Anticorrelations between Active Brain Regions: An Agent-Based Model Simulation Study.

Anticorrelations among brain areas observed in fMRI acquisitions under resting state are not endowed with a well-defined set of characters. Some evidence points to a possible physiological role for them, and simulation models showed that it is appropriate to explore such an issue. A large-scale brain representation was considered, implementing an agent-based brain-inspired model (ABBM) incorporating the SER (susceptible-excited-refractory) cyclic mechanism of state change. The experimental data used for validation included 30 selected functional images of healthy controls from the 1000 Functional Connectomes Classic collection. To study how different fractions of positive and negative connectivities could modulate the model efficiency, the correlation coefficient was systematically used to check the goodness-of-fit of empirical data by simulations under different combinations of parameters. The results show that a small fraction of positive connectivity is necessary to match at best the empirical data. Similarly, a goodness-of-fit improvement was observed upon addition of negative links to an initial pattern of only-positive connections, indicating a significant information intrinsic to negative links. As a general conclusion, anticorrelations showed that it is crucial to improve the performance of our simulation and, since these cannot be assimilated to noise, should be always considered in order to refine any brain functional model.

Investigation on the capability of polysulphone for measuring biologically effective solar UV exposures.

Polysulphone (PS) dosimetry is a well-known technique broadly used to assess the erythemally effective solar UV dose received by anatomical sites (personal exposure). We investigate the capability of PS dosimetry to convert doses absorbed by PS badges into biologically effective solar UV exposures taking as examples two relevant effects for human skin: erythema induction and pre-vitamin D3 production. PS calibration curves for erythemal and pre-vitamin D3 were distinctly determined by using an empirical relationship between the biologically effective UV exposures and the PS absorbance change. This relationship is parameterized by a coefficient, distinct for each of the two considered biological effects, multiplying the same cubic polynomial function. It is shown how the multiplying coefficient is related to the ratio between the biologically effective and the PS weighted irradiances which is the prevailing factor affecting the accuracy of the calibration and, consequently, the capability of PS films for measuring biologically effective solar UV exposures. The points addressed in this paper can be extended to other biological effects of interest whose action spectra have some similarity with the PS film response.

Exploring the Therapeutic Potential of Quadripulse rTMS over the Visual Cortex: A Proof-of-Concept Study in Healthy Volunteers and Chronic Migraine Patients with Medication Overuse Headache.

In chronic migraine with medication overuse (CM-MOH), sensitization of visual cortices is reflected by (i) increased amplitude of stimulus-evoked responses and (ii) habituation deficit during repetitive stimulation. Both abnormalities might be mitigated by inhibitory transcranial neurostimulation. Here, we tested an inhibitory quadripulse repetitive transcranial magnetic stimulation (rTMS-QPI) protocol to decrease durably visual cortex excitability in healthy subjects (HS) and explored its therapeutic potential in CM-MOH patients. Pattern-reversal visual evoked potentials (VEP) were used as biomarkers of effect and recorded before (T1), immediately after (T2), and 3 h after stimulation (T3). In HS, rTMS-QPI durably decreased the VEP 1st block amplitude (p < 0.05) and its habituation (p < 0.05). These changes were more pronounced for the P1N2 component that was modified already at T2 up to T3, while for N1P1 they were significant only at T3. An excitatory stimulation protocol (rTMS-QPE) tended to have an opposite effect, restricted to P1N2. In 12 CM-MOH patients, during a four-week treatment (2 sessions/week), rTMS-QPI significantly reduced monthly headache days (p < 0.01). In patients reversing from CM-MOH to episodic migraine (n = 6), VEP habituation significantly improved after treatment (p = 0.005). rTMS-QPI durably decreases visual cortex responsivity in healthy subjects. In a proof-of-concept study of CM-MOH patients, rTMS-QPI also has beneficial clinical and electrophysiological effects, but sham-controlled trials are needed.

Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine.

