Multimodal integration of functional and structural brain connectivity. An application to the characterization of Mild Cognitive Impairment

La investigación para el conocimiento del cerebro es una ciencia joven, su inicio se remonta a Santiago Ramón y Cajal en 1888. Desde esta fecha a nuestro tiempo la neurociencia ha avanzado mucho en el desarrollo de técnicas que permiten su estudio. Desde la neurociencia cognitiva hoy se explican muchos modelos que nos permiten acercar a nuestro entendimiento a capacidades cognitivas complejas. Aun así hablamos de una ciencia casi en pañales que tiene un lago recorrido por delante. Una de las claves del éxito en los estudios de la función cerebral ha sido convertirse en una disciplina que combina conocimientos de diversas áreas: de la física, de las matemáticas, de la estadística y de la psicología. Esta es la razón por la que a lo largo de este trabajo se entremezclan conceptos de diferentes campos con el objetivo de avanzar en el conocimiento de un tema tan complejo como el que nos ocupa: el entendimiento de la mente humana. Concretamente, esta tesis ha estado dirigida a la integración multimodal de la magnetoencefalografía (MEG) y la resonancia magnética ponderada en difusión (dMRI). Estas técnicas son sensibles, respectivamente, a los campos magnéticos emitidos por las corrientes neuronales, y a la microestructura de la materia blanca cerebral. A lo largo de este trabajo hemos visto que la combinación de estas técnicas permiten descubrir sinergias estructurofuncionales en el procesamiento de la información en el cerebro sano y en el curso de patologías neurológicas. Más específicamente en este trabajo se ha estudiado la relación entre la conectividad funcional y estructural y en cómo fusionarlas. Para ello, se ha cuantificado la conectividad funcional mediante el estudio de la sincronización de fase o la correlación de amplitudes entre series temporales, de esta forma se ha conseguido un índice que mide la similitud entre grupos neuronales o regiones cerebrales. Adicionalmente, la cuantificación de la conectividad estructural a partir de imágenes de resonancia magnética ponderadas en difusión, ha permitido hallar índices de la integridad de materia blanca o de la fuerza de las conexiones estructurales entre regiones. Estas medidas fueron combinadas en los capítulos 3, 4 y 5 de este trabajo siguiendo tres aproximaciones que iban desde el nivel más bajo al más alto de integración. Finalmente se utilizó la información fusionada de MEG y dMRI para la caracterización de grupos de sujetos con deterioro cognitivo leve, la detección de esta patología resulta relevante en la identificación precoz de la enfermedad de Alzheimer. Esta tesis está dividida en seis capítulos. En el capítulos 1 se establece un contexto para la introducción de la connectómica dentro de los campos de la neuroimagen y la neurociencia. Posteriormente en este capítulo se describen los objetivos de la tesis, y los objetivos específicos de cada una de las publicaciones científicas que resultaron de este trabajo. En el capítulo 2 se describen los métodos para cada técnica que fue empleada: conectividad estructural, conectividad funcional en resting state, redes cerebrales complejas y teoría de grafos y finalmente se describe la condición de deterioro cognitivo leve y el estado actual en la búsqueda de nuevos biomarcadores diagnósticos. En los capítulos 3, 4 y 5 se han incluido los artículos científicos que fueron producidos a lo largo de esta tesis. Estos han sido incluidos en el formato de la revista en que fueron publicados, estando divididos en introducción, materiales y métodos, resultados y discusión. Todos los métodos que fueron empleados en los artículos están descritos en el capítulo 2 de la tesis. Finalmente, en el capítulo 6 se concluyen los resultados generales de la tesis y se discuten de forma específica los resultados de cada artículo. ABSTRACT In this thesis I apply concepts from mathematics, physics and statistics to the neurosciences. This field benefits from the collaborative work of multidisciplinary teams where physicians, psychologists, engineers and other specialists fight for a common well: the understanding of the brain. Research on this field is still in its early years, being its birth attributed to the neuronal theory of Santiago Ramo´n y Cajal in 1888. In more than one hundred years only a very little percentage of the brain functioning has been discovered, and still much more needs to be explored. Isolated techniques aim at unraveling the system that supports our cognition, nevertheless in order to provide solid evidence in such a field multimodal techniques have arisen, with them we will be able to improve current knowledge about human cognition. Here we focus on the multimodal integration of magnetoencephalography (MEG) and diffusion weighted magnetic resonance imaging. These techniques are sensitive to the magnetic fields emitted by the neuronal currents and to the white matter microstructure, respectively. The combination of such techniques could bring up evidences about structural-functional synergies in the brain information processing and which part of this synergy fails in specific neurological pathologies. In particular, we are interested in the relationship between functional and structural connectivity, and how two integrate this information. We quantify the functional connectivity by studying the phase synchronization or the amplitude correlation between time series obtained by MEG, and so we get an index indicating similarity between neuronal entities, i.e. brain regions. In addition we quantify structural connectivity by performing diffusion tensor estimation from the diffusion weighted images, thus obtaining an indicator of the integrity of the white matter or, if preferred, the strength of the structural connections between regions. These quantifications are then combined following three different approaches, from the lowest to the highest level of integration, in chapters 3, 4 and 5. We finally apply the fused information to the characterization or prediction of mild cognitive impairment, a clinical entity which is considered as an early step in the continuum pathological process of dementia. The dissertation is divided in six chapters. In chapter 1 I introduce connectomics within the fields of neuroimaging and neuroscience. Later in this chapter we describe the objectives of this thesis, and the specific objectives of each of the scientific publications that were produced as result of this work. In chapter 2 I describe the methods for each of the techniques that were employed, namely structural connectivity, resting state functional connectivity, complex brain networks and graph theory, and finally, I describe the clinical condition of mild cognitive impairment and the current state of the art in the search for early biomarkers. In chapters 3, 4 and 5 I have included the scientific publications that were generated along this work. They have been included in in their original format and they contain introduction, materials and methods, results and discussion. All methods that were employed in these papers have been described in chapter 2. Finally, in chapter 6 I summarize all the results from this thesis, both locally for each of the scientific publications and globally for the whole work.

