Brain rhythms alterations and their effect in functional networks: A simultaneous EEG/fMRI study in Fixation-off epilepsy

Fixation-off sensitivity (FOS) denotes the forms of EEG abnormalities, which are elicited by elimination of central vision or fixation. The phenomenon seems to depend on variables that modulate the alpha rhythm, however, the cerebral mechanisms underlying FOS remain unclear [1]. The scarce previous fMRI findings related to FOS have shown activation in extrastriate cortex [2] and also in frontal areas [3][4]. On the other hand, simultaneous EEG-fMRI technique has been used to assess the relationship between spontaneous power fluctuations of electrical rhythms and associated fMRI signal modulations. These studies have identified that lateral frontoparietal networks show a negative correlation with alpha band in healthy subjects. This neuroanatomical pattern is related to attentional processes and cognitive resources. Moreover, a sub-beta band (17-23 Hz) has been identified with posterior cingulate, temporoparietal junction and dorso-medial prefrontal cortex activations, which correspond to the DMN [5][6].

Objective Assessment of Olfactory Function Using Functional Magnetic Resonance Imaging=Estudio objetivo del olfato mediante resonancia magnética funcional

Objective: To show the results of a device that generates automated olfactory stimuli suitable for functional magnetic resonance imaging (fMRI) experiments. Material and methods: Te n normal volunteers, 5 women and 5 men, were studied. The system allows the programming of several sequences, providing the capability to synchronise the onset of odour presentation with acquisition by a trigger signal of the MRI scanner. The olfactometer is a device that allows selection of the odour, the event paradigm, the time of stimuli and the odour concentration. The paradigm used during fMRI scanning consisted of 15-s blocks. The odorant event took 2 s with butanol, mint and coffee. Results: We observed olfactory activity in the olfactory bulb, entorhinal cortex (4%), amygdala (2.5%) and temporo-parietal cortex, especially in the areas related to emotional integration. Conclusions: The device has demonstrated its effectiveness in stimulating olfactory areas and its capacity to adapt to fMRI equipment.RESUMEN Objetivo: Mostrar los resultados del olfatómetro capaz de generar tareas olfativas en un equipo de resonancia magnética funcional (fMRI). Material y métodos: Estudiamos 10 sujetos normales: 5 varones y 5 mujeres. El olfatómetro está dise ̃ nado para que el estímulo que produce se sincronice con el equipo de fMRI mediante la se ̃ nal desencadenante que suministra el propio equipo. El olfatómetro es capaz de: selec- cionar el olor, secuenciar los distintos olores, programar la frecuencia y duración de los olores y controlar la intensidad del olor. El paradigma utilizado responde a un dise ̃ no de activación asociada a eventos, en el que la duración del bloque de activación y de reposo es de 15 s. La duración del estímulo olfativo (butanol, menta o café) es de 2 segundos, durante toda la serie que consta de 9 ciclos. Resultados: Se ha observado reactividad (contraste BOLD) en las diferentes áreas cerebrales involucradas en las tareas olfativas: bulbo olfatorio, córtex entorrinal (4%), amigdala (2,5%) y córtex temporoparietal. Las áreas relacionadas con integración de las emociones tienen una reactividad mayor. Conclusiones: El dispositivo propuesto nos permite controlar de forma automática y sincronizada los olores necesarios para estudiar la actividad de las áreas olfatorias cerebrales mediante fMRI.

Functional and effective connectivity in MEG. Application to the study of epilepsy