BACKGROUND: Preventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing. OBJECTIVE: To study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention. METHODS: We recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy. RESULTS: In HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication intake significantly decreased during the treatment period compared to pre-treatment baseline (all p < 0.05), and this benefit persisted on average 4.8 weeks after the end of tDCS. CONCLUSIONS: Anodal tDCS over the visual cortex is thus able to increase habituation to repetitive visual stimuli in healthy volunteers and in episodic migraineurs, who on average lack habituation interictally. Moreover, 2 weekly sessions of anodal tDCS had a significant preventive anti- migraine effect, proofing the concept that the low preactivation level of the visual cortex in migraine patients can be corrected by an activating neurostimulation. The therapeutic results indicate that a larger sham-controlled trial using the same tDCS protocol is worthwhile.

Modelling a multiplex brain network by local transfer entropy.

This paper deals with the information transfer mechanisms underlying causal relations between brain regions under resting condition. fMRI images of a large set of healthy individuals from the 1000 Functional Connectomes Beijing Zang dataset have been considered and the causal information transfer among brain regions studied using Transfer Entropy concepts. Thus, we explored the influence of a set of states in two given regions at time t (At Bt.) over the state of one of them at a following time step (Bt+1) and could observe a series of time-dependent events corresponding to four kinds of interactions, or causal rules, pointing to (de)activation and turn off mechanisms and sharing some features with positive and negative functional connectivity. The functional architecture emerging from such rules was modelled by a directional multilayer network based upon four interaction matrices and a set of indexes describing the effects of the network structure in several dynamical processes. The statistical significance of the models produced by our approach was checked within the used database of homogeneous subjects and predicts a successful extension, in due course, to detect differences among clinical conditions and cognitive states.

Functional connections between and within brain subnetworks under resting-state.

The focus of this paper is on the functional role of brain regions focusing on their modular architecture and individual variability. Our main assumption is that the more variable anti-correlation patterns reflect random connections, while the more conserved ones play a functional role. Within this framework, we expanded on previous results using a different database and a different methodological approach. Aiming to identify the role of specific functional connections within a global network organization which includes subnetworks, we found that the fronto-parietal module acts as the main source of anti-correlations. In addition, the pre-frontal regions (namely: frontal middle, frontal middle orbital, frontal inferior triangular) and the parietal inferior region are highly conserved and, at the same time, act as highly connected nodes, thus confirming their importance in functional modulation.

Haemoglobin polymorphisms affect the oxygen-binding properties in Atlantic cod populations.

A major challenge in evolutionary biology is to identify the genes underlying adaptation. The oxygen-transporting haemoglobins directly link external conditions with metabolic needs and therefore represent a unique system for studying environmental effects on molecular evolution. We have discovered two haemoglobin polymorphisms in Atlantic cod populations inhabiting varying temperature and oxygen regimes in the North Atlantic. Three-dimensional modelling of the tetrameric haemoglobin structure demonstrated that the two amino acid replacements Met55beta1Val and Lys62beta1Ala are located at crucial positions of the alpha1beta1 subunit interface and haem pocket, respectively. The replacements are proposed to affect the oxygen-binding properties by modifying the haemoglobin quaternary structure and electrostatic feature. Intriguingly, the same molecular mechanism for facilitating oxygen binding is found in avian species adapted to high altitudes, illustrating convergent evolution in water- and air-breathing vertebrates to reduction in environmental oxygen availability. Cod populations inhabiting the cold Arctic waters and the low-oxygen Baltic Sea seem well adapted to these conditions by possessing the high oxygen affinity Val55-Ala62 haplotype, while the temperature-insensitive Met55-Lys62 haplotype predominates in the southern populations. The distinct distributions of the functionally different haemoglobin variants indicate that the present biogeography of this ecologically and economically important species might be seriously affected by global warming.

Epileptiform synchronization in the cingulate cortex.

