Statistical thermodynamics of the human brain activity, the Hagedorn temperature and the Zipf law.

It is well established that the brain spontaneously traverses through a very large number of states. Nevertheless, despite its relevance to understanding brain function, a formal description of this phenomenon is still lacking. To this end, we introduce a machine learning based method allowing for the determination of the probabilities of all possible states at a given coarse-graining, from which all the thermodynamics can be derived. This is a challenge not unique to the brain, since similar problems are at the heart of the statistical mechanics of complex systems. This paper uncovers a linear scaling of the entropies and energies of the brain states, a behaviour first conjectured by Hagedorn to be typical at the limiting temperature in which ordinary matter disintegrates into quark matter. Equivalently, this establishes the existence of a Zipf law scaling underlying the appearance of a wide range of brain states. Based on our estimation of the density of states for large scale functional magnetic resonance imaging (fMRI) human brain recordings, we observe that the brain operates asymptotically at the Hagedorn temperature. The presented approach is not only relevant to brain function but should be applicable for a wide variety of complex systems.

Beehive scale-free emergent dynamics.

It has been repeatedly reported that the collective dynamics of social insects exhibit universal emergent properties similar to other complex systems. In this note, we study a previously published data set in which the positions of thousands of honeybees in a hive are individually tracked over multiple days. The results show that the hive dynamics exhibit long-range spatial and temporal correlations in the occupancy density fluctuations, despite the characteristic short-range bees' mutual interactions. The variations in the occupancy unveil a non-monotonic function between density and bees' flow, reminiscent of the car traffic dynamic near a jamming transition at which the system performance is optimized to achieve the highest possible throughput. Overall, these results suggest that the beehive collective dynamics are self-adjusted towards a point near its optimal density.

Trial-by-trial variability in cortical responses exhibits scaling of spatial correlations predicted from critical dynamics.

In the mammalian cortex, even simple sensory inputs or movements activate many neurons, with each neuron responding variably to repeated stimuli-a phenomenon known as trial-by-trial variability. Understanding the spatial patterns and dynamics of this variability is challenging. Using cellular 2-photon imaging, we study visual and auditory responses in the primary cortices of awake mice. We focus on how individual neurons' responses differed from the overall population. We find consistent spatial correlations in these differences that are unique to each trial and linearly scale with the cortical area observed, a characteristic of critical dynamics as confirmed in our neuronal simulations. Using chronic multi-electrode recordings, we observe similar scaling in the prefrontal and premotor cortex of non-human primates during self-initiated and visually cued motor tasks. These results suggest that trial-by-trial variability, rather than being random noise, reflects a critical, fluctuation-dominated state in the cortex, supporting the brain's efficiency in processing information.

Beehive scale-free emergent dynamics.

It has been repeatedly reported that the collective dynamics of social insects exhibit universal emergent properties similar to other complex systems. In this note, we study a previously published data set in which the positions of thousands of honeybees in a hive are individually tracked over multiple days. The results show that the hive dynamics exhibit long-range spatial and temporal correlations in the occupancy density fluctuations, despite the characteristic short-range bees' mutual interactions. The variations in the occupancy unveil a non-monotonic function between density and bees' flow, reminiscent of the car traffic dynamic near a jamming transition at which the system performance is optimized to achieve the highest possible throughput. Overall, these results suggest that the beehive collective dynamics are self-adjusted towards a point near its optimal density.

Scale-free correlations in the dynamics of a small (N∼10000) cortical network.

The advent of novel optogenetics technology allows the recording of brain activity with a resolution never seen before. The characterization of these very large data sets offers new challenges as well as unique theory-testing opportunities. Here we discuss whether the spatial and temporal correlations of the collective activity of thousands of neurons are tangled as predicted by the theory of critical phenomena. The analysis shows that both the correlation length ξ and the correlation time τ scale as predicted as a function of the system size. With some peculiarities that we discuss, the analysis uncovers evidence consistent with the view that the large-scale brain cortical dynamics corresponds to critical phenomena.

Evaluation of a polymeric topical formulation of Endoxifen in an estrogen receptor positive breast cancer murine model.

