Sound objects in time, space and action

SOUND OBJECTS IN TIME, SPACE AND ACTIONThe term "sound object" describes an auditory experience that is associated with an acoustic event produced by a sound source. At cortical level, sound objects are represented by temporo-spatial activity patterns within distributed neural networks. This investigation concerns temporal, spatial and action aspects as assessed in normal subjects using electrical imaging or measurement of motor activity induced by transcranial magnetic stimulation (TMS).Hearing the same sound again has been shown to facilitate behavioral responses (repetition priming) and to modulate neural activity (repetition suppression). In natural settings the same source is often heard again and again, with variations in spectro-temporal and spatial characteristics. I have investigated how such repeats influence response times in a living vs. non-living categorization task and the associated spatio-temporal patterns of brain activity in humans. Dynamic analysis of distributed source estimations revealed differential sound object representations within the auditory cortex as a function of the temporal history of exposure to these objects. Often heard sounds are coded by a modulation in a bilateral network. Recently heard sounds, independently of the number of previous exposures, are coded by a modulation of a left-sided network.With sound objects which carry spatial information, I have investigated how spatial aspects of the repeats influence neural representations. Dynamics analyses of distributed source estimations revealed an ultra rapid discrimination of sound objects which are characterized by spatial cues. This discrimination involved two temporo-spatially distinct cortical representations, one associated with position-independent and the other with position-linked representations within the auditory ventral/what stream.Action-related sounds were shown to increase the excitability of motoneurons within the primary motor cortex, possibly via an input from the mirror neuron system. The role of motor representations remains unclear. I have investigated repetition priming-induced plasticity of the motor representations of action sounds with the measurement of motor activity induced by TMS pulses applied on the hand motor cortex. TMS delivered to the hand area within the primary motor cortex yielded larger magnetic evoked potentials (MEPs) while the subject was listening to sounds associated with manual than non- manual actions. Repetition suppression was observed at motoneuron level, since during a repeated exposure to the same manual action sound the MEPs were smaller. I discuss these results in terms of specialized neural network involved in sound processing, which is characterized by repetition-induced plasticity.Thus, neural networks which underlie sound object representations are characterized by modulations which keep track of the temporal and spatial history of the sound and, in case of action related sounds, also of the way in which the sound is produced.LES OBJETS SONORES AU TRAVERS DU TEMPS, DE L'ESPACE ET DES ACTIONSLe terme "objet sonore" décrit une expérience auditive associée avec un événement acoustique produit par une source sonore. Au niveau cortical, les objets sonores sont représentés par des patterns d'activités dans des réseaux neuronaux distribués. Ce travail traite les aspects temporels, spatiaux et liés aux actions, évalués à l'aide de l'imagerie électrique ou par des mesures de l'activité motrice induite par stimulation magnétique trans-crânienne (SMT) chez des sujets sains. Entendre le même son de façon répétitive facilite la réponse comportementale (amorçage de répétition) et module l'activité neuronale (suppression liée à la répétition). Dans un cadre naturel, la même source est souvent entendue plusieurs fois, avec des variations spectro-temporelles et de ses caractéristiques spatiales. J'ai étudié la façon dont ces répétitions influencent le temps de réponse lors d'une tâche de catégorisation vivant vs. non-vivant, et les patterns d'activité cérébrale qui lui sont associés. Des analyses dynamiques d'estimations de sources ont révélé des représentations différenciées des objets sonores au niveau du cortex auditif en fonction de l'historique d'exposition à ces objets. Les sons souvent entendus sont codés par des modulations d'un réseau bilatéral. Les sons récemment entendus sont codé par des modulations d'un réseau du côté gauche, indépendamment du nombre d'expositions. Avec des objets sonores véhiculant de l'information spatiale, j'ai étudié la façon dont les aspects spatiaux des sons répétés influencent les représentations neuronales. Des analyses dynamiques d'estimations de sources ont révélé une discrimination ultra rapide des objets sonores caractérisés par des indices spatiaux. Cette discrimination implique deux représentations corticales temporellement et spatialement distinctes, l'une associée à des représentations indépendantes de la position et l'autre à des représentations liées à la position. Ces représentations sont localisées dans la voie auditive ventrale du "quoi".Des sons d'actions augmentent l'excitabilité des motoneurones dans le cortex moteur primaire, possiblement par une afférence du system des neurones miroir. Le rôle des représentations motrices des sons d'actions reste peu clair. J'ai étudié la plasticité des représentations motrices induites par l'amorçage de répétition à l'aide de mesures de potentiels moteurs évoqués (PMEs) induits par des pulsations de SMT sur le cortex moteur de la main. La SMT appliquée sur le cortex moteur primaire de la main produit de plus grands PMEs alors que les sujets écoutent des sons associée à des actions manuelles en comparaison avec des sons d'actions non manuelles. Une suppression liée à la répétition a été observée au niveau des motoneurones, étant donné que lors de l'exposition répétée au son de la même action manuelle les PMEs étaient plus petits. Ces résultats sont discuté en termes de réseaux neuronaux spécialisés impliqués dans le traitement des sons et caractérisés par de la plasticité induite par la répétition. Ainsi, les réseaux neuronaux qui sous-tendent les représentations des objets sonores sont caractérisés par des modulations qui gardent une trace de l'histoire temporelle et spatiale du son ainsi que de la manière dont le son a été produit, en cas de sons d'actions.