PURPOSE: The anterior cingulate cortex (ACC)--which plays a role in pain, emotions and behavior--can generate epileptic seizures. To date, little is known on the neuronal mechanisms leading to epileptiform synchronization in this structure. Therefore, we investigated the role of excitatory and inhibitory synaptic transmission in epileptiform activity in this cortical area. In addition, since the ACC presents with a high density of opioid receptors, we studied the effect of opioid agonism on epileptiform synchronization in this brain region. METHODS: We used field and intracellular recordings in conjunction with pharmacological manipulations to characterize the epileptiform activity generated by the rat ACC in a brain slice preparation. RESULTS: Bath-application of the convulsant 4-aminopyridine (4AP, 50 microM) induced both brief and prolonged periods of epileptiform synchronization resembling interictal- and ictal-like discharges, respectively. Interictal events could occur more frequently before the onset of ictal activity that was contributed by N-methyl-D-aspartate (NMDA) receptors. Mu-opioid receptor activation abolished 4AP-induced ictal events and markedly reduced the occurrence of the pharmacologically isolated GABAergic synchronous potentials. Ictal discharges were replaced by interictal events during GABAergic antagonism; this GABA-independent activity was influenced by subsequent mu-opioid agonist application. CONCLUSIONS: Our results indicate that both glutamatergic and GABAergic signaling contribute to epileptiform synchronization leading to the generation of electrographic ictal events in the ACC. In addition, mu-opioid receptors appear to modulate both excitatory and inhibitory mechanisms, thus influencing epileptiform synchronization in the ACC.

Short-term UV exposure of sunbathers at a Mediterranean Sea site.

The aim of this study was to investigate whether systematic differences in solar UV exposure on a specific anatomical site (chest) exist among three groups of Italian sunbathers: healthy subjects (suntanned and non-suntanned individuals) and subjects affected by abnormally high sensitivity to solar exposure. A second aim of the study was to search for a possible relation among biological markers of individual response to UV exposure (such as skin colorimetric parameters, skin temperature and changes in free radical amounts [FR] in the blood) and photosensitivity. FR in the blood were analyzed because of their possible influence on UV carcinogenesis. Measurements of ambient doses (i.e. incident erythemally weighted irradiance on a horizontal surface over a specified period of time) and erythemally effective UV dose received by an anatomical site (here called personal dose or exposure on a specific anatomical site) were investigated. Personal doses received by the chest were determined using polysulfone dosimetry. Exposure Ratio (ER), defined as the ratio between the personal dose and the corresponding ambient dose during the same exposure period, was then calculated. Measuring of skin color in the Commission Internationale de l'Eclairage L (luminance), a (redness), b (yellowness) system and skin temperature were also carried out on the inner upper arm (nonexposed skin site) and on the chest. It was found that the median value of ER was 0.20 (min: 0.09 and max: 0.34) for suntanned individuals, it was 0.17 (min: 0.13 and max: 0.42) for non-suntanned individuals and it was 0.19 (min: 0.14 and max: 0.34) for photosensitive individuals. There were no significant differences across the groups in their median ER scores. In addition, the statistical analysis showed that L on the exposed site before exposure demonstrated consistently higher median scores after exposure in all groups. The b value after exposure was significantly lower than before exposure in all participants, while no significant differences for a were observed before or after exposure between or within the groups. Our findings suggest that photodermatoses are not significantly related to ER and to the changes in biological markers due to too short-term UV exposure.

Collective behavior in gene regulation: post-transcriptional regulation and the temporal compartmentalization of cellular cycles.