Substitution of a mutant α2a-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Norepinephrine contributes to antinociceptive, sedative, and sympatholytic responses in vivo, and α2 adrenergic receptor (α2AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each α2AR subtype (α2A, α2B, and α2C) plays in these central effects. Here we demonstrate that α2AR agonist-elicited sedative, anesthetic-sparing, and analgesic responses are lost in a mouse line expressing a subtly mutated α2AAR, D79N α2AAR, created by two-step homologous recombination. These functional changes are accompanied by failure of the D79N α2AAR to inhibit voltage-gated Ca2+ currents and spontaneous neuronal firing, a measure of K+ current activation. These results provide definitive evidence that the α2AAR subtype is the primary mediator of clinically important central actions of α2AR agonists and suggest that the D79N α2AAR mouse may serve as a model for exploring other possible α2AAR functions in vivo.

Benthic–pelagic links and rocky intertidal communities: Bottom-up effects on top-down control?

Insight into the dependence of benthic communities on biological and physical processes in nearshore pelagic environments, long considered a “black box,” has eluded ecologists. In rocky intertidal communities at Oregon coastal sites 80 km apart, differences in abundance of sessile invertebrates, herbivores, carnivores, and macrophytes in the low zone were not readily explained by local scale differences in hydrodynamic or physical conditions (wave forces, surge flow, or air temperature during low tide). Field experiments employing predator and herbivore manipulations and prey transplants suggested top-down (predation, grazing) processes varied positively with bottom-up processes (growth of filter-feeders, prey recruitment), but the basis for these differences was unknown. Shore-based sampling revealed that between-site differences were associated with nearshore oceanographic conditions, including phytoplankton concentration and productivity, particulates, and water temperature during upwelling. Further, samples taken at 19 sites along 380 km of coastline suggested that the differences documented between two sites reflect broader scale gradients of phytoplankton concentration. Among several alternative explanations, a coastal hydrodynamics hypothesis, reflecting mesoscale (tens to hundreds of kilometers) variation in the interaction between offshore currents and winds and continental shelf bathymetry, was inferred to be the primary underlying cause. Satellite imagery and offshore chlorophyll-a samples are consistent with the postulated mechanism. Our results suggest that benthic community dynamics can be coupled to pelagic ecosystems by both trophic and transport linkages.