Nuestro cerebro contiene cerca de 1014 sinapsis neuronales. Esta enorme cantidad de conexiones proporciona un entorno ideal donde distintos grupos de neuronas se sincronizan transitoriamente para provocar la aparición de funciones cognitivas, como la percepción, el aprendizaje o el pensamiento. Comprender la organización de esta compleja red cerebral en base a datos neurofisiológicos, representa uno de los desafíos más importantes y emocionantes en el campo de la neurociencia. Se han propuesto recientemente varias medidas para evaluar cómo se comunican las diferentes partes del cerebro a diversas escalas (células individuales, columnas corticales, o áreas cerebrales). Podemos clasificarlos, según su simetría, en dos grupos: por una parte, la medidas simétricas, como la correlación, la coherencia o la sincronización de fase, que evalúan la conectividad funcional (FC); mientras que las medidas asimétricas, como la causalidad de Granger o transferencia de entropía, son capaces de detectar la dirección de la interacción, lo que denominamos conectividad efectiva (EC). En la neurociencia moderna ha aumentado el interés por el estudio de las redes funcionales cerebrales, en gran medida debido a la aparición de estos nuevos algoritmos que permiten analizar la interdependencia entre señales temporales, además de la emergente teoría de redes complejas y la introducción de técnicas novedosas, como la magnetoencefalografía (MEG), para registrar datos neurofisiológicos con gran resolución. Sin embargo, nos hallamos ante un campo novedoso que presenta aun varias cuestiones metodológicas sin resolver, algunas de las cuales trataran de abordarse en esta tesis. En primer lugar, el creciente número de aproximaciones para determinar la existencia de FC/EC entre dos o más señales temporales, junto con la complejidad matemática de las herramientas de análisis, hacen deseable organizarlas todas en un paquete software intuitivo y fácil de usar. Aquí presento HERMES (http://hermes.ctb.upm.es), una toolbox en MatlabR, diseñada precisamente con este fin. Creo que esta herramienta será de gran ayuda para todos aquellos investigadores que trabajen en el campo emergente del análisis de conectividad cerebral y supondrá un gran valor para la comunidad científica. La segunda cuestión practica que se aborda es el estudio de la sensibilidad a las fuentes cerebrales profundas a través de dos tipos de sensores MEG: gradiómetros planares y magnetómetros, esta aproximación además se combina con un enfoque metodológico, utilizando dos índices de sincronización de fase: phase locking value (PLV) y phase lag index (PLI), este ultimo menos sensible a efecto la conducción volumen. Por lo tanto, se compara su comportamiento al estudiar las redes cerebrales, obteniendo que magnetómetros y PLV presentan, respectivamente, redes más densamente conectadas que gradiómetros planares y PLI, por los valores artificiales que crea el problema de la conducción de volumen. Sin embargo, cuando se trata de caracterizar redes epilépticas, el PLV ofrece mejores resultados, debido a la gran dispersión de las redes obtenidas con PLI. El análisis de redes complejas ha proporcionado nuevos conceptos que mejoran caracterización de la interacción de sistemas dinámicos. Se considera que una red está compuesta por nodos, que simbolizan sistemas, cuyas interacciones se representan por enlaces, y su comportamiento y topología puede caracterizarse por un elevado número de medidas. Existe evidencia teórica y empírica de que muchas de ellas están fuertemente correlacionadas entre sí. Por lo tanto, se ha conseguido seleccionar un pequeño grupo que caracteriza eficazmente estas redes, y condensa la información redundante. Para el análisis de redes funcionales, la selección de un umbral adecuado para decidir si un determinado valor de conectividad de la matriz de FC es significativo y debe ser incluido para un análisis posterior, se convierte en un paso crucial. En esta tesis, se han obtenido resultados más precisos al utilizar un test de subrogadas, basado en los datos, para evaluar individualmente cada uno de los enlaces, que al establecer a priori un umbral fijo para la densidad de conexiones. Finalmente, todas estas cuestiones se han aplicado al estudio de la epilepsia, caso práctico en el que se analizan las redes funcionales MEG, en estado de reposo, de dos grupos de pacientes epilépticos (generalizada idiopática y focal frontal) en comparación con sujetos control sanos. La epilepsia es uno de los trastornos neurológicos más comunes, con más de 55 millones de afectados en el mundo. Esta enfermedad se caracteriza por la predisposición a generar ataques epilépticos de actividad neuronal anormal y excesiva o bien síncrona, y por tanto, es el escenario perfecto para este tipo de análisis al tiempo que presenta un gran interés tanto desde el punto de vista clínico como de investigación. Los resultados manifiestan