Self-sustained oscillations are perhaps the most studied objects in science. The accomplishment of such a task reliably and accurately requires the presence of specific control mechanisms to face the presence of variable and largely unpredictable environmental stimuli and noise. Self-sustained oscillations of transcript abundance are, in fact, widespread and are not limited to the reproductive cycle but are also observed during circadian rhythms, metabolic cycles, developmental cycles and so on. To date, much of the literature has focused on the transcriptional machinery underlying control of the basic timing of transcript abundance. However, mRNA abundance is known to be regulated at the post-transcriptional level also and the relative contribution of the two mechanisms to gene-expression programmes is currently a major challenge in molecular biology. Here, we review recent results showing the relevance of the post-transcriptional regulation layer and present a statistical reanalysis of the yeast metabolic cycle using publicly available gene-expression and RNA-binding data. Taken together, the recent theoretical and experimental developments reviewed and the results of our reanalysis strongly indicate that regulation of mRNA stability is a widespread, phase-specific and finely tuned mechanism for the multi-layer control of gene expression needed to achieve high flexibility and adaptability to external and internal signals.

Structure of the cortical networks during successful memory encoding in TV commercials.

OBJECTIVE: This work intends to evaluate the functional characteristics of the cerebral network during the successful memory encoding of TV commercials. METHODS: We estimated the functional networks in the frequency domain from a set of high-resolution EEG data in a group of healthy subjects during the showing of commercial spots within a neutral documentary. We evaluated the differences in the cortical network associated with later remembered and not-remembered commercials by calculating the global-E(g) and local-efficiency E(l) indexes. RESULTS: Successful encoding of TV spots significantly affects the functional communication among cortical areas irrespectively of the frequency band. During the visualization of the video-clips that will be forgotten (FRG), the cortical network exhibited high values of global- and local-efficiency, reflecting a small-world configuration. During the visualization of the video-clips that will be remembered (RMB), the same indexes appeared significantly lower. This difference was especially evident for E(l) in the alpha band and for E(g) in the beta and gamma bands. CONCLUSIONS: The presence of attentional and semantic processes during the RMB condition leads to a significant reduction of the network communication efficiency. SIGNIFICANCE: Such a reduction could represent a predictive measure of accurate recalls of TV spots.

Multi-agent Simulations of Population Behavior: A Promising Tool for Systems Biology.

This contribution reports on the simulation of some dynamical events observed in the collective behavior of different kinds of populations, ranging from shape-changing cells in a Petri dish to functionally correlated brain areas in vivo. The unifying methodological approach, based upon a Multi-Agent Simulation (MAS) paradigm as incorporated in the NetLogo™ interpreter, is a direct consequence of the cornerstone that simple, individual actions within a population of interacting agents often give rise to complex, collective behavior.The discussion will mainly focus on the emergence and spreading of synchronous activities within the population, as well as on the modulation of the collective behavior exerted by environmental force-fields. A relevant section of this contribution is dedicated to the extension of the MAS paradigm to Brain Network models. In such a general framework some recent applications taken from the direct experience of the author, and exploring the activation patterns characteristic of specific brain functional states, are described, and their impact on the Systems-Biology universe underlined.

Negative functional brain networks.

The anticorrelations in fMRI measurements are still not well characterized, but some new evidences point to a possible physiological role. We explored the topology of functional brain networks characterized by negative edgess and their possible alterations in schizophrenia, using functional images of 8 healthy subjects and 8 schizophrenic patients in a resting state condition. In order to minimize the insertion of artifactual negative correlations, the preprocessing of images was carried out by the CompCorr procedure, and the results compared with the Global Signal Regression (GSR) procedure. The degree distribution, the centrality, the efficiency and the rich-club behavior were used to characterize the functional brain network with negative links of healthy controls in comparison with schizophrenic patients. The results show that functional brain networks with both positive and negative values have a truncated power-law degree distribution. Moreover, although functional brain networks characterized by negative values have not small-world topology, they show a specific disassortative configuration: the more connected nodes tend to have fewer connections between them. This feature is lost using the GSR procedure. Finally, the comparison with schizophrenic patients showed a decreased (local and global) efficiency associated to a decreased connectivity among central nodes. As a conclusion, functional brain networks characterized by negative values, despite lacking a well defined topology, show specific features, different from random, and indicate an implication in the alterations associated to schizophrenia.