Breast cancer (BC) has surpassed lung cancer as the most diagnosed cancer and, in terms of mortality, is the fifth leading cause with 684,996 new deaths (6.7% of all cancer-related deaths) and the highest mortality amongst all cancers (15.5%) in women. Selective estrogen-receptor modulators (SERMs) have been used for the last thirty years for estrogen receptor-positive (ER+) BC prevention and treatment. Tamoxifen (TAM), the most widely used SERM, is orally administered and its long-term oral administration has been associated to toxicity and adverse side effects. Endoxifen (EDX) is one of the known active metabolites of TAM, with an affinity to ERα 100 times higher than TAM. Furthermore, EDX has shown antiproliferative activity against the ER+ BC cell line MCF-7. Alternative administration routes that avoid the metabolic processing of TAM seem an appealing alternative to its oral administration. With this aim, we have prepared a polymeric gel-like solution of Pluronic® F127 as vehicle for topical administration of EDX. In order to shed light on the potential clinical use of this formulation, we have compared it with the standard pharmaceutical form, i.e. orally administered TAM. The biodistribution, antitumor efficacy and toxic effects of topical EDX and oral TAM were evaluated in ER+ tumor xenograft athymic nu/nu mouse models. The results showed a statistically significant antitumor effect and reduced toxicity of topical EDX as compared to oral TAM or empty F127 gel. This novel administration route of SERMs could also have a strong impact in the prevention of BC at early development stages and could help to ameliorate the mortality and morbidity related to this disease.

Parabolic avalanche scaling in the synchronization of cortical cell assemblies.

Neurons in the cerebral cortex fire coincident action potentials during ongoing activity and in response to sensory inputs. These synchronized cell assemblies are fundamental to cortex function, yet basic dynamical aspects of their size and duration are largely unknown. Using 2-photon imaging of neurons in the superficial cortex of awake mice, we show that synchronized cell assemblies organize as scale-invariant avalanches that quadratically grow with duration. The quadratic avalanche scaling was only found for correlated neurons, required temporal coarse-graining to compensate for spatial subsampling of the imaged cortex, and suggested cortical dynamics to be critical as demonstrated in simulations of balanced E/I-networks. The corresponding time course of an inverted parabola with exponent of χ = 2 described cortical avalanches of coincident firing for up to 5 s duration over an area of 1 mm2. These parabolic avalanches maximized temporal complexity in the ongoing activity of prefrontal and somatosensory cortex and in visual responses of primary visual cortex. Our results identify a scale-invariant temporal order in the synchronization of highly diverse cortical cell assemblies in the form of parabolic avalanches.

Self-tuned criticality: Controlling a neuron near its bifurcation point via temporal correlations.

Previous work showed that the collective activity of large neuronal networks can be tamed to remain near its critical point by a feedback control that maximizes the temporal correlations of the mean-field fluctuations. Since such correlations behave similarly near instabilities across nonlinear dynamical systems, it is expected that the principle should control also low-dimensional dynamical systems exhibiting continuous or discontinuous bifurcations from fixed points to limit cycles. Here we present numerical evidence that the dynamics of a single neuron can be controlled in the vicinity of its bifurcation point. The approach is tested in two models: a two-dimensional generic excitable map and the paradigmatic FitzHugh-Nagumo neuron model. The results show that in both cases, the system can be self-tuned to its bifurcation point by modifying the control parameter according to the first coefficient of the autocorrelation function.

Finite-size correlation behavior near a critical point: A simple metric for monitoring the state of a neural network.

In this article, a correlation metric κ_{c} is proposed for the inference of the dynamical state of neuronal networks. κ_{C} is computed from the scaling of the correlation length with the size of the observation region, which shows qualitatively different behavior near and away from the critical point of a continuous phase transition. The implementation is first studied on a neuronal network model, where the results of this new metric coincide with those obtained from neuronal avalanche analysis, thus well characterizing the critical state of the network. The approach is further tested with brain optogenetic recordings in behaving mice from a publicly available database. Potential applications and limitations for its use with currently available optical imaging techniques are discussed.

Tricritical behavior in a neural model with excitatory and inhibitory units.

While the support for the relevance of critical dynamics to brain function is increasing, there is much less agreement on the exact nature of the advocated critical point. Thus, a considerable number of theoretical efforts are currently concentrated on which mechanisms and what type(s) of transition can be exhibited by neuronal network models. In that direction, the present work describes the effect of incorporating a fraction of inhibitory neurons on the collective dynamics. As we show, this results in the appearance of a tricritical point for highly connected networks and a nonzero fraction of inhibitory neurons.