Electrophysiological markers of rapid cognitive decline in mild cognitive impairment

Electroencephalography (EEG) is an easily accessible and low-cost modality that might prove to be a particularly powerful tool for the identification of subtle functional changes preceding structural or metabolic deficits in progressive mild cognitive impairment (PMCI). Most previous contributions in this field assessed quantitative EEG differences between healthy controls, MCI and Alzheimer's disease(AD) cases leading to contradictory data. In terms of MCI conversion to AD, certain longitudinal studies proposed various quantitative EEG parameters for an a priori distinction between PMCI and stable MCI. However, cross-sectional comparisons revealed a substantial overlap in these parameters between MCI patients and elderly controls. Methodological differences including variable clinical definition of MCI cases and substantial interindividual differences within the MCI group could partly explain these discrepancies. Most importantly, EEG measurements without cognitive demand in both cross-sectional and longitudinal designs have demonstrated limited sensitivity and generally do not produce significant group differences in spectral EEG parameters. Since the evolution of AD is characterized by the progressive loss of functional connectivity within neocortical association areas, event-modulated EEG dynamic analysis which makes it possible to investigate the functional activation of neocortical circuits may represent a more sensitive method to identify early alterations of neuronal networks predictive of AD development among MCI cases. The present review summarizes clinically significant results of EEG activation studies in this field and discusses future perspectives of research aiming to reach an early and individual prediction of cognitive decline in healthy elderly controls.

Neural plasticity associated with recently versus often heard objects.

In natural settings the same sound source is often heard repeatedly, with variations in spectro-temporal and spatial characteristics. We investigated how such repetitions influence sound representations and in particular how auditory cortices keep track of recently vs. often heard objects. A set of 40 environmental sounds was presented twice, i.e. as prime and as repeat, while subjects categorized the corresponding sound sources as living vs. non-living. Electrical neuroimaging analyses were applied to auditory evoked potentials (AEPs) comparing primes vs. repeats (effect of presentation) and the four experimental sections. Dynamic analysis of distributed source estimations revealed i) a significant main effect of presentation within the left temporal convexity at 164-215ms post-stimulus onset; and ii) a significant main effect of section in the right temporo-parietal junction at 166-213ms. A 3-way repeated measures ANOVA (hemisphere×presentation×section) applied to neural activity of the above clusters during the common time window confirmed the specificity of the left hemisphere for the effect of presentation, but not that of the right hemisphere for the effect of section. In conclusion, spatio-temporal dynamics of neural activity encode the temporal history of exposure to sound objects. Rapidly occurring plastic changes within the semantic representations of the left hemisphere keep track of objects heard a few seconds before, independent of the more general sound exposure history. Progressively occurring and more long-lasting plastic changes occurring predominantly within right hemispheric networks, which are known to code for perceptual, semantic and spatial aspects of sound objects, keep track of multiple exposures.