Stretch-activated single K+ channels account for whole-cell currents elicited by swelling

Functionally significant stretch-activated ion channels have been clearly identified in excitable cells. Although single-channel studies suggest their expression in other cell types, their activity in the whole-cell configuration has not been shown. This discrepancy makes their physiological significance doubtful and suggests that their mechanical activation is artifactual. Possible roles for these molecules in nonexcitable cells are acute cell-volume regulation and, in epithelial cells, the complex adjustment of ion fluxes across individual cell membranes when the rate of transepithelial transport changes. We report the results of experiments on isolated epithelial cells expressing in the basolateral membrane stretch-activated K+ channels demonstrable by the cell-attached patch-clamp technique. In these cells, reversible whole-cell currents were elicited by both isosmotic and hyposmotic cell swelling. Cation selectivity and block by inorganic agents were the same for single-channel and whole-cell currents, indicating that the same entity underlies single-channel and whole-cell currents and that the single-channel events are not artifactual. In these cells, when the rate of apical-membrane NaCl entry increases, the cell Na+ content and volume also increase, stimulating the Na+,K+-ATPase at the basolateral membrane, i.e., both Na+ extrusion and K+ uptake increase. We speculate that, under these conditions, the parallel activation of basolateral K+ channels (by the swelling) elevates conductive K+ loss, tending to maintain the cell K+ content constant (“pump-leak parallelism”). This study describes a physiologically relevant stretch-activated channel, at both the single-channel and whole-cell levels, in a nonneural cell type.

Disfacilitation and active inhibition in the neocortex during the natural sleep-wake cycle: An intracellular study

Earlier extracellular recordings during natural sleep have shown that, during slow-wave sleep (SWS), neocortical neurons display long-lasting periods of silence, whereas they are tonically active and discharge at higher rates during waking and sleep with rapid eye movements (REMs). We analyzed the nature of long-lasting periods of neuronal silence in SWS and the changes in firing rates related to ocular movements during REM sleep and waking using intracellular recordings from electrophysiologically identified neocortical neurons in nonanesthetized and nonparalyzed cats. We found that the silent periods during SWS are associated with neuronal hyperpolarizations, which are due to a mixture of K+ currents and disfacilitation processes. Conventional fast-spiking neurons (presumably local inhibitory interneurons) increased their firing rates during REMs and eye movements in waking. During REMs, the firing rates of regular-spiking neurons from associative areas decreased and intracellular traces revealed numerous, short-lasting, low-amplitude inhibitory postsynaptic potentials (IPSPs), that were reversed after intracellular chloride infusion. In awake cats, regular-spiking neurons could either increase or decrease their firing rates during eye movements. The short-lasting IPSPs associated with eye movements were still present in waking; they preceded the spikes and affected their timing. We propose that there are two different forms of firing rate control: disfacilitation induces long-lasting periods of silence that occur spontaneously during SWS, whereas active inhibition, consisting of low-amplitude, short-lasting IPSPs, is prevalent during REMs and precisely controls the timing of action potentials in waking.

Structural conservation of ion conduction pathways in K channels and glutamate receptors.

Single channel recordings demonstrate that ion channels switch stochastically between an open and a closed pore conformation. In search of a structural explanation for this universal open/close behavior, we have uncovered a striking degree of amino acid homology across the pore-forming regions of voltage-gated K channels and glutamate receptors. This suggested that the pores of these otherwise unrelated classes of channels could be structurally conserved. Strong experimental evidence supports a hairpin structure for the pore-forming region of K channels. Consequently, we hypothesized the existence of a similar structure for the pore of glutamate receptors. In ligand-gated channels, the pore is formed by M2, the second of four putative transmembrane segments. A hairpin structure for M2 would affect the subsequent membrane topology, inverting the proposed orientation of the next segments, M3. We have tested this idea for the NR1 subunit of the N-methyl-D-aspartate receptor. Mutations that affected the glycosylation pattern of the NR1 subunit localize both extremes of the M3-M4 linker to the extracellular space. Whole cell currents and apparent agonist affinities were not affected by these mutations. Therefore it can be assumed that they represent the native transmembrane topology. The extracellular assignment of the M3-M4 linker challenged the current topology model by inverting M3. Taken together, the amino acid homology and the new topology suggest that the pore-forming M2 segment of glutamate receptors does not transverse the membrane but, rather, forms a hairpin structure, similar to that found in K channels.