Universal dynamics of mitochondrial networks: a finite-size scaling analysis.

Evidence from models and experiments suggests that the networked structure observed in mitochondria emerges at the critical point of a phase transition controlled by fission and fusion rates. If mitochondria are poised at criticality, the relevant network quantities should scale with the system's size. However, whether or not the expected finite-size effects take place has not been demonstrated yet. Here, we first provide a theoretical framework to interpret the scaling behavior of mitochondrial network quantities by analyzing two conceptually different models of mitochondrial dynamics. Then, we perform a finite-size scaling analysis of real mitochondrial networks extracted from microscopy images and obtain scaling exponents comparable with critical exponents from models and theory. Overall, we provide a universal description of the structural phase transition in mammalian mitochondria.

Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

Learning by mistakes in memristor networks.

Recent results revived the interest in the implementation of analog devices able to perform brainlike operations. Here we introduce a training algorithm for a memristor network which is inspired by previous work on biological learning. Robust results are obtained from computer simulations of a network of voltage-controlled memristive devices. Its implementation in hardware is straightforward, being scalable and requiring very little peripheral computation overhead.

Mortality due to COVID-19 in Spain and its association with environmental factors and determinants of health.

Background: The objective of this study was to identify which air pollutants, atmospheric variables and health determinants could influence COVID-19 mortality in Spain. This study used information from 41 of the 52 provinces in Spain (from Feb. 1, to May 31, 2021). Generalized Linear Models (GLM) with Poisson link were carried out for the provinces, using the Rate of Mortality due to COVID-19 (CM) per 1,000,000 inhabitants as dependent variables, and average daily concentrations of PM10 and NO2 as independent variables. Meteorological variables included maximum daily temperature (Tmax) and average daily absolute humidity (HA). The GLM model controlled for trend, seasonalities and the autoregressive character of the series. Days with lags were established. The relative risk (RR) was calculated by increases of 10 g/m3 in PM10 and NO2 and by 1 â„ƒ in the case of Tmax and 1 g/m3 in the case of HA. Later, a linear regression was carried out that included the social determinants of health. Results: Statistically significant associations were found between PM10, NO2 and the CM. These associations had a positive value. In the case of temperature and humidity, the associations had a negative value. PM10 being the variable that showed greater association, with the CM followed of NO2 in the majority of provinces. Anyone of the health determinants considered, could explain the differential geographic behavior. Conclusions: The role of PM10 is worth highlighting, as the chemical air pollutant for which there was a greater number of provinces in which it was associated with CM. The role of the meteorological variables-temperature and HA-was much less compared to that of the air pollutants. None of the social determinants we proposed could explain the heterogeneous geographical distribution identified in this study. Supplementary Information: The online version contains supplementary material available at 10.1186/s12302-022-00617-z.

Short-term influence of environmental factors and social variables COVID-19 disease in Spain during first wave (Feb-May 2020).

This study aims to identify the combined role of environmental pollutants and atmospheric variables at short term on the rate of incidence (TIC) and on the hospital admission rate (TIHC) due to COVID-19 disease in Spain. This study used information from 41 of the 52 provinces of Spain (from Feb. 1, 2021 to May 31, 2021). Using TIC and TIHC as dependent variables, and average daily concentrations of PM10 and NO2 as independent variables. Meteorological variables included maximum daily temperature (Tmax) and average daily absolute humidity (HA). Generalized linear models (GLM) with Poisson link were carried out for each provinces The GLM model controlled for trend, seasonalities, and the autoregressive character of the series. Days with lags were established. The relative risk (RR) was calculated by increases of 10 µg/m3 in PM10 and NO2 and by 1 °C in the case of Tmax and 1 g/m3 in the case of HA. Later, a linear regression was carried out that included the social determinants of health. Statistically significant associations were found between PM10, NO2, and the rate of COVID-19 incidence. NO2 was the variable that showed greater association, both for TIC as well as for TIHC in the majority of provinces. Temperature and HA do not seem to have played an important role. The geographic distribution of RR in the studied provinces was very much heterogeneous. Some of the health determinants considered, including income per capita, presence of airports, average number of diesel cars per inhabitant, average number of nursing personnel, and homes under 30 m2 could explain the differential geographic behavior. As findings indicates, environmental factors only could modulate the incidence and severity of COVID-19. Moreover, the social determinants and public health measures could explain some patterns of geographically distribution founded.

