Brain criticality has emerged as a rapidly growing focus of research among neuroscientists and physicists. The latest experimental evidence suggests that even isolated neurons display signs of criticality. Using a stochastic type-I parametrization of the Hodgkin-Huxley model, we investigate the origin of these critical dynamics. We show that the model adequately approximates the experimentally observed behavior, as it reproduces the qualitative relationship between the critical state and both the applied external stimulation and the spiking rate. External white noise further enhances any pre-existing critical intermittency but cannot by itself toggle the system into a critical state. The emergence of the critical state is conditional on the system's proximity to its spiking bifurcation point, and any divergence from it results in the abolition of the dynamics. We treat the neuronal membrane as a complex self-organizing system composed of interacting ion channels and propose that the observed dynamics result from an almost critical state.

Background/Objectives: Epilepsy is a brain condition that affects millions of people worldwide. Although there are many antiepileptic drugs with different mechanisms of action, many patients still fail to control their agonizing symptoms, a situation that highlights the need for more strategies to address this issue. In this in vitro study, we elucidated and characterized the alterations in intracellular Ca2+ levels in cell cultures where diazepam and repetitive transcranial magnetic stimulation were implemented, alone or in combination. Methods: Using the differentiated human-derived neuroblastoma cell line SH-SY5Y, we measured the alterations in intracellular Ca2+ levels under the impact of either low-frequency repetitive transcranial magnetic stimulation (1 Hz), diazepam (14 μM), or their combination. We used the Ca2+-sensitive fluorescent indicator Fluo-4 acetoxymethyl ester for calcium imaging, while neuronal excitation was achieved with 50 mM KCl. Results: The highest median fluorescence intensity increase (%ΔF/F = 24.80) was observed in control cell cultures, followed by rTMS cultures (%ΔF/F = 16.96) and diazepam cultures (%ΔF/F = 11.46). The lowest median fluorescence intensity value (%ΔF/F =−0.44) was observed when diazepam was used concomitantly with repetitive transcranial magnetic stimulation. Post hoc analysis assessed pairwise differences, showing statistically significant differentiation between the control group and all other groups. Additionally, statistically significant results were observed between repetitive transcranial magnetic stimulation or diazepam and their combination, but not between them. Conclusions: The combination of diazepam and repetitive transcranial magnetic stimulation resulted in the most significant reduction in intracellular Ca2+ levels, as indicated by the lowest fluorescence values compared with the control group. Individually, each treatment produced a notable but less pronounced effect. We conclude that both diazepam and low-frequency repetitive transcranial magnetic stimulation can control epileptiform activity in vitro, while their combination is the most effective treatment.

Background/Objectives: Epilepsy is identified by irregular neuronal hyperexcitability, generating recurrent seizures. Despite many available pharmacological treatments, certain patients with drug-resistant epilepsy may require novel therapeutic approaches. In the present study, we aimed to evaluate the effects of lacosamide, low-frequency repetitive transcranial magnetic stimulation, and their combination on intracellular calcium dynamics in an in vitro model of neuronal excitability, hypothesizing that these interventions could mitigate potassium chloride-induced neuronal excitation. Methods: We utilized differentiated SH-SY5Y human neuroblastoma cells as an in vitro model of neuronal excitability. Neuronal excitability was induced with 50 mM KCl, and cells were treated with lacosamide (300 µM), rTMS (1 Hz), or their combination. Intracellular calcium levels were quantified using fluo-4 AM fluorescence calcium imaging, with changes expressed as percentage change in fluorescence intensity (%ΔF/F) relative to baseline. Results: The combination of lacosamide and rTMS was the most effective, significantly reducing KCl-induced calcium elevation (ΔF/F = 9.15) compared to lacosamide alone (ΔF/F = 17.11), rTMS alone (ΔF/F = 23.70), and the untreated cells serving as controls (ΔF/F = 66.70). The combination showed a statistically significant effect, with enhanced suppression of neuronal excitability compared to individual treatments. Conclusions: Lacosamide and low-frequency rTMS (1 Hz) effectively attenuated KCl-induced changes in intracellular calcium levels in vitro, with their combination demonstrating the highest efficacy. These findings suggest a promising foundation in the management of drug-resistant epilepsy. Future studies are necessitated to validate these results and benefit clinical translation.

Background: Critical states present scale-free dynamics, optimizing neuronal complexity. We explored electroencephalogram (EEG) criticality in amnesic Mild Cognitive Impairment (aMCI) patients with clinical improvement in working memory, verbal memory, verbal fluency and overall executive functions after the completion of a 6-month prospective memory training. (2) Methods: We compared “before” and “after” stationary resting-state EEG records of right-handed MCI patients (n = 17; 11 females), using the method of critical fluctuations and Haar wavelet analysis. (3) Results: Significant criticality enhancement was present in frontotemporal electrodes [mean dif: 0.10; Z = 7, p = .019] and isolated electrodes T6 [mean dif: 0.204; t (10) = - 2.3, p = .044] and F4 [mean dif: 0.0194; t (10) = - 2.82; p = .018]. (4) Conclusions: EEG criticality agreed with clinical improvement, consisting a possible monitoring biomarker in MCI and Alzheimer’s disease. Further evaluation is needed in patients under cognitive training or even drug-modifying therapies.