alteraciones especificas en la conectividad y un cambio en la topología de las redes en cerebros epilépticos, desplazando la importancia del ‘foco’ a la ‘red’, enfoque que va adquiriendo relevancia en las investigaciones recientes sobre epilepsia. ABSTRACT There are about 1014 neuronal synapses in the human brain. This huge number of connections provides the substrate for neuronal ensembles to become transiently synchronized, producing the emergence of cognitive functions such as perception, learning or thinking. Understanding the complex brain network organization on the basis of neuroimaging data represents one of the most important and exciting challenges for systems neuroscience. Several measures have been recently proposed to evaluate at various scales (single cells, cortical columns, or brain areas) how the different parts of the brain communicate. We can classify them, according to their symmetry, into two groups: symmetric measures, such as correlation, coherence or phase synchronization indexes, evaluate functional connectivity (FC); and on the other hand, the asymmetric ones, such as Granger causality or transfer entropy, are able to detect effective connectivity (EC) revealing the direction of the interaction. In modern neurosciences, the interest in functional brain networks has increased strongly with the onset of new algorithms to study interdependence between time series, the advent of modern complex network theory and the introduction of powerful techniques to record neurophysiological data, such as magnetoencephalography (MEG). However, when analyzing neurophysiological data with this approach several questions arise. In this thesis, I intend to tackle some of the practical open problems in the field. First of all, the increase in the number of time series analysis algorithms to study brain FC/EC, along with their mathematical complexity, creates the necessity of arranging them into a single, unified toolbox that allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of them. I developed such a toolbox for this aim, it is named HERMES (http://hermes.ctb.upm.es), and encompasses several of the most common indexes for the assessment of FC and EC running for MatlabR environment. I believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis and will entail a great value for the scientific community. The second important practical issue tackled in this thesis is the evaluation of the sensitivity to deep brain sources of two different MEG sensors: planar gradiometers and magnetometers, in combination with the related methodological approach, using two phase synchronization indexes: phase locking value (PLV) y phase lag index (PLI), the latter one being less sensitive to volume conduction effect. Thus, I compared their performance when studying brain networks, obtaining that magnetometer sensors and PLV presented higher artificial values as compared with planar gradiometers and PLI respectively. However, when it came to characterize epileptic networks it was the PLV which gives better results, as PLI FC networks where very sparse. Complex network analysis has provided new concepts which improved characterization of interacting dynamical systems. With this background, networks could be considered composed of nodes, symbolizing systems, whose interactions with each other are represented by edges. A growing number of network measures is been applied in network analysis. However, there is theoretical and empirical evidence that many of these indexes are strongly correlated with each other. Therefore, in this thesis I reduced them to a small set, which could more efficiently characterize networks. Within this framework, selecting an appropriate threshold to decide whether a certain connectivity value of the FC matrix is significant and should be included in the network analysis becomes a crucial step, in this thesis, I used the surrogate data tests to make an individual data-driven evaluation of each of the edges significance and confirmed more accurate results than when just setting to a fixed value the density of connections. All these methodologies were applied to the study of epilepsy, analysing resting state MEG functional networks, in two groups of epileptic patients (generalized and focal epilepsy) that were compared to matching control subjects. Epilepsy is one of the most common neurological disorders, with more than 55 million people affected worldwide, characterized by its predisposition to generate epileptic seizures of abnormal excessive or synchronous neuronal activity, and thus, this scenario and analysis, present a great interest from both the clinical and the research perspective. Results revealed specific disruptions in connectivity and network topology and evidenced that networks’ topology is changed in epileptic brains, supporting the shift from ‘focus’ to ‘networks’ which is gaining importance in modern epilepsy research.