Neurophysiological Measures of the Perception of Antismoking Public Service Announcements Among Young Population.

Tobacco constitutes a global emergency with totally preventable millions of deaths per year and smoking-related illnesses. Public service announcements (PSAs) are the main tool against smoking and by now their efficacy is still assessed through questionnaires and metrics, only months after their circulation. The present study focused on the young population, because at higher risk of developing tobacco addiction, investigating the reaction to the vision of Effective, Ineffective and Awarded antismoking PSAs through: electroencephalography (EEG), autonomic activity variation (Galvanic skin response-GSR- and Heart Rate-HR-) and Eye-Tracking (ET). The employed indices were: the EEG frontal alpha band asymmetry and the frontal theta; the Emotional Index (EI), deriving from the GSR and HR signals matching; the ET Visual Attention (VA) index, based on the ratio between the total time spent fixating an area of interest (AOI) and its area. Smokers expressed higher frontal alpha asymmetry values in comparison to non-smokers. Concerning frontal theta, Awarded PSAs reported the highest values in comparison to both Effective and Ineffective PSAs. EI results highlighted that lowest values were expressed by Heavy Smokers (HS), and Effective PSAs obtained the highest EI values. Finally, concerning the Effective PSAs, regression analysis highlighted a correlation between the number of cigarettes smoked by participants (independent variable) and frontal alpha asymmetry, frontal theta and EI values. ET results suggested that for the Ineffective PSAs the main focus were texts, while for the Effective and Awarded PSAs were the visual elements. Results support the use of methods aimed at assessing the physiological reaction for the evaluation of PSAs images, in particular when considering the smoking habits of target populations.

Unsupervised versus Supervised Identification of Prognostic Factors in Patients with Localized Retroperitoneal Sarcoma: A Data Clustering and Mahalanobis Distance Approach.

The aim of this report is to unveil specific prognostic factors for retroperitoneal sarcoma (RPS) patients by univariate and multivariate statistical techniques. A phase I-II study on localized RPS treated with high-dose ifosfamide and radiotherapy followed by surgery (ISG-STS 0303 protocol) demonstrated that chemo/radiotherapy was safe and increased the 3-year relapse-free survival (RFS) with respect to historical controls. Of 70 patients, twenty-six developed local, 10 distant, and 5 combined relapse. Median disease-free interval (DFI) was 29.47 months. According to a discriminant function analysis, DFI, histology, relapse pattern, and the first treatment approach at relapse had a statistically significant prognostic impact. Based on scientific literature and clinical expertise, clinicopathological data were analyzed using both a supervised and an unsupervised classification method to predict the prognosis, with similar sample sizes (66 and 65, resp., in casewise approach and 70 in mean-substitution one). This is the first attempt to predict patients' prognosis by means of multivariate statistics, and in this light, it looks noticable that (i) some clinical data have a well-defined prognostic value, (ii) the unsupervised model produced comparable results with respect to the supervised one, and (iii) the appropriate combination of both models appears fruitful and easily extensible to different clinical contexts.

Essentiality is an emergent property of metabolic network wiring.

The topological bases of essentiality in the yeast metabolic network from the perspective of double mutations are the subject of this study. A strong relationship between essentiality and the 'missing alternative' topological property is shown in terms of the presence of multiple genes synthesizing the same enzyme, supplementary enzymes participating in the same metabolic reaction, and availability of other pathways in the graph connecting the separated nodes after the knockouts. We demonstrate that the 'missing alternative' paradigm is sufficient to explain the generation of essentiality for double mutations in which each single deleted element is non-essential.

Gene expression waves. Cell cycle independent collective dynamics in cultured cells.

