Jana Cernanova Krohova, Jana Oleksakova, Zuzana Turianikova, Barbora Czippelova, Milan Grofik, Egon Kurca, Michal Javorka
{"title":"Early parasympathetic dysfunction in Parkinson's disease: insights from information-theoretic analysis.","authors":"Jana Cernanova Krohova, Jana Oleksakova, Zuzana Turianikova, Barbora Czippelova, Milan Grofik, Egon Kurca, Michal Javorka","doi":"10.3389/fnetp.2025.1680069","DOIUrl":"10.3389/fnetp.2025.1680069","url":null,"abstract":"<p><strong>Introduction: </strong>Parasympathetic nervous system (PNS) dysfunction in Parkinson's disease (PD) has been frequently evaluated using heart rate variability (HRV) analysis in the time and frequency domains. Findings across studies have been inconsistent, limiting a unified understanding of early autonomic impairment.</p><p><strong>Methods: </strong>In this study, we applied both conventional and advanced analytical methods to evaluate cardiovascular PNS function in the early-stage PD patients. Sixteen individuals with PD (<6 months after motor signs occurrence) and sixteen age- and sex-matched healthy controls were assessed across three protocol phases (supine rest, head-up tilt, and supine recovery). Traditional HRV analysis in the high-frequency band was used to estimate the overall respiratory heart rate variability (RespHRV; updated and more appropriate term for the respiration-related heart rate oscillations formerly called respiratory sinus arrhythmia, RSA) magnitude. To distinguish between baroreflex-mediated and non-baroreflex RespHRV mechanisms, we employed multiscale Partial Information Decomposition (PID), an information-theoretic method. Cardiac baroreflex sensitivity (BRS), reflecting reflex parasympathetic control, was assessed using a causal estimation approach, further supported by a PID-derived parameter quantifying coupling between systolic arterial pressure and R-R intervals. Additionally, the presence of constipation - a clinically relevant non-motor symptom indicative of parasympathetic dysfunction was used to stratify the PD cohort.</p><p><strong>Results: </strong>Early-stage PD patients exhibited signs of parasympathetic impairment, particularly during orthostatic stress. HRV analysis showed reduced HF power during head-up tilt, while causal BRS was significantly lower across all protocol phases in the PD group. PID analysis further demonstrated a significant reduction in baroreflex-mediated mechanism of RespHRV during head-up tilt in PD patients compared with healthy controls, indicating early dysfunction of the cardiac chronotropic baroreflex. This impairment was more pronounced in the group with gastrointestinal issues (with the presence of constipation).</p><p><strong>Discussion: </strong>These findings support the α-Synuclein Origin site and Connectome model, which proposes that PD patients whose neurodegeneration originates in the peripheral autonomic nervous system are characterized by early and more severe autonomic dysfunction.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1680069"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aurora Rosato, Emanuele Perra, Eric Rullman, Seraina A Dual
{"title":"Walking-induced inertial effects on the cardiovascular system.","authors":"Aurora Rosato, Emanuele Perra, Eric Rullman, Seraina A Dual","doi":"10.3389/fnetp.2025.1637551","DOIUrl":"10.3389/fnetp.2025.1637551","url":null,"abstract":"<p><strong>Introduction: </strong>During exercise, the cardiovascular, respiratory, and locomotor systems interplay dynamically, yet the specific mechanisms of cardiovascular and locomotor interaction during simple rhythmic exercise like walking remain unclear. Computational models constitute a powerful tool to investigate the interplay of networked physiological systems, but while gravitational and postural effects on circulation have been explored, the influence of inertial forces from body motion on hemodynamics has not been addressed.</p><p><strong>Methods: </strong>Here, we present a closed-loop cardiovascular model that incorporates inertial effects during walking. The lumped parameter model includes 25 vascular compartments, a four-chamber heart with valves, pericardial and intrathoracic pressures, interventricular septal dynamics, and a baroreflex mechanism. Inertial effects are modeled as additional hydrodynamic pressure sources in each vascular segment, equivalent to the acceleration of blood mass, caused by gravity and motion. Three protocols are used: a head-up tilt test to validate baroreflex and gravity effects; a synthetic walking simulation with controlled heart rate (HR) and step rate (SR); and a human walking experiment (n=2) linking beat-wise simulated aortic pressure to measured brachial pressure using recorded HR and body acceleration. Beat-wise morphology similarity (K-stat) between experimental and simulated hemodynamic waveforms is quantified with a two-sample Kolmogorov-Smirnov test.