PDF file - 55K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by NRAS and ERK cluster status.

PDF file - 65K, REMARK Flow Chart of E2303 translational research study.

PDF file - 64K, Summary of Biomarker AQUA Scores at Baseline.

PDF file - 67K, Odds Ratio and Hazard Ratio (with 95% Confidence Interval) with A Unit Increase in the Form of log10 Transformation in AQUA Scores by Biomarker.

PDF file - 81K, Primary antibodies Used for Immunohistochemistry.

EEG recordings give extremely noisy signals that do not allow classical methods to clearly display such as the existence of power laws or even more so the critical state that is a signature of the normal operation of biological tissues (Contoyiannis et al., Phys Rev Lett 93:098101, 2004; Contoyiannis et al., Nat Hazards Earth Syst Sci 13:125–139, 2013; Kosmidis et al., Eur J Neurosci, 2018. https://doi.org/10.1111/ejn.14117 ). We have recently introduced a method, based on Haar wavelet transformation (Contoyiannis et al. Phys. Rev. E 101:052104, 2020), that completely ignores noise and thus can reveal the information of the power law in EEGs. It calculates the exponent of the power law and thus gives us the ability to determine whether the brain is in critical state in terms of physics, i.e., in a state of normal biological function. Pathological conditions, such as epilepsy, are quantified through this method so we can observe their evolution.

In this paper, we present a new method for successfully simulating the dynamics of COVID-19, experimentally focusing on the third wave. This method, namely, the Method of Parallel Trajectories (MPT), is based on the recently introduced self-organized diffusion model. According to this method, accurate simulation of the dynamics of the COVID-19 infected population evolution is accomplished by considering not the total data for the infected population, but successive segments of it. By changing the initial conditions with which each segment of the simulation is produced, we achieve close and detailed monitoring of the evolution of the pandemic, providing a tool for evaluating the overall situation and the fine-tuning of the restrictive measures. Finally, the application of the proposed MPT on simulating the pandemic's third wave dynamics in Greece and Italy is presented, verifying the method's effectiveness.

The recently introduced [Contoyiannis et al., 2021] hybrid artificial neural network can simulate the dynamics of membrane potential fluctuations of real neurons based on fundamental principles of Physics. Here, we propose a temporal description of the membrane potential fluctuations, which resembles the soliton solutions in φ4 field theory. Within this framework, kink-antikink dynamics are associated with spike generation. Furthermore, we show that the simulation can also reproduce the distribution of inter-spike intervals of biological neurons in their critical state [Kosmidis et al., 2018]. A proposal for the intermittency origin of these fluctuations is discussed.

Recently, it has been successfully shown that the temporal evolution of the fraction of COVID-19 infected people possesses the same dynamics as the ones demonstrated by a self-organizing diffusion model over a lattice, in the frame of universality. In this brief, the relevant emerging dynamics are further investigated. Evidence that this nonlinear model demonstrates critical dynamics is scrutinized within the frame of the physics of critical phenomena. Additionally, the concept of criticality over the infected population fraction in epidemics (or a pandemic) is introduced and its importance is discussed, highlighting the emergence of the critical slowdown phenomenon. A simple method is proposed for estimating how far away a population is from this "singular" state, by utilizing the theory of critical phenomena. Finally, a dynamic approach applying the self-organized diffusion model is proposed, resulting in more accurate simulations, which can verify the effectiveness of restrictive measures. All the above are supported by real epidemic data case studies.

Combining concepts of artificial neural networks (ANNs) with the stochastic dynamics of Ising spin lattices we introduce a hybrid model, the hybrid spin model (HSM). We find that the HSM carries the critical/tricritical fluctuations of the 2D Ising model and allows for an accurate estimation of the isothermal critical/tricritical exponents of 2D Ising universality class. Our work clearly demonstrates that HSM launches a new category of models supporting alternative pathways for the realization of criticality in complex networks artificial or real.

The CA1 area in the mammalian hippocampus is essential for spatial learning. Pyramidal cells are the hippocampus output neurons and their activities are regulated by inhibition exerted by a diversified population of interneurons. Lateral inhibition has been suggested as the mechanism enabling the reconfiguration of pyramidal cell assembly activity observed during spatial learning tasks in rodents. However, lateral inhibition in the CA1 lacks the overwhelming evidence reported in other hippocampal areas such as the CA3 and the dentate gyrus. The use of genetically encoded voltage indicators and fast optical recordings permits the construction of cell-type specific response maps of neuronal activity. Here, we labelled mouse CA1 pyramidal neurons with the genetically encoded voltage indicator ArcLight and optically recorded their response to Schaffer Collaterals stimulation in vitro. By undertaking a manifold learning approach, we report a hyperpolarization-dominated area focused in the perisomatic region of pyramidal cells receiving late excitatory synaptic input. Functional network organization metrics revealed that information transfer was higher in this area. The localized hyperpolarization disappeared when GABAA receptors were pharmacologically blocked. This is the first report where the spatiotemporal pattern of lateral inhibition is visualized in the CA1 by expressing a genetically encoded voltage indicator selectively in principal neurons. Our analysis suggests a fundamental role of lateral inhibition in CA1 information processing.