White matter damage disorganizes brain functional networks in amnestic mild cognitive impairment

Although progressive functional brain network disruption has been one of the hallmarks of Alzheimer?s Dis- ease, little is known about the origin of this functional impairment that underlies cognitive symptoms. We in- vestigated how the loss of white matter (WM) integrity disrupts the organization of the functional networks at different frequency bands. The analyses were performed in a sample of healthy elders and mild cognitive im- pairment (MCI) subjects. Spontaneous brain magnetic activity (measured with magnetoencephalography) was characterized with phase synchronization analysis, and graph theory was applied to the functional networks. We identified WM areas (using diffusion weighted magnetic resonance imaging) that showed a statistical de- pendence between the fractional anisotropy and the graph metrics. These regions are part of an episodic mem- ory network and were also related to cognitive functions. Our data support the hypothesis that disruption of the anatomical networks influences the organization at the functional level resulting in the prodromal dementia syndrome of MCI.

Disparate connectivity for structural and functional networks is revealed when physical location of the connected nodes is considered

Macroscopic brain networks have been widely described with the manifold of metrics available using graph theory. However, most analyses do not incorporate information about the physical position of network nodes. Here, we provide a multimodal macroscopic network characterization while considering the physical positions of nodes. To do so, we examined anatomical and functional macroscopic brain networks in a sample of twenty healthy subjects. Anatomical networks are obtained with a graph based tractography algorithm from diffusion-weighted magnetic resonance images (DW-MRI). Anatomical con- nections identified via DW-MRI provided probabilistic constraints for determining the connectedness of 90 dif- ferent brain areas. Functional networks are derived from temporal linear correlations between blood-oxygenation level-dependent signals derived from the same brain areas. Rentian Scaling analysis, a technique adapted from very- large-scale integration circuits analyses, shows that func- tional networks are more random and less optimized than the anatomical networks. We also provide a new metric that allows quantifying the global connectivity arrange- ments for both structural and functional networks. While the functional networks show a higher contribution of inter-hemispheric connections, the anatomical networks highest connections are identified in a dorsal?ventral arrangement. These results indicate that anatomical and functional networks present different connectivity organi- zations that can only be identified when the physical locations of the nodes are included in the analysis.

Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas

Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas.

Planning and Management of Mobility in Natural Protected Areas

The paper describes some relevant results of an on-going research aiming to elaborate a methodology to help the mobility management in natural parks, compatible with their protection missions: it has been developed a procedure to reproduce the mobility-environment relationships in various operational conditions. The final purpose is the identification of: a) the effects of various choices in transport planning, both at long term and strategic level; b) the most effective policies of mobility management. The work is articulated in the following steps: 1) definition of protected area on the basis of ecological and socio-economic criteria and legislative constraints; 2) analysis of mobility needs in the protected areas; 3) reconstruction of the state of the art of mobility management in natural parks at European level; 4) analysis of used traffic flows measurement methods; 5) analysis of environmental impacts due to transport systems modelling (air pollution and noise only); 6) identification of mitigation measures to be potentially applied. The whole methodology has been tested and validated on Italian case studies: i) the concerned area has been zoned according to the land-use peculiarities; ii) the local situations of transport infrastructure (roads and parking), services (public transport systems) and rules (traffic regulations) have been mapped with references to physical and functional attributes; iii) the mobility, both systematic and touristic, has been represented in an origin-destination matrix. By means of an assignment model the flows have been distributed and the corresponding average speeds to quantify gaseous and noise emissions was calculated, the criticalities in the reference scenario have been highlighted, as well as some alternative scenarios, including both operational and infrastructural measures have been identified. The comparison between projects and reference scenario allowed the quantification of effects (variation of emissions) for each scenario and a selection of the most effective management actions to be taken.