</p><p><strong>Results: </strong>The model reproduces expected physiological responses to head-up tilt. During synthetic walking, inertial effects result in pressure augmentation, increasing systolic or diastolic pressure depending on the phase between HR and SR. With SR > HR, phase variability produces a low-frequency \"beating\" in the pressure waveforms and mean arterial pressure, corresponding to the difference between SR and HR. In the human subject experiment, the model accurately replicates beat-wise pressure changes at varying phase shifts between HR and SR. Quantitative comparison shows a substantial increase in similarity of waveform when hydrodynamic pressure is included (K-stat: 0.123 vs. 0.029 for P1; 0.164 vs. 0.059 for P2).</p><p><strong>Conclusion: </strong>Introducing contributions of body acceleration as an additional hydrodynamic pressure source in the vascular compartments seems a valid way to capture walking-induced inertial effects. This work contributes to the broader effort to characterize physiological network adaptations to exercise and offers a foundation for future research studying and optimizing cardiac-locomotor interaction.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1637551"},"PeriodicalIF":3.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Herbert F Jelinek, Mohanad Alkhodari, Ahsan H Khandoker, Leontios J Hadjileontiadis
{"title":"Oscillatory components of bidirectional cardio-respiratory coupling in depression and suicidal ideation: insights from swarm decomposition and entropy analysis.","authors":"Herbert F Jelinek, Mohanad Alkhodari, Ahsan H Khandoker, Leontios J Hadjileontiadis","doi":"10.3389/fnetp.2025.1620862","DOIUrl":"10.3389/fnetp.2025.1620862","url":null,"abstract":"<p><strong>Introduction: </strong>Major depressive disorder (MDD) and MDD with suicidal ideation (MDDSI) present with heterogeneous symptoms, complicating diagnosis and treatment. Precision psychiatry addresses this challenge by applying computational methods and digital biomarkers to objectively distinguish psychiatric states. While psychiatric research has traditionally focused on neural activity, increasing evidence highlights the value of autonomic indices, particularly heart rate variability (HRV), in capturing clinically relevant dysregulation. Cardio-respiratory coupling (CRC), which reflects bidirectional interactions between cardiovascular and respiratory systems, represents a physiologically grounded extension of this approach. Although less frequently applied in psychiatry compared to HRV, CRC offers a sensitive window into autonomic network dynamics and holds promise for differentiating between MDD and MDDSI.</p><p><strong>Methods: </strong>A total of 74 participants were assigned to Control (n = 35), MDD (n = 21), or MDDSI (n = 18) groups. ECG, PPG, and respiratory signals were recorded at rest and segmented into 2-min intervals. Swarm Decomposition (SwD) was applied to extract four oscillatory components (OC1-OC4) from each signal that go from low to high frequency, respectively. Fractal dimension (Higuchi, Katz) and Shannon entropy quantified coupling complexity. Bidirectional (λbi) and unidirectional (λ) coupling measures and phase angles were computed between respiratory signals and cardiovascular markers: pulse wave amplitude (PWA), pulse transit time (PTT), and pulse rate (PR). Group differences were evaluated using Kruskal-Wallis and <i>post hoc</i> tests (p < 0.05).</p><p><strong>Results: </strong>Bidirectional PR coupling in OC3 showed significant group differences (p < 0.01). Higuchi fractal dimension of PTT in OC3 was reduced in MDDSI compared to MDD and controls (p = 0.018), suggesting diminished complexity. For PWA in OC4, high-frequency power significantly differed between controls and MDDSI (p = 0.004). Directional coupling entropy also distinguished MDD from MDDSI (p = 0.039).