016

Using social media to quantify spatial and temporal dynamics of wildlife tourism activities

Big data offer a great opportunity for nature-based recreation (NbR) mapping and evaluation. However, it is important to determine when and how it is appropriate to use this resource. We used Scotland as a case study to validate the use of data from Flickr as an indicator of NbR on a national scale and at several regional spatial and temporal resolutions. We compared Flickr photographs to visitor statistics in the Cairngorms National Park (CNP) and determined whether temporal variability in photo counts could be explained by known annual estimates of CNP visitor numbers. We then used a unique recent national survey of nature recreation in Scotland to determine whether the spatial distribution of Flickr photos could be explained by known spatial variability in nature use. Following this validation work, we used Flickr data to identify hotspots of wildlife watching in Scotland and investigated how they changed between 2005 and 2015.We found that spatial and temporal patterns in Flickr count are explained by measures of visitation obtained through surveys and that this relationship is reliable down to a 10 Km scale resolution. Our findings have implications for planning and management of NbR as they suggest that photographs uploaded on Flickr reflect patterns of NbR at spatial and temporal scales that are relevant for ecosystem management.

ecology↗