Alfredo Colosimo

Tracking the Time-Varying Cortical Connectivity Patterns by Adaptive Multivariate Estimators

The directed transfer function (DTF) and the partial directed coherence (PDC) are frequency-domain estimators that are able to describe interactions between cortical areas in terms of the concept of Granger causality. However, the classical estimation of these methods is based on the multivariate autoregressive modelling (MVAR) of time series, which requires the stationarity of the signals. In this way, transient pathways of information transfer remains hidden. The objective of this study is to test a time-varying multivariate method for the estimation of rapidly changing connectivity relationships between cortical areas of the human brain, based on DTF/PDC and on the use of adaptive MVAR modelling (AMVAR) and to apply it to a set of real high resolution EEG data. This approach will allow the observation of rapidly changing influences between the cortical areas during the execution of a task. The simulation results indicated that time-varying DTF and PDC are able to estimate correctly the imposed connectivity patterns under reasonable operative conditions of signal-to-noise ratio (SNR) ad number of trials. An SNR of Ave and a number of trials of at least 20 provide a good accuracy in the estimation. After testing the method by the simulation study, we provide an application to the cortical estimations obtained from high resolution EEG data recorded from a group of healthy subject during a combined foot-lips movement and present the time-varying connectivity patterns resulting from the application of both DTF and PDC. Two different cortical networks were detected with the proposed methods, one constant across the task and the other evolving during the preparation of the joint movement.

Cortical Functional Connectivity Networks in Normal and Spinal Cord Injured Patients: Evaluation by Graph Analysis

The present work aims at analyzing the structure of cortical connectivity during the attempt to move a paralyzed limb by a group of spinal cord injured (SCI) patients. Connectivity patterns were obtained by means of the Directed Transfer Function applied to the cortical signals estimated from high resolution EEG recordings. Electrical activity were estimated in normals (Healthy) and SCI patients on twelve regions of interest (ROIs) coincident with Brodmann areas. Degree distributions showed the presence of few cortical regions with a lot of outgoing connections in all the cortical networks estimated irrespectively of the frequency band investigated. For both of the groups (SCI and Healthy), bilateral cingulate motor area (CMA) acts as hub transmitting information flows. The efficiency index, allowed to assert the ordered properties of such estimated cortical networks in both populations. The comparison of such estimated networks with those obtained from random networks, elicited significant differences (P < 0.05, Bonferroni‐corrected for multiple comparisons). A statistical comparison (ANOVA) between SCI patients and healthy subjects showed a significant difference (P < 0.05) between the local efficiency of their respective networks. For three frequency bands (theta 4–7 Hz, alpha 8–12 Hz, and beta 13–29 Hz) the higher value observed in the spinal cord injured population entails a larger level of internal organization and fault tolerance. This fact suggests a sort of compensative mechanism as local response to the alteration in their MIF areas, which is probably due to the indirect effects of the spinal injury. Hum Brain Mapp, 2007.

Neural Basis for Brain Responses to TV Commercials: A High-Resolution EEG Study

We investigated brain activity during the observation of TV commercials by tracking the cortical activity and the functional connectivity changes in normal subjects. The aim was to elucidate if the TV commercials that were remembered by the subjects several days after their first observation elicited particular brain activity and connectivity compared with those generated during the observation of TV commercials that were quickly forgotten. High-resolution electroencephalogram (EEG) recordings were performed in a group of healthy subjects and the cortical activity during the observation of TV commercials was evaluated in several regions of interest coincident with the Brodmann areas (BAs). The patterns of cortical connectivity were obtained in the four principal frequency bands, Theta (3-7 Hz), Alpha (8-12 Hz), Beta (13-30 Hz), Gamma (30-40 Hz) and the directed influences between any given pair of the estimated cortical signals were evaluated by use of a multivariate spectral technique known as partial directed coherence. The topology of the cortical networks has been identified with tools derived from graph theory. Results suggest that the cortical activity and connectivity elicited by the viewing of the TV commercials that were remembered by the experimental subjects are markedly different from the brain activity elicited during the observation of the TV commercials that were forgotten. In particular, during the observation of the TV commercials that were remembered, the amount of cortical spectral activity from the frontal areas (BA 8 and 9) and from the parietal areas (BA 5, 7, and 40) is higher compared with the activity elicited by the observation of TV commercials that were forgotten. In addition, network analysis suggests a clear role of the parietal areas as a target of the incoming flow of information from all the other parts of the cortex during the observation of TV commercials that have been remembered. The techniques presented here shed new light on all the cortical networks and their behavior during the memorization of TV commercials. Such techniques could also be relevant in neuroeconomics and neuromarketing for the investigation of the neural substrates subserving other decision-making and recognition tasks.

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 Met55β1Val and Lys62β1Ala are located at crucial positions of the α1β1 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.