</p><p><strong>Conclusion: </strong>This study reveals that frequency-specific disruptions in bidirectional cardiorespiratory coupling, along with reduced signal complexity and entropy, are characteristic of MDDSI. These features may reflect impaired autonomic adaptability and emotional regulation. Phase-based coupling metrics and SwD show promise as physiological biomarkers for early identification of high-risk depressive states in digital psychiatry.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1620862"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Analysis of a model for bacteriophage infections and bacteria defense: a synergetics perspective.","authors":"T D Frank","doi":"10.3389/fnetp.2025.1657313","DOIUrl":"10.3389/fnetp.2025.1657313","url":null,"abstract":"<p><p>A model for bacteriophage infections and bacteria defense is analyzed using the concepts of synergetics. The model order parameter is determined and the corresponding amplitude equations are derived. Within this framework it is shown how the order parameter defines a multi-species building block that captures the organization of infection outbreaks and the initial defense reaction and how the order parameter amplitude determines the corresponding temporal characteristics. Two approximative models with different domains of application are derived as well. In doing so, a supplementary perspective of bacteriophage infections that provides insights beyond the classical state space perspective is provided.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1657313"},"PeriodicalIF":3.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial: Wearable technology: the new ornament of network physiology.","authors":"Ankita Srivastava, Santosh Kumar Yadav","doi":"10.3389/fnetp.2025.1690563","DOIUrl":"https://doi.org/10.3389/fnetp.2025.1690563","url":null,"abstract":"","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1690563"},"PeriodicalIF":3.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhigang Zheng, Lin Yan, Tao Li, Jiajing Liu, Lei Wang, Yu Qian
{"title":"Competitive oscillatory dynamics in excitable neuron networks.","authors":"Zhigang Zheng, Lin Yan, Tao Li, Jiajing Liu, Lei Wang, Yu Qian","doi":"10.3389/fnetp.2025.1613288","DOIUrl":"10.3389/fnetp.2025.1613288","url":null,"abstract":"<p><p>Collective dynamics of networks of excitable neurons can be considered as the emergence of ordering from microscopic self-organization at the macroscopic scale. Sustained oscillation can emerge on networks of neurons even if a single neuron is dynamical excitable and non-oscillatory. Fundamental ingredients of networks such as loops, trees, and hubs, play distinct roles in supporting, propagating and impeding sustained oscillations. In this paper, we explore the mechanism of collective self-sustained oscillations on neuron networks by analyzing the functions of different topologies in shaping the oscillatory patterns on excitable neuron networks. The Winfree loops are revealed to be responsible for generating collective oscillations as the oscillation core, and other neurons act as the propagating paths. The existence of large numbers of loops in a network indicates potential competitions of the formation of collective oscillatory dynamics. The roles of loop-loop competition in homogeneous networks and loop-hub competition in heterogeneous networks are extensively discussed.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1613288"},"PeriodicalIF":3.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145115026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vincenzo Ronca, Lidia Castagneto Gissey, Maria Irene Bellini, Alessandra Iodice, Pietro Aricò, Gianluca Di Flumeri, Andrea Giorgi, Alessia Vozzi, Rossella Capotorto, Stefano Bonelli, Laura Moens, Fabio Babiloni, Giovanni Casella, Gianluca Borghini
{"title":"Mutual information-based teamwork evaluation in real-world environments: an exploratory investigation with professional surgeons.","authors":"Vincenzo Ronca, Lidia Castagneto Gissey, Maria Irene Bellini, Alessandra Iodice, Pietro Aricò, Gianluca Di Flumeri, Andrea Giorgi, Alessia Vozzi, Rossella Capotorto, Stefano Bonelli, Laura Moens, Fabio Babiloni, Giovanni Casella, Gianluca Borghini","doi":"10.3389/fnetp.2025.1608824","DOIUrl":"10.3389/fnetp.2025.1608824","url":null,"abstract":"<p><strong>Purpose: </strong>Teamwork involves intricate interactions among individuals or groups with shared goals. It necessitates effective communication, defined roles, decision-making processes, and the allocation of cognitive and emotional resources. Objective teamwork assessment demands a comprehensive set of metrics. Although subjective and behavioral metrics, such as self-evaluation and task completion time, are generally applied, they are prone to bias and a lack of objectivity, highlighting the inherent limitations of capturing the unconscious processes of human behavior.