Planning and management of mobility in natural protected areas

The final purpose is the identification of: a) the effects of various choices in transport planning, both at long term and strategic level; b) the most effective policies of mobility management. The preliminary work was articulated in the following steps: 1) definition of protected area on the basis of ecological and socio-economic criteria and legislative constraints; 2) analysis of mobility needs in the protected areas; 3) reconstruction of the state of the art of mobility management in natural parks at European level; 4) analysis of used traffic flows measurement methods; 5) analysis of environmental impacts due to transport systems modelling (limited to air pollution and noise); 6) identification of mitigation measures to the potentially applied. The whole methodology has been firstly tested on the case study of the National Park of ?Gran Sasso and Monti della Laga? and further validated on the National Park of ?Gargano?, both located Italy: i) the concerned area has been zoned according to the land-use peculiarities; ii) the local situations of transport infrastructure (roads and parking), services (public transport systems) and rules (traffic regulations) have been mapped with references to physical and functional attributes; iii) the mobility, both systematic and touristic, has been synthetically represented in an origin-destination matrix. By means of an assignment model it has been determined the distribution of flows and the corresponding average speeds to quantify gaseous and noise emissions. On this basis the environmental criticalities in the reference scenario have been highlighted, as well as some alternative scenarios including both operational and infrastructural measures have been identified. The comparison between the projects and the reference scenario allowed the quantification of the effects (variation of emissions) for each scenario and a selection of the most effective management actions to be taken.

Mental chronometry using latency-resolved functional MRI

Vascular responses to neural activity are exploited as the basis of a number of brain imaging techniques. The vascular response is thought to be too slow to resolve the temporal sequence of events involved in cognitive tasks, and hence, imaging studies of mental chronometry have relied on techniques such as the evoked potential. Using rapid functional MRI (fMRI) of single trials of two simple behavioral tasks, we demonstrate that while the microvascular response to the onset of neural activity is delayed consistently by several seconds, the relative timing between the onset of the fMRI responses in different brain areas appears preserved. We examined a number of parameters that characterize the fMRI response and determined that its onset time is best defined by the inflection point from the resting baseline. We have found that fMRI onset latencies determined in this manner correlate well with independently measurable parameters of the tasks such as reaction time or stimulus presentation time and can be used to determine the origin of processing delays during cognitive or perceptual tasks with a temporal accuracy of tens of milliseconds and spatial resolution of millimeters.

Functional activation in motor cortex reflects the direction and the degree of handedness

Handedness is the clearest example of behavioral lateralization in humans. It is not known whether the obvious asymmetry manifested by hand preference is associated with similar asymmetry in brain activation during movement. We examined the functional activation in cortical motor areas during movement of the dominant and nondominant hand in groups of right-handed and left-handed subjects and found that use of the dominant hand was associated with a greater volume of activation in the contralateral motor cortex. Furthermore, there was a separate relation between the degree of handedness and the extent of functional lateralization in the motor cortex. The patterns of functional activation associated with the direction and degree of handedness suggest that these aspects are independent and are coded separately in the brain.

Neural fate of seen and unseen faces in visuospatial neglect: A combined event-related functional MRI and event-related potential study

To compare neural activity produced by visual events that escape or reach conscious awareness, we used event-related MRI and evoked potentials in a patient who had neglect and extinction after focal right parietal damage, but intact visual fields. This neurological disorder entails a loss of awareness for stimuli in the field contralateral to a brain lesion when stimuli are simultaneously presented on the ipsilateral side, even though early visual areas may be intact, and single contralateral stimuli may still be perceived. Functional MRI and event-related potential study were performed during a task where faces or shapes appeared in the right, left, or both fields. Unilateral stimuli produced normal responses in V1 and extrastriate areas. In bilateral events, left faces that were not perceived still activated right V1 and inferior temporal cortex and evoked nonsignificantly reduced N1 potentials, with preserved face-specific negative potentials at 170 ms. When left faces were perceived, the same stimuli produced greater activity in a distributed network of areas including right V1 and cuneus, bilateral fusiform gyri, and left parietal cortex. Also, effective connectivity between visual, parietal, and frontal areas increased during perception of faces. These results suggest that activity can occur in V1 and ventral temporal cortex without awareness, whereas coupling with dorsal parietal and frontal areas may be critical for such activity to afford conscious perception.