How environmental sounds become meaningful

The term "sound object" describes an auditory experience that is associated with an acoustic event produced by a sound source. In natural settings, a sound produced by a living being or an object provides information about the identity and the location of the sound source. Sound's identity is orocessed alono the ventral "What" pathway which consists of regions within the superior and middle temporal cortices as well as the inferior frontal gyrus. This work concerns the creation of individual auditory object representations in narrow semantic categories and their plasticity using electrical imaging. Discrimination of sounds from broad category has been shown to occur along a temporal hierarchy and in different brain regions along the ventral "What" pathway. However, sounds belonging to the same semantic category, such as faces or voices, were shown to be discriminated in specific brain areas and are thought to represent a special class of stimuli. I have investigated how cortical representations of a narrow category, here birdsongs, is modulated by training novices to recognized songs of individual bird species. Dynamic analysis of distributed source estimations revealed differential sound object representations within the auditory ventral "What" pathway as a function of the level of expertise newly acquired. Correct recognition of trained items induces a sharpening within a left-lateralized semantic network starting around 200ms, whereas untrained items' processing occurs later in lower-level and memory-related regions. With another category of sounds belonging to the same category, here heartbeats, I investigated the cortical representations of correct and incorrect recognition of sounds. Source estimations revealed differential representations partially overlapping with regions involved in the semantic network that is activated when participants became experts in the task. Incorrect recognition also induces a higher activation when compared to correct recognition in regions processing lower-level features. The discrimination of heartbeat sounds is a difficult task and requires a continuous listening. I investigated whether the repetition effects are modulated by participants' behavioral performance. Dynamic source estimations revealed repetition suppression in areas located outside of the semantic network. Therefore, individual environmental sounds become meaningful with training. Their representations mainly involve a left-lateralized network of brain regions that are tuned with expertise, as well as other brain areas, not related to semantic processing, and occurring in early stages of semantic processing. -- Le terme objet sonore" décrit une expérience auditive associée à un événement acoustique produit par une source sonore. Dans l'environnement, un son produit par un être vivant ou un objet fournit des informations concernant l'identité et la localisation de la source sonore. Les informations concernant l'identité d'un son sont traitée le long de la voie ventrale di "Quoi". Cette voie est composée de regions situées dans le cortex temporal et frontal. L'objet de ce travail est d'étudier quels sont les neuro-mecanismes impliqués dans la représentation de nouveaux objets sonores appartenant à une meme catégorie sémantique ainsi que les phénomènes de plasticité à l'aide de l'imagerie électrique. Il a été montré que la discrimination de sons appartenant à différentes catégories sémantiques survient dans différentes aires situées le long la voie «Quoi» et suit une hiérarchie temporelle II a également été montré que la discrimination de sons appartenant à la même catégorie sémantique tels que les visages ou les voix, survient dans des aires spécifiques et représenteraient des stimuli particuliers. J'ai étudié comment les représentations corticales de sons appartenant à une même catégorie sémantique, dans ce cas des chants d'oiseaux, sont modifiées suite à un entraînement Pour ce faire, des sujets novices ont été entraînés à reconnaître des chants d'oiseaux spécifiques L'analyse des estimations des sources neuronales au cours du temps a montré que les representations des objets sonores activent de manière différente des régions situées le long de la vo,e ventrale en fonction du niveau d'expertise acquis grâce à l'entraînement. La reconnaissance des chants pour lesquels les sujets ont été entraînés implique un réseau sémantique principalement situé dans l'hémisphère gauche activé autour de 200ms. Au contraire, la reconnaissance des chants pour lesquels les sujets n'ont pas été entraînés survient plus tardivement dans des régions de plus bas niveau. J'ai ensuite étudié les mécanismes impliqués dans la reconnaissance et non reconnaissance de sons appartenant à une autre catégorie, .es battements de coeur. L'analyse des sources neuronales a montre que certaines régions du réseau sémantique lié à l'expertise acquise sont recrutées de maniere différente en fonction de la reconnaissance ou non reconnaissance du son La non reconnaissance des sons recrute des régions de plus bas niveau. La discrimination des bruits cardiaques est une tâche difficile et nécessite une écoute continue du son. J'ai étudié l'influence des réponses comportementales sur les effets de répétitions. L'analyse des sources neuronales a montré que la reconnaissance ou non reconnaissance des sons induisent des effets de repétition différents dans des régions situées en dehors des aires du réseau sémantique. Ainsi, les sons acquièrent un sens grâce à l'entraînement. Leur représentation corticale implique principalement un réseau d'aires cérébrales situé dans l'hémisphère gauche, dont l'activité est optimisée avec l'acquisition d'un certain niveau d'expertise, ainsi que d'autres régions qui ne sont pas liée au traitement de l'information sémantique. L'activité de ce réseau sémantique survient plus rapidemement que la prédiction par le modèle de la hiérarchie temporelle.

Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.

MOTIVATION: Combinatorial interactions of transcription factors with cis-regulatory elements control the dynamic progression through successive cellular states and thus underpin all metazoan development. The construction of network models of cis-regulatory elements, therefore, has the potential to generate fundamental insights into cellular fate and differentiation. Haematopoiesis has long served as a model system to study mammalian differentiation, yet modelling based on experimentally informed cis-regulatory interactions has so far been restricted to pairs of interacting factors. Here, we have generated a Boolean network model based on detailed cis-regulatory functional data connecting 11 haematopoietic stem/progenitor cell (HSPC) regulator genes. RESULTS: Despite its apparent simplicity, the model exhibits surprisingly complex behaviour that we charted using strongly connected components and shortest-path analysis in its Boolean state space. This analysis of our model predicts that HSPCs display heterogeneous expression patterns and possess many intermediate states that can act as 'stepping stones' for the HSPC to achieve a final differentiated state. Importantly, an external perturbation or 'trigger' is required to exit the stem cell state, with distinct triggers characterizing maturation into the various different lineages. By focusing on intermediate states occurring during erythrocyte differentiation, from our model we predicted a novel negative regulation of Fli1 by Gata1, which we confirmed experimentally thus validating our model. In conclusion, we demonstrate that an advanced mammalian regulatory network model based on experimentally validated cis-regulatory interactions has allowed us to make novel, experimentally testable hypotheses about transcriptional mechanisms that control differentiation of mammalian stem cells. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

How unethical actions can be learned : the analysis of the sporting life courses of doping athletes

The aim of the present article was to present a specific activity approach called the 'life course of a practice' that could be used for the analysis of the long-term dynamic of learning within diverse social practices. The cases of unethical actions (doping) within a population of high-level athletes were examined, considering they could be fruitful exam- 10 ples for this type of analysis. After describing the theoretical construct 'life course of a practice', the places of these unethical actions in the sporting life courses and elements that characterize their emergence in the long-term dynamics are described. Last, targeted prevention measures of unethical actions over a lifetime are presented.

Dynamic simulation of regulatory networks using SQUAD.

BACKGROUND: The ambition of most molecular biologists is the understanding of the intricate network of molecular interactions that control biological systems. As scientists uncover the components and the connectivity of these networks, it becomes possible to study their dynamical behavior as a whole and discover what is the specific role of each of their components. Since the behavior of a network is by no means intuitive, it becomes necessary to use computational models to understand its behavior and to be able to make predictions about it. Unfortunately, most current computational models describe small networks due to the scarcity of kinetic data available. To overcome this problem, we previously published a methodology to convert a signaling network into a dynamical system, even in the total absence of kinetic information. In this paper we present a software implementation of such methodology. RESULTS: We developed SQUAD, a software for the dynamic simulation of signaling networks using the standardized qualitative dynamical systems approach. SQUAD converts the network into a discrete dynamical system, and it uses a binary decision diagram algorithm to identify all the steady states of the system. Then, the software creates a continuous dynamical system and localizes its steady states which are located near the steady states of the discrete system. The software permits to make simulations on the continuous system, allowing for the modification of several parameters. Importantly, SQUAD includes a framework for perturbing networks in a manner similar to what is performed in experimental laboratory protocols, for example by activating receptors or knocking out molecular components. Using this software we have been able to successfully reproduce the behavior of the regulatory network implicated in T-helper cell differentiation. CONCLUSION: The simulation of regulatory networks aims at predicting the behavior of a whole system when subject to stimuli, such as drugs, or determine the role of specific components within the network. The predictions can then be used to interpret and/or drive laboratory experiments. SQUAD provides a user-friendly graphical interface, accessible to both computational and experimental biologists for the fast qualitative simulation of large regulatory networks for which kinetic data is not necessarily available.