Non-linear Functional Brain Co-activations in Short-Term Memory Distortion Tasks.

Recent works shed light on the neural correlates of true and false recognition and the influence of time of day on cognitive performance. The current study aimed to investigate the modulation of the false memory formation by the time of day using a non-linear correlation analysis originally designed for fMRI resting-state data. Fifty-four young and healthy participants (32 females, mean age: 24.17 ± 3.56 y.o.) performed in MR scanner the modified Deese-Roediger-McDermott paradigm in short-term memory during one session in the morning and another in the evening. Subjects' responses were modeled with a general linear model, which includes as a predictor the non-linear correlations of regional BOLD activity with the stimuli, separately for encoding and retrieval phases. The results show the dependence of the non-linear correlations measures with the time of day and the type of the probe. In addition, the results indicate differences in the correlations measures with hippocampal regions between positive and lure probes. Besides confirming previous results on the influence of time-of-day on cognitive performance, the study demonstrates the effectiveness of the non-linear correlation analysis method for the characterization of fMRI task paradigms.

Revisiting Nonlinear Functional Brain Co-activations: Directed, Dynamic, and Delayed.

The center stage of neuro-imaging is currently occupied by studies of functional correlations between brain regions. These correlations define the brain functional networks, which are the most frequently used framework to represent and interpret a variety of experimental findings. In the previous study, we first demonstrated that the relatively stronger blood oxygenated level dependent (BOLD) activations contain most of the information relevant to understand functional connectivity, and subsequent work confirmed that a large compression of the original signals can be obtained without significant loss of information. In this study, we revisit the correlation properties of these epochs to define a measure of nonlinear dynamic directed functional connectivity (nldFC) across regions of interest. We show that the proposed metric provides at once, without extensive numerical complications, directed information of the functional correlations, as well as a measure of temporal lags across regions, overall offering a different and complementary perspective in the analysis of brain co-activation patterns. In this study, we provide further details for the computations of these measures and for a proof of concept based on replicating existing results from an Autistic Syndrome database, and discuss the main features and advantages of the proposed strategy for the study of brain functional correlations.

Observing changes in human functioning during induced sleep deficiency and recovery periods.

Prolonged periods of sleep restriction seem to be common in the contemporary world. Sleep loss causes perturbations of circadian rhythmicity and degradation of waking alertness as reflected in attention, cognitive efficiency and memory. Understanding whether and how the human brain recovers from chronic sleep loss is important not only from a scientific but also from a public health perspective. In this work we report on behavioral, motor, and neurophysiological correlates of sleep loss in healthy adults in an unprecedented study conducted in natural conditions and comprising 21 consecutive days divided into periods of 4 days of regular life (a baseline), 10 days of chronic partial sleep restriction (30% reduction relative to individual sleep need) and 7 days of recovery. Throughout the whole experiment we continuously measured the spontaneous locomotor activity by means of actigraphy with 1-minute resolution. On a daily basis the subjects were undergoing EEG measurements (64-electrodes with 500 Hz sampling frequency): resting state with eyes open and closed (8 minutes long each) followed by Stroop task lasting 22 minutes. Altogether we analyzed actigraphy (distributions of rest and activity durations), behavioral measures (reaction times and accuracy from Stroop task) and EEG (amplitudes, latencies and scalp maps of event-related potentials from Stroop task and power spectra from resting states). We observed unanimous deterioration in all the measures during sleep restriction. Further results indicate that a week of recovery subsequent to prolonged periods of sleep restriction is insufficient to recover fully. Only one measure (mean reaction time in Stroop task) reverted to baseline values, while the others did not.

Box scaling as a proxy of finite size correlations.

The scaling of correlations as a function of size provides important hints to understand critical phenomena on a variety of systems. Its study in biological structures offers two challenges: usually they are not of infinite size, and, in the majority of cases, dimensions can not be varied at will. Here we discuss how finite-size scaling can be approximated in an experimental system of fixed and relatively small extent, by computing correlations inside of a reduced field of view of various widths (we will refer to this procedure as "box-scaling"). A relation among the size of the field of view, and measured correlation length, is derived at, and away from, the critical regime. Numerical simulations of a neuronal network, as well as the ferromagnetic 2D Ising model, are used to verify such approximations. Numerical results support the validity of the heuristic approach, which should be useful to characterize relevant aspects of critical phenomena in biological systems.