Requirement of the nicotinic acetylcholine receptor β2 subunit for the anatomical and functional development of the visual system

In the mammalian visual system the formation of eye-specific layers at the thalamic level depends on retinal waves of spontaneous activity, which rely on nicotinic acetylcholine receptor activation. We found that in mutant mice lacking the β2 subunit of the neuronal nicotinic receptor, but not in mice lacking the α4 subunit, retinofugal projections do not segregate into eye-specific areas, both in the dorso-lateral geniculate nucleus and in the superior colliculus. Moreover, β2−/− mice show an expansion of the binocular subfield of the primary visual cortex and a decrease in visual acuity at the cortical level but not in the retina. We conclude that the β2 subunit of the nicotinic acetylcholine receptor is necessary for the anatomical and functional development of the visual system.

Functional and structural mapping of human cerebral cortex: Solutions are in the surfaces

The human cerebral cortex is notorious for the depth and irregularity of its convolutions and for its variability from one individual to the next. These complexities of cortical geography have been a chronic impediment to studies of functional specialization in the cortex. In this report, we discuss ways to compensate for the convolutions by using a combination of strategies whose common denominator involves explicit reconstructions of the cortical surface. Surface-based visualization involves reconstructing cortical surfaces and displaying them, along with associated experimental data, in various complementary formats (including three-dimensional native configurations, two-dimensional slices, extensively smoothed surfaces, ellipsoidal representations, and cortical flat maps). Generating these representations for the cortex of the Visible Man leads to a surface-based atlas that has important advantages over conventional stereotaxic atlases as a substrate for displaying and analyzing large amounts of experimental data. We illustrate this by showing the relationship between functionally specialized regions and topographically organized areas in human visual cortex. Surface-based warping allows data to be mapped from individual hemispheres to a surface-based atlas while respecting surface topology, improving registration of identifiable landmarks, and minimizing unwanted distortions. Surface-based warping also can aid in comparisons between species, which we illustrate by warping a macaque flat map to match the shape of a human flat map. Collectively, these approaches will allow more refined analyses of commonalities as well as individual differences in the functional organization of primate cerebral cortex.

Functional analysis of primary visual cortex (V1) in humans

Human area V1 offers an excellent opportunity to study, using functional MRI, a range of properties in a specific cortical visual area, whose borders are defined objectively and convergently by retinotopic criteria. The retinotopy in V1 (also known as primary visual cortex, striate cortex, or Brodmann’s area 17) was defined in each subject by using both stationary and phase-encoded polar coordinate stimuli. Data from V1 and neighboring retinotopic areas were displayed on flattened cortical maps. In additional tests we revealed the paired cortical representations of the monocular “blind spot.” We also activated area V1 preferentially (relative to other extrastriate areas) by presenting radial gratings alternating between 6% and 100% contrast. Finally, we showed evidence for orientation selectivity in V1 by measuring transient functional MRI increases produced at the change in response to gratings of differing orientations. By systematically varying the orientations presented, we were able to measure the bandwidth of the orientation “transients” (45°).

The effects of practice on the functional anatomy of task performance

The effects of practice on the functional anatomy observed in two different tasks, a verbal and a motor task, are reviewed in this paper. In the first, people practiced a verbal production task, generating an appropriate verb in response to a visually presented noun. Both practiced and unpracticed conditions utilized common regions such as visual and motor cortex. However, there was a set of regions that was affected by practice. Practice produced a shift in activity from left frontal, anterior cingulate, and right cerebellar hemisphere to activity in Sylvian-insular cortex. Similar changes were also observed in the second task, a task in a very different domain, namely the tracing of a maze. Some areas were significantly more activated during initial unskilled performance (right premotor and parietal cortex and left cerebellar hemisphere); a different region (medial frontal cortex, “supplementary motor area”) showed greater activity during skilled performance conditions. Activations were also found in regions that most likely control movement execution irrespective of skill level (e.g., primary motor cortex was related to velocity of movement). One way of interpreting these results is in a “scaffolding-storage” framework. For unskilled, effortful performance, a scaffolding set of regions is used to cope with novel task demands. Following practice, a different set of regions is used, possibly representing storage of particular associations or capabilities that allow for skilled performance. The specific regions used for scaffolding and storage appear to be task dependent.