Development of spatial integration depends on top-down and interhemispheric connections that can be perturbed in migraine: a DCM analysis.

In humans, spatial integration develops slowly, continuing through childhood into adolescence. On the assumption that this protracted course depends on the formation of networks with slowly developing top-down connections, we compared effective connectivity in the visual cortex between 13 children (age 7-13) and 14 adults (age 21-42) using a passive perceptual task. The subjects were scanned while viewing bilateral gratings, which either obeyed Gestalt grouping rules [colinear gratings (CG)] or violated them [non-colinear gratings (NG)]. The regions of interest for dynamic causal modeling were determined from activations in functional MRI contrasts stimuli > background and CG > NG. They were symmetrically located in V1 and V3v areas of both hemispheres. We studied a common model, which contained reciprocal intrinsic and modulatory connections between these regions. An analysis of effective connectivity showed that top-down modulatory effects generated at an extrastriate level and interhemispheric modulatory effects between primary visual areas (all inhibitory) are significantly weaker in children than in adults, suggesting that the formation of feedback and interhemispheric effective connections continues into adolescence. These results are consistent with a model in which spatial integration at an extrastriate level results in top-down messages to the primary visual areas, where they are supplemented by lateral (interhemispheric) messages, making perceptual encoding more efficient and less redundant. Abnormal formation of top-down inhibitory connections can lead to the reduction of habituation observed in migraine patients.

Dynamic responses of oxygen uptake at the onset and end of moderate and heavy exercise in trained subjects.

Inconsistencies about dynamic asymmetry between the on- and off-transient responses in VO2 are found in the literature. Therefore the purpose of this study was to examine VO2 on- and off-transients during moderate- and heavy-intensity cycling exercise in trained subjects. Ten men underwent an initial incremental test for the estimation of ventilatory threshold (VT) and, on different days, two bouts of square-wave exercise at moderate (<VT) and heavy (>VT) intensities. VO2 kinetics in exercise and recovery were better described by a single exponential model (<VT), or by a double exponential with two time delays (>VT). For moderate exercise, we found a symmetry of VO2 kinetics between the on- and off-transients (i.e., fundamental component), consistent with a system manifesting linear control dynamics. For heavy exercise, a slow component superimposed on the fundamental phase was expressed in both the exercise and recovery, with similar parameter estimates. But the on-transient values of the time constant were appreciably faster than the associated off-transient, and independent of the work rate imposed (<VT and >VT). Our results do not support a dynamically linear system model of VO2 during cycling exercise in the heavy-intensity domain.

An assessment of donor-to-recipient transmission patterns of human cytomegalovirus by analysis of viral genomic variants.

BACKGROUND: We studied human cytomegalovirus (CMV) donor-to-recipient transmission patterns in organ transplantation by analyzing genomic variants on the basis of CMV glycoprotein B (gB) genotyping. METHODS: Organ transplant recipients were included in the study if they had CMV viremia, if they had received an organ from a CMV-seropositive donor, and if there was at least 1 other recipient of an organ from the same donor who developed CMV viremia. Genotypes (gB1-4) were determined by real-time polymerase chain reaction. RESULTS: Forty-seven recipients of organs from 21 donors developed CMV viremia. Twenty-three recipients had a pretransplant donor/recipient (D/R) CMV serostatus of D(+)/R(+), and 24 had a serostatus of D(+)/R(-). The prevalences of genotypes in recipients were as follows: for gB1, 51% (n = 24); for gB2, 19% (n = 9); for gB3, 9% (n = 4); for gB4, 0% (n = 0); and for mixed infection, 21% (n = 10). Recipients of an organ from a common donor had infection with CMV of the same gB genotype in 12 (57%) of 21 instances. Concordance between genotypes was higher among seronegative (i.e., D(+)/R(-)) recipients than among seropositive (D(+)/R(+)) recipients, although discordances resulting from the transmission of multiple strains were seen. In seropositive recipients, transmission of multiple strains from the donor could not be differentiated from reactivation of a recipient's own strains. CONCLUSION: Our analysis of strain concordance among recipients of organs from common donors showed that transmission of CMV has complex dynamic patterns. In seropositive recipients, transmission or reactivation of multiple CMV strains is possible.