New York Bay and Harbor, and vicinity, 1844 (Image 2 of 6) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of New-York Bay and Harbor and the environs : sheet no. 2, founded upon a trigonometrical survey under the direction of F.R. Hassler, superintendent of the Survey of the Coast of the United States ; triangulation by James Ferguson and Edmund Blunt, assistants ; the hydrography under the direction of Thomas R. Gedney, lieutenant U.S. Navy ; the topography by C. Renard and T.A. Jenkins assists. It was published by Survey of the Coast of the United States in 1844-1845. Scale 1:30,000. This layer is image 2 of 6 total images of the six sheet source map, representing the southeast portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, bottom soil types, wharves, and more. Includes also selected land features such as roads, drainage, land cover, forts, selected buildings, towns, and more. Relief shown by hachures. Depths are shown by soundings and shading. Includes text, table of currents and stations, notes, sailing directions, 4 coastal panoramas and 2 views of Sandy Hook Light. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York Bay and Harbor, and vicinity, 1844 (Image 1 of 6) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of New-York Bay and Harbor and the environs : sheet no. 1, founded upon a trigonometrical survey under the direction of F.R. Hassler, superintendent of the Survey of the Coast of the United States ; triangulation by James Ferguson and Edmund Blunt, assistants ; the hydrography under the direction of Thomas R. Gedney, lieutenant U.S. Navy ; the topography by C. Renard and T.A. Jenkins assists. It was published by Survey of the Coast of the United States in 1844-1845. Scale 1:30,000. This layer is image 1 of 6 total images of the six sheet source map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, bottom soil types, wharves, and more. Includes also selected land features such as roads, drainage, land cover, forts, selected buildings, towns, and more. Relief shown by hachures. Depths are shown by soundings and shading. Includes text, table of currents and stations, notes, sailing directions, 4 coastal panoramas and 2 views of Sandy Hook Light. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York Bay and Harbor, and vicinity, 1844 (Image 4 of 6) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of New-York Bay and Harbor and the environs : sheet no. 4, founded upon a trigonometrical survey under the direction of F.R. Hassler, superintendent of the Survey of the Coast of the United States ; triangulation by James Ferguson and Edmund Blunt, assistants ; the hydrography under the direction of Thomas R. Gedney, lieutenant U.S. Navy ; the topography by C. Renard and T.A. Jenkins assists. It was published by Survey of the Coast of the United States in 1844-1845. Scale 1:30,000. This layer is image 4 of 6 total images of the six sheet source map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, bottom soil types, wharves, and more. Includes also selected land features such as roads, drainage, land cover, forts, selected buildings, towns, and more. Relief shown by hachures. Depths are shown by soundings and shading. Includes text, table of currents and stations, notes, sailing directions, 4 coastal panoramas and 2 views of Sandy Hook Light. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York Bay and Harbor, and vicinity, 1844 (Image 1 of 6) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of New-York Bay and Harbor and the environs : sheet no. 3, founded upon a trigonometrical survey under the direction of F.R. Hassler, superintendent of the Survey of the Coast of the United States ; triangulation by James Ferguson and Edmund Blunt, assistants ; the hydrography under the direction of Thomas R. Gedney, lieutenant U.S. Navy ; the topography by C. Renard and T.A. Jenkins assists. It was published by Survey of the Coast of the United States in 1844-1845. Scale 1:30,000. This layer is image 3 of 6 total images of the six sheet source map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, bottom soil types, wharves, and more. Includes also selected land features such as roads, drainage, land cover, forts, selected buildings, towns, and more. Relief shown by hachures. Depths are shown by soundings and shading. Includes text, table of currents and stations, notes, sailing directions, 4 coastal panoramas and 2 views of Sandy Hook Light. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York Bay and Harbor, and vicinity, 1844 (Image 5 of 6) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of New-York Bay and Harbor and the environs : sheet no. 5, founded upon a trigonometrical survey under the direction of F.R. Hassler, superintendent of the Survey of the Coast of the United States ; triangulation by James Ferguson and Edmund Blunt, assistants ; the hydrography under the direction of Thomas R. Gedney, lieutenant U.S. Navy ; the topography by C. Renard and T.A. Jenkins assists. It was published by Survey of the Coast of the United States in 1844-1845. Scale 1:30,000. This layer is image 5 of 6 total images of the six sheet source map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, bottom soil types, wharves, and more. Includes also selected land features such as roads, drainage, land cover, forts, selected buildings, towns, and more. Relief shown by hachures. Depths are shown by soundings and shading. Includes text, table of currents and stations, notes, sailing directions, 4 coastal panoramas and 2 views of Sandy Hook Light. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York Bay and Harbor, and vicinity, 1844 (Image 6 of 6) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of New-York Bay and Harbor and the environs : sheet no. 6, founded upon a trigonometrical survey under the direction of F.R. Hassler, superintendent of the Survey of the Coast of the United States ; triangulation by James Ferguson and Edmund Blunt, assistants ; the hydrography under the direction of Thomas R. Gedney, lieutenant U.S. Navy ; the topography by C. Renard and T.A. Jenkins assists. It was published by Survey of the Coast of the United States in 1844-1845. Scale 1:30,000. This layer is image 6 of 6 total images of the six sheet source map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, bottom soil types, wharves, and more. Includes also selected land features such as roads, drainage, land cover, forts, selected buildings, towns, and more. Relief shown by hachures. Depths are shown by soundings and shading. Includes text, table of currents and stations, notes, sailing directions, 4 coastal panoramas and 2 views of Sandy Hook Light. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Pacific Ocean, Currents, 1892 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Streams, currents and drifts in the Pacific Ocean : mainly from the British Admirality chart No. 2640. It was published by the Hydrographic Office in 1892. Scale [ca. 1:33,000,000]. The image inside the map neatline is georeferenced to the surface of the earth and fit to a non-standard 'Mercator' projection with the central meridian at 180 degrees west. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. Note: The central meridian of this map is not the same as the Prime Meridian and may wrap the International Date Line or overlap itself when displayed in GIS software. This map shows features such as ocean currents, drainage, cities and other human settlements, shoreline features, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