The ergodic hypothesis, which assumes the independence of each cell of the ensemble from all the others, is a necessary prerequisite to attach single cell based explanations to the grand averages taken from population data. This was the prevailing view about the interpretation of cellular biology experiments that typically are performed on colonies of billions of cells. By analysing gene expression data of different cells going from yeast to mammalian cell cultures, we demonstrate that cell cultures display a sort of "ecology-in-a-plate" giving rise to a rich dynamics of gene expression that are independent from reproductive cycles, hence contradicting simple ergodic assumptions The aspecific character of the observed coordinated gene expression activity inhibits any simple mechanistic hypothesis and highlights the need to consider population effects in the interpretation of data coming from cell cultures.

Brain Interaction during Cooperation: Evaluating Local Properties of Multiple-Brain Network.

Subjects' interaction is the core of most human activities. This is the reason why a lack of coordination is often the cause of missing goals, more than individual failure. While there are different subjective and objective measures to assess the level of mental effort required by subjects while facing a situation that is getting harder, that is, mental workload, to define an objective measure based on how and if team members are interacting is not so straightforward. In this study, behavioral, subjective and synchronized electroencephalographic data were collected from couples involved in a cooperative task to describe the relationship between task difficulty and team coordination, in the sense of interaction aimed at cooperatively performing the assignment. Multiple-brain connectivity analysis provided information about the whole interacting system. The results showed that averaged local properties of a brain network were affected by task difficulty. In particular, strength changed significantly with task difficulty and clustering coefficients strongly correlated with the workload itself. In particular, a higher workload corresponded to lower clustering values over the central and parietal brain areas. Such results has been interpreted as less efficient organization of the network when the subjects' activities, due to high workload tendencies, were less coordinated.

Passive BCI in Operational Environments: Insights, Recent Advances, and Future Trends.

GOAL: This minireview aims to highlight recent important aspects to consider and evaluate when passive brain-computer interface (pBCI) systems would be developed and used in operational environments, and remarks future directions of their applications. METHODS: Electroencephalography (EEG) based pBCI has become an important tool for real-time analysis of brain activity since it could potentially provide covertly-without distracting the user from the main task-and objectively-not affected by the subjective judgment of an observer or the user itself-information about the operator cognitive state. RESULTS: Different examples of pBCI applications in operational environments and new adaptive interface solutions have been presented and described. In addition, a general overview regarding the correct use of machine learning techniques (e.g., which algorithm to use, common pitfalls to avoid, etc.) in the pBCI field has been provided. CONCLUSION: Despite recent innovations on algorithms and neurotechnology, pBCI systems are not completely ready to enter the market yet, mainly due to limitations of the EEG electrodes technology, and algorithms reliability and capability in real settings. SIGNIFICANCE: High complexity and safety critical systems (e.g., airplanes, ATM interfaces) should adapt their behaviors and functionality accordingly to the user' actual mental state. Thus, technologies (i.e., pBCIs) able to measure in real time the user's mental states would result very useful in such "high risk" environments to enhance human machine interaction, and so increase the overall safety.

Evaluation of different cochlear implants in unilateral hearing patients during word listening tasks: A brain connectivity study.

Advanced methodologies used for the biomedical signal interpretation allow using cerebral signals to assess important cognitive functions in humans. In the present study, as parameter of cerebral effort, has been employed the isolated effective coherence, in order to estimate the effective connectivity and network organization. The hypothesis was that the lower the number of inter-connections engaged, the lower the cerebral effort induced by the experimental condition. In the present research this index has been applied to test the reaction to the use of different cochlear implant processors (Freedom, CP810 and CP910 - Cochlear Ltd), with the aim to identify the most performing device during a word in noise recognition task. Results support the capability of identifying the device eliciting less brain area connections. In particular, the CP910 was the processor inducing the lower number of inter-connections among the tested ones. This investigation appeared to be worthy, since representing a tool to identify devices that would make available user's cognitive resources for additional tasks, a matter susceptible of generalization to various fields of application. The employment of the cerebral signals therefore open the way to the evaluation of the impact of different sensors and prosthetic devices, also using connectivity measures.