The objective of this cross-sectional study is to compare the prevalence of sexual dysfunction in premenopausal women with breast cancer in Greece, who receive adjuvant endocrine therapy with either tamoxifen or aromatase inhibitors (AI), with or without ovarian function suppression (OFS). A second endpoint is to investigate and compare the incidence of genitourinary symptoms and conditions. A questionnaire was distributed on hardcopy and through an online platform from November 2018 to March 2019, to Greek-speaking women of 18 years of age or older, who had been receiving adjuvant endocrine therapy for breast cancer for at least three months and were deemed premenopausal/perimenopausal at diagnosis. The questionnaire included investigator-generated items regarding demographics, sexual and gynecologic history, as well as validated instruments for sexual functioning and urogenital tract disorders (FSFI, QLQ-BR23, UDI-6 and PFIQ-7). Of the 108 received responses, 70 were considered eligible for analysis. Most participants were currently on treatment with tamoxifen/OFS (N=35). Women on AI/OFS reported great deterioration of their sex life compared to women on tamoxifen with OFS (p=0.001). Sexual dysfunction was evident in 74% (N=49) of our participants, as defined by the cutoff value of 26 for the FSFI total score (median: 17.45, IQR=26.18). In particular, women on AI/OFS had significantly lower scores compared to those on tamoxifen with (20.8, 95%CI [14.58;22.67] vs 8.8, 95%CI [4.86;13.60], p=0.040) and without OFS (19.95, 95%CI [13;22.91] vs 8.8, 95%CI [4.86;13.60], p=0.039). Sexual enjoyment of women on AI/OFS was significantly affected compared to women on tamoxifen with or without OFS (p=0.019 and p=0.020, respectively). No differences in vaginal atrophy symptoms or gynecologic conditions were detected. Sexual dysfunction is highly prevalent in premenopausal women on endocrine therapy, especially in those treated with aromatase inhibitors and ovarian function suppression. Health professionals should promote discussions with their patients in order to decide the optimal treatment choice.

Evidence that neural circuits are operating near criticality has been provided at various levels of brain organisation with a presumed role in maximising information processing and multiscale activity association. Criticality has been linked to excitation at both the single‐cell and network levels, as action potential generation marks an obvious phase transition from a resting to an excitable state. Using in vitro intracellular recordings, we examine irregular, small amplitude membrane potential fluctuations from CA1 pyramidal neurons of Wistar male rats. We show that these fluctuations, confounded with noise, carry information relevant to the neuronal state. The underlying dynamics exhibit intermittent characteristics shown to describe the temporal fluctuations of the order parameter of a macroscopic system at its critical point even in the absence of firing. An externally applied stimulus serves as the control parameter, driving the system in and out of its critical state. Based on our experimental observations we calculate the equivalent of the isothermal critical exponent δh finding a value which depends on the applied stimulus. For each neuron there is a stimulus amplitude for which the critical behaviour becomes most pronounced. The corresponding mean value of δh in the considered ensemble of neurons is δh ≈ 1.89, close to theoretical predictions for critical networks. Finally, we show that the firing rate of a neuron decreases exponentially with δh.

•LCM, PHT and TPM exert significant effects on peripheral nerve excitability.•PHT has a neurotoxic potential even at subtherapeutic levels.•TPM, at low concentrations, may exert a neuroprotective effect on the PNS.•LCM appears to increase the viability of peripheral nerves at therapeutic levels.•The possible antinociceptive potential of LCM warrants further study.

The axonal translocation of two commonly used nanoparticles in medicine, namely CeO2 and SiO2, is investigated. The study was conducted on frog sciatic nerve fibers in an ex vivo preparation. Nanoparticles were applied at the proximal end of the excised nerve. A nerve stimulation protocol was followed for over 35 hours. Nerve vitality curve comparison between control and exposed nerves showed that CeO2 has no neurotoxic effect at the concentrations tested. After exposure, specimens were fixed and then screen scanned every 1 mm along their length for nanoparticle presence by means of Fourier transform infrared microscopy. We demonstrated that both nanoparticles translocate within the nerve by formation of narrow bands in the Fourier transform infrared spectrum. For the CeO2, we also demonstrated that the translocation depends on both axonal integrity and electrical activity. The speed of translocation for the two species was estimated in the range of 0.45-0.58 mm/h, close to slow axonal transportation rate. Transmission electron microscopy provided direct evidence for the presence of SiO2 in the treated nerves.