(Table 3) Textural and bulk mineralogy of Pliocene and Pleistocene sediments from ODP Hole 161-976B

The Pliocene and Pleistocene deposits recovered at Site 976 from the northwestern Alboran Sea at the Málaga base-of-slope include five main sedimentary facies: hemipelagic, turbidite, homogeneous gravity-flow, contourite, and debris-flow facies. The thickness and vertical distribution of these facies into lithostratigraphic Units I, II, and III show that the turbidites and hemipelagic facies are the dominant associations. The Pliocene and Pleistocene depositional history has been divided into three sedimentary stages: Stage I of early Pliocene age, in which hemipelagic and low-energy turbidites were the dominant processes; Stage II of early Pleistocene/late Pliocene age, in which the dominant processes were the turbidity currents interrupted by short episodes of other gravity flows (debris-flows and homogeneous gravity-flow facies) and bottom currents; and Stage III of Pleistocene age, in which both hemipelagic and low-energy gravity-flow processes occurred. The sedimentation during these three stages was controlled mainly by sea-level changes and also by the sediment supply that caused rapid terrigenous sedimentation variations from a proximal source represented by the Fuengirola Canyon.

Sedimentological, geochemical, micropaleontological and rock magnetic proxies of sediment core GeoB6211-2

Surface currents and sediment distribution of the SE South American upper continental margin are under influence of the South American Monsoon System (SAMS) and the Southern Westerly Wind Belt (SWWB). Both climatic systems determine the meridional position of the Subtropical Shelf Front (STSF) and probably also of the Brazil-Malvinas Confluence (BMC). We reconstruct the changing impact of the SAMS and the SWWB on sediment composition at the upper Rio Grande Cone off southern Brazil during the last 14 cal kyr combining sedimentological, geochemical, micropaleontological and rock magnetic proxies of marine sediment core GeoB 6211-2. Sharp reciprocal changes in ferri- and paramagnetic mineral content and prominent grain-size shifts give strong clues to systematic source changes and transport modes of these mostly terrigenous sediments. Our interpretations support the assumption that the SAMS over SE South America was weaker than today during most of the Late Glacial and entire Early Holocene, while the SWWB was contracted to more southern latitudes, resembling modern austral summer-like conditions. In consequence, the STSF and the BMC were driven to more southern positions than today's, favoring the deposition of Fe-rich but weakly magnetic La Plata River silts at the Rio Grande Cone. During the Mid Holocene, the northern boundary of the SWWB migrated northward, while the STSF reached its northernmost position of the last 14 cal kyr and the BMC most likely arrived at its modern position. This shift enabled the transport of Antarctic diatoms and more strongly magnetic Argentinean shelf sands to the Rio Grande Cone, while sediment contributions from the La Plata River became less important. During the Late Holocene, the modern El Niño Southern Oscillation set in and the SAMS and the austral tradewinds intensified, causing a southward shift of the STSF to its modern position. This reinforced a significant deposition of La Plata River silts at the Rio Grande Cone. These higher magnetic silts with intermediate Fe contents mirror the modern more humid terrestrial climatic conditions over SE South America.