</p><p><strong>Methods: </strong>To mitigate these limitations, the present study proposed a novel approach to teamwork evaluation based on neurophysiological signals (electroencephalograms, EEGs) compatible with real-world applications, i.e., surgical teams engaged in real-world surgeries. To the best of our knowledge, there is no scientific evidence of an objective teamwork measure performed among more than two members and relying on neurophysiological signals in real-world environments. Therefore, the present work aimed at i) developing and investigating the reliability of an objective EEG-based teamwork index using mutual information (MI) methods and ii) providing additional and objective insights for surgeons' supervisors in healthcare training.</p><p><strong>Findings: </strong>The results demonstrated the capability of the EEG-based training index to provide additional and objective information, along with its added value and reliability compared to conventional measures (all R > 0.62, all <i>p</i> < 0.002). Furthermore, the EEG-based teamwork index allowed the determination (all <i>p</i> < 0.001) of surgeons' experience levels (expert vs novice) in terms of cooperative behavior.</p><p><strong>Conclusion: </strong>The results pave the way for targeted interventions, adaptive training sessions, and optimizations in team dynamics and open up opportunities for applying neurophysiological measurements for teamwork evaluation in all operational fields, where proper and granular teamwork optimization could play a crucial role in terms of safety.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1608824"},"PeriodicalIF":3.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12443683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145114973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Livio Clemente, Marianna La Rocca, Sebastiano Stramaglia, Daniele Marinazzo, Raffaella Lombardi, Giuseppe Lauria, Marina de Tommaso
{"title":"Temporal interaction information and laser evoked responses: preliminary results in fibromyalgia patients with small fibers pathology.","authors":"Livio Clemente, Marianna La Rocca, Sebastiano Stramaglia, Daniele Marinazzo, Raffaella Lombardi, Giuseppe Lauria, Marina de Tommaso","doi":"10.3389/fnetp.2025.1592518","DOIUrl":"10.3389/fnetp.2025.1592518","url":null,"abstract":"<p><strong>Objectives: </strong>We propose a novel application of higher-order information-theoretic measures to assess the temporal interaction information (TII) between laser-evoked potentials (LEPs) and individual pain ratings in healthy subjects and patients with fibromyalgia (FM) affected by small fiber pathology.</p><p><strong>Methods: </strong>Seventy-nine FM patients, categorized into three groups based on skin biopsy findings (normal innervation n 19, proximal denervation n 53, and both proximal and distal denervation n 7), and 14 control subjects were studied. We used cluster-based permutation tests (p < 0.05) to identify significant clusters of TII between cortical components recorded using a 64-channel electroencephalography (EEG) system - with focus on the Cz electrode - and subjective pain ratings to quantify synergy or redundancy between the LEP signal time points and Visual Analog Scale (VAS).</p><p><strong>Results: </strong>Control subjects generally exhibited synergy clusters corresponding to N2 and P2 peaks, whereas patients with fibromyalgia (FM), particularly those with distal denervation, exhibited increased redundancy and decreased synergy.</p><p><strong>Conclusion: </strong>Patients with FM and small fiber pathology exhibited an alteration in higher-order integration mechanisms due to a complex interaction between cortical processing of pain and denervation of nociceptive fibers.</p><p><strong>Significance: </strong>These findings highlight the potential of TII in elucidating the complex interplay between peripheral nerve integrity and central sensitization in FM and other chronic pain disorders.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1592518"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cristiana Dimulescu, Ronja Strömsdörfer, Agnes Flöel, Klaus Obermayer