Functional essentiality from topology features in metabolic networks: A case study in yeast

The relation between the position of mutations in Saccharomyces cerevisiae metabolic network and their lethality is the subject of this work. We represent the topology of the network by a directed graph: nodes are metabolites and arcs represent the reactions; a mutation corresponds to the removal of all the arcs referring to the deleted enzyme. Using publicly available knock‐out data, we show that lethality corresponds to the lack of alternative paths in the perturbed network linking the nodes affected by the enzyme deletion. Such feature is at the basis of the recently recognized importance of ‘marginal’ arcs of metabolic networks.

Molecular dynamics study of a hyperthermophilic and a mesophilic rubredoxin

In recent years, increased interest in the origin of protein thermal stability has gained attention both for its possible role in understanding the forces governing the folding of a protein and for the design of new highly stable engineered biocatalysts. To study the origin of thermostability, we have performed molecular dynamics simulations of two rubredoxins, from the mesophile Clostridium pasteurianum and from the hyperthermophile Pyrococcus furiosus. The simulations were carried out at two temperatures, 300 and 373 K, for each molecule. The length of the simulations was within the range of 6–7.2 ns. The rubredoxin from the hyperthermophilic organism was more flexible than its mesophilic counterpart at both temperatures; however, the overall flexibility of both molecules at their optimal growth temperature was the same, despite 59% sequence homology. The conformational space sampled by both molecules was larger at 300 K than at 373 K. The essential dynamics analysis showed that the principal overall motions of the two molecules are significantly different. On the contrary, each molecule showed similar directions of motion at both temperatures. Proteins 2002;46:287–294.

Nonlinear Methods in the Analysis of Protein Sequences: A Case Study in Rubredoxins

Two computational methods widely used in time series analysis were applied to protein sequences, and their ability to derive structural information not directly accessible through classical sequence comparisons methods was assessed. The primary structures of 19 rubredoxins of both mesophilic and thermophilic bacteria, coded with hydrophobicity values of amino acid residues, were considered as time series and were analyzed by 1) recurrence quantification analysis and 2) spectral analysis of the sequence major eigenfunctions. The results of the two methods agreed to a large extent and generated a classification consistent with known 3D structural characteristics of the studied proteins. This classification separated in a clearcut manner a thermophilic protein from mesophilic proteins. The classification of primary structures given by the two dynamical methods was demonstrated to be basically different from classification stemming from classical sequence homology metrics. Moreover, on a more detailed scale, the method was able to discriminate between thermophilic and mesophilic proteins from a set of chimeric sequences generated from the mixing of a mesophilic (Rubr Clopa) and a thermophilic (Rubr Pyrfu) protein. Overall, our results point to a new way of looking at protein sequence comparisons.

The balance sheet of a hemoglobin. Thermodynamics of CO binding by hemoglobin trout I.

Direct step-by-step calorimetric measurements of the heat of combination of trout I hemoglobin with CO, together with a closely related set of measurements of the CO binding curves at 20°C and 4°C, make it possible to establish a complete thermodynamic balance sheet for the process within the framework of the concerted model. The results show that the introduction of ligand into a subunit when the molecule is in the T state is characterized by a positive value of ΔH , probably due to an endothermic tertiary conformational change which is conditioned by the presence of the subunit in the T state. The final value of ΔH , realized when the molecule is in the R state, is negative, as is the value of ΔH for the reaction of human hemoglobin with oxygen over the whole range of saturations. This change of sign as shown by trout hemoglobin represents a striking difference between the properties, and presumably the structures, of the two hemoglobins.

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

BackgroundPreventive 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.ObjectiveTo 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.MethodsWe 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.ResultsIn 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.ConclusionsAnodal 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.

Cortical Activity and Connectivity of Human Brain during the Prisoner's Dilemma: an EEG Hyperscanning Study

A major limitation of the approaches used in most of the studies performed so far for the characterization of the brain responses during social interaction is that only one of the participating brains is measured each time. The ldquointeractionrdquo between cooperating, competing or communicating brains is thus not measured directly, but inferred by independent observations aggregated by cognitive models and assumptions that link behavior and neural activation. In this paper, we use the simultaneous neuroelectric recording of several subjects engaged in cooperative games (EEG hyperscanning). This EEG hyperscanning allow us to observe and model directly the neural signature of human interactions in order to understand the cerebral processes generating and generated by social cooperation or competition. We used a paradigm called Prisoners Dilemma derived from the game theory. Results collected in a population of 22 subjects suggested that the most consistently activated structure in social interaction paradigms is the medial prefrontal cortex, which is found to be active in all the conflict situations analyzed. The role of the anterior cingulated cortex (ACC) assumes a main character being a discriminant factor for the ldquodefectrdquo attitude of the entire population examined. This observation is compatible with the role that the Theory of Mind assigns to the ACC.