BMI group-related differences in physical fitness and physical activity in preschool-age children: a cross-sectional analysis.

In the Ballabeina study, we investigated age- and BMI-group-related differences in aerobic fitness (20 m shuttle run), agility (obstacle course), dynamic (balance beam) and static balance (balance platform), and physical activity (PA, accelerometers) in 613 children (M age = 5.1 years, SD = 0.6). Normal weight (NW) children performed better than overweight (OW) children in aerobic fitness, agility, and dynamic balance (all p <.001), while OWchildren had a better static balance (p < .001). BMI-group-related differences in aerobic fitness and agility were larger in older children (p for interaction with age = .01) in favor of the NW children. PA did not differ between NW and OW (p > or = .1), but did differ between NW and obese children (p < .05). BMI-group-related differences in physical fitness can already be present in preschool-age children.

Longitudinal analysis of patterns and predictors of changes in self-reported adherence to antiretroviral therapy: Swiss HIV Cohort Study.

BACKGROUND: Adherence to combination antiretroviral therapy (cART) is a dynamic process, however, changes in adherence behavior over time are insufficiently understood. METHODS: Data on self-reported missed doses of cART was collected every 6 months in Swiss HIV Cohort Study participants. We identified behavioral groups associated with specific cART adherence patterns using trajectory analyses. Repeated measures logistic regression identified predictors of changes in adherence between consecutive visits. RESULTS: Six thousand seven hundred nine individuals completed 49,071 adherence questionnaires [median 8 (interquartile range: 5-10)] during a median follow-up time of 4.5 years (interquartile range: 2.4-5.1). Individuals were clustered into 4 adherence groups: good (51.8%), worsening (17.4%), improving (17.6%), and poor adherence (13.2%). Independent predictors of worsening adherence were younger age, basic education, loss of a roommate, starting intravenous drug use, increasing alcohol intake, depression, longer time with HIV, onset of lipodystrophy, and changing care provider. Independent predictors of improvements in adherence were regimen simplification, changing class of cART, less time on cART, and starting comedications. CONCLUSIONS: Treatment, behavioral changes, and life events influence patterns of drug intake in HIV patients. Clinical care providers should routinely monitor factors related to worsening adherence and intervene early to reduce the risk of treatment failure and drug resistance.

Kinematics and dynamic complexity of postural transitions in frail elderly subjects.

The aim of this study was to propose a methodology allowing a detailed characterization of body sit-to-stand/stand-to-sit postural transition. Parameters characterizing the kinematics of the trunk movement during sit-to-stand (Si-St) postural transition were calculated using one initial sensor system fixed on the trunk and a data logger. Dynamic complexity of these postural transitions was estimated by fractal dimension of acceleration-angular velocity plot. We concluded that this method provides a simple and accurate tool for monitoring frail elderly and to objectively evaluate the efficacy of a rehabilitation program.

Update of the FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation.

The international Functional Annotation Of the Mammalian Genomes 4 (FANTOM4) research collaboration set out to better understand the transcriptional network that regulates macrophage differentiation and to uncover novel components of the transcriptome employing a series of high-throughput experiments. The primary and unique technique is cap analysis of gene expression (CAGE), sequencing mRNA 5'-ends with a second-generation sequencer to quantify promoter activities even in the absence of gene annotation. Additional genome-wide experiments complement the setup including short RNA sequencing, microarray gene expression profiling on large-scale perturbation experiments and ChIP-chip for epigenetic marks and transcription factors. All the experiments are performed in a differentiation time course of the THP-1 human leukemic cell line. Furthermore, we performed a large-scale mammalian two-hybrid (M2H) assay between transcription factors and monitored their expression profile across human and mouse tissues with qRT-PCR to address combinatorial effects of regulation by transcription factors. These interdependent data have been analyzed individually and in combination with each other and are published in related but distinct papers. We provide all data together with systematic annotation in an integrated view as resource for the scientific community (http://fantom.gsc.riken.jp/4/). Additionally, we assembled a rich set of derived analysis results including published predicted and validated regulatory interactions. Here we introduce the resource and its update after the initial release.