{"title":"On the robustness of the emergent spatiotemporal dynamics in biophysically realistic and phenomenological whole-brain models at multiple network resolutions.","authors":"Cristiana Dimulescu, Ronja Strömsdörfer, Agnes Flöel, Klaus Obermayer","doi":"10.3389/fnetp.2025.1589566","DOIUrl":"10.3389/fnetp.2025.1589566","url":null,"abstract":"<p><p>The human brain is a complex dynamical system which displays a wide range of macroscopic and mesoscopic patterns of neural activity, whose mechanistic origin remains poorly understood. Whole-brain modelling allows us to explore candidate mechanisms causing the observed patterns. However, it is not fully established how the choice of model type and the networks' spatial resolution influence the simulation results, hence, it remains unclear, to which extent conclusions drawn from these results are limited by modelling artefacts. Here, we compare the dynamics of a biophysically realistic, linear-nonlinear cascade model of whole-brain activity with a phenomenological Wilson-Cowan model using three structural connectomes based on the Schaefer parcellation scheme with 100, 200, and 500 nodes. Both neural mass models implement the same mechanistic hypotheses, which specifically address the interaction between excitation, inhibition, and a slow adaptation current which affects the excitatory populations. We quantify the emerging dynamical states in detail and investigate how consistent results are across the different model variants. Then we apply both model types to the specific phenomenon of slow oscillations, which are a prevalent brain rhythm during deep sleep. We investigate the consistency of model predictions when exploring specific mechanistic hypotheses about the effects of both short- and long-range connections and of the antero-posterior structural connectivity gradient on key properties of these oscillations. Overall, our results demonstrate that the coarse-grained dynamics is robust to changes in both model type and network resolution. In some cases, however, model predictions do not generalize. Thus, some care must be taken when interpreting model results.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1589566"},"PeriodicalIF":3.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ethan Israel, Joseph K Hall, Yuqing Deng, Jason H T Bates, Béla Suki
{"title":"Bifurcation in the healing or fibrotic response in a network model of fibrosis: role of the initial injury structure.","authors":"Ethan Israel, Joseph K Hall, Yuqing Deng, Jason H T Bates, Béla Suki","doi":"10.3389/fnetp.2025.1589216","DOIUrl":"10.3389/fnetp.2025.1589216","url":null,"abstract":"<p><strong>Introduction: </strong>Pulmonary fibrosis (PF) is a heterogeneous progressive lung disease characterized by excessive extracellular matrix (ECM) deposition and cross-linking, leading to irreversible tissue stiffening and loss of function. Previous evidence suggests that percolation behavior, where increasing local stiffness facilitates the emergence of stiff regions that span the tissue, underlies the stiffening of the ECM and drives the irreversible mechanical dysfunction. However, it is not fully understood how percolation emerges from the complex interactions between cells and the ECM.</p><p><strong>Methods: </strong>In this study, we investigated a previously published agent-based spring network model of PF that exhibited bifurcation behavior between healing and fully developed fibrosis as network members were gradually stiffened. By systematically analyzing the configuration of the initial tissue injury, we identify key structural determinants that govern whether an injury heals or transitions into fibrosis.</p><p><strong>Results: </strong>Results demonstrate that fibrosis is strongly associated with increased initial clustering of injured springs, reduced intercluster distances, and the presence of critical stiffening sites, or hotspots, that act as bifurcation points for disease progression. Furthermore, we show that selectively modifying the stiffness of pivotal network regions at the time of injury can shift the network's trajectory from fibrosis to healing, highlighting potential intervention targets. These findings suggest that the network structure of tissue injury may serve as a predictive marker for fibrosis susceptibility and provide a mechanistic basis for understanding the nonlinear progression of PF.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"5 ","pages":"1589216"},"PeriodicalIF":3.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}