Transmodal Learning of Functional Networks for Alzheimer's Disease Prediction

International audienceFunctional connectivity describes neural activity from resting-state functional magnetic resonance imaging (rs-fMRI). This noninvasive modality is a promising imaging biomarker of neurodegenerative diseases, such as Alzheimer's disease (AD), where the connectome can be an indicator to assess and to understand the pathology. However, it only provides noisy measurements of brain activity. As a consequence, it has shown fairly limited discrimination power on clinical groups. So far, the reference functional marker of AD is the fluorodeoxyglucose positron emission tomography (FDG-PET). It gives a reliable quantification of metabolic activity, but it is costly and invasive. Here, our goal is to analyze AD populations solely based on rs-fMRI, as functional connectivity is correlated to metabolism. We introduce transmodal learning: leveraging a prior from one modality to improve results of another modality on different subjects. A metabolic prior is learned from an independent FDG-PET dataset to improve functional connectivity-based prediction of AD. The prior acts as a regularization of connectivity learning and improves the estimation of discriminative patterns from distinct rs-fMRI datasets. Our approach is a two-stage classification strategy that combines several seed-based connectivity maps to cover a large number of functional networks that identify AD physiopathology. Experimental results show that our transmodal approach increases classification accuracy compared to pure rs-fMRI approaches, without resorting to additional invasive acquisitions. The method successfully recovers brain regions known to be impacted by the disease

Reorganisation of brain networks in frontotemporal dementia and progressive supranuclear palsy.

The disruption of large-scale brain networks is increasingly recognised as a consequence of neurodegenerative dementias. We assessed adults with behavioural variant frontotemporal dementia and progressive supranuclear palsy using magnetoencephalography during an auditory oddball paradigm. Network connectivity among bilateral temporal, frontal and parietal sources was examined using dynamic causal modelling. We found evidence for a systematic change in effective connectivity in both diseases. Compared with healthy subjects, who had focal modulation of intrahemispheric frontal-temporal connections, the patient groups showed abnormally extensive and inefficient networks. The changes in connectivity were accompanied by impaired responses of the auditory cortex to unexpected deviant tones (MMNm), despite normal responses to standard stimuli. Together, these results suggest that neurodegeneration in two distinct clinical syndromes with overlapping profiles of prefrontal atrophy, causes a similar pattern of reorganisation of large-scale networks. We discuss this network reorganisation in the context of other focal brain disorders and the specific vulnerability of functional brain networks to neurodegenerative disease

Multimodal connectivity of the human basal forebrain

The cholinergic innervation of the cortex originates from neurons in the basal forebrain (BF) and plays a crucial role in cognitive processing. However, it is unclear how the organization of BF cholinergic neurons in the human brain is related to their functional and structural integration with the cortex. To address this, we have used high-resolution 7 Tesla diffusion and resting-state functional MRI to examine multimodal forebrain cholinergic connectivity with the neocortex in humans. Discrete parcellation analyses revealed that structural and functional parcellation broadly differentiated the anteromedial from posterolateral nuclei of BF. Next, we used gradient estimation to capture more fine-grained connectivity profile of the BF-cortical projectome and found moving from anteromedial to posterolateral BF, structural and functional gradients became progressively detethered, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). Additionally, functional but not structural connectivity with the BF grew stronger at shorter geodesic distances, with weakly myelinated transmodal cortical areas most strongly expressing this divergence. Moreover, [18F] FEOBV PET imaging was used to demonstrate that these transmodal cortical areas are also among the most densely innervated regions. This intrinsic BF cholinergic connectivity map of cortex was compared with meta-analytic connectivity map of cholinergic modulation on attention, demonstrating that patterns of brain activity evoked by directed attention are altered by pharmacological activation of acetylcholine (ACh) compared to placebo and these patterns spatially overlap with the intrinsic BF cholinergic connectivity map. Altogether, our findings provide new insights into how cholinergic signaling is organized in the human brain

Salience and default-mode network connectivity during threat and safety processing in older adults.

The appropriate assessment of threat and safety is important for decision-making but might be altered in old age due to neurobiological changes. The literature on threat and safety processing in older adults is sparse and it is unclear how healthy ageing affects the brain's functional networks associated with affective processing. We measured skin conductance responses as an indicator of sympathetic arousal and used functional magnetic resonance imaging and independent component analysis to compare young and older adults' functional connectivity in the default mode (DMN) and salience networks (SN) during a threat conditioning and extinction task. While our results provided evidence for differential threat processing in both groups, they also showed that functional connectivity within the SN - but not the DMN - was weaker during threat processing in older compared to young adults. This reduction of within-network connectivity was accompanied by an age-related decrease in low frequency spectral power in the SN and a reduction in inter-network connectivity between the SN and DMN during threat and safety processing. Similarly, we found that skin conductance responses were generally lower in older compared to young adults. Our results are the first to demonstrate age-related changes in brain activation during aversive conditioning and suggest that the ability to adaptively filter affective information is reduced in older adults

Identifying the Neurocognitive bases of creativity to increase human and computational creativity

En esta Tesis Doctoral se ha identificado la estructura neurocognitiva que sustenta la creatividad humana a partir del análisis conjunto de más de 800 referencias bibliográficas que muestran las investigaciones más importantes realizadas hasta la fecha. Sobre la base de esta estructura, se ha identificado un paradigma neurocognitivo de la creatividad humana y se ha propuesto un modelo neurocognitivo del proceso creativo. Finalmente, también se ha propuesto un paradigma creativo neurocognitivo computacional y se ha diseñado la estructura de un sistema computacional creativo, basado en una estructura multiagente. La investigación que se ha realizado sobre el tema hasta la fecha es muy especializada y se centra en aspectos muy concretos de la creatividad, y en muchos casos tienen poca relación entre sí. Por ello, y para tener una idea conjunta y holística de los procesos neurocognitivos de la creatividad humana, es necesario estudiar todas estas investigaciones de forma interconectada. Esta idea conjunta permitiría dirigir investigaciones más específicas para ser más efectivos. Por ello, lo primero que se ha hecho ha sido clasificar, agrupar, analizar, entrelazar y estructurar, de forma ordenada, las investigaciones más importantes que se han realizado hasta la fecha. Sin embargo, el trabajo realizado va mucho más allá, ya que estructurando y entrelazando las investigaciones existentes ha sido posible identificar ciertos patrones, correlaciones y paralelismos, y realizar ciertas deducciones, que en su conjunto, han permitido identificar los procesos neurocognitivos fundamentales. bases de la creatividad humana. La Tesis se estructura en los siguientes capítulos: Capitulo 2 Análisis de los principales métodos para estimular la creatividad Se analizan las principales definiciones de creatividad, y se ha decidido que el mejor enfoque para su análisis es estructurarla taxonómicamente, bajo el modelo 4P. Se ha realizado una recopilación y análisis de los métodos más efectivos que estimulan la creatividad humana, mostrando las ventajas y desventajas de cada uno. Capítulo 3 Estructura funcional del cerebro humano y su relación con el proceso creativo Se identifica la estructura neurocognitiva general del cerebro humano que permite generar los procesos fundamentales y básicos de su actividad creativa. Capítulo 4 El papel fundamental de la DMN en el proceso creativo Se ha observado que la red de modo predeterminado (DMN) tiene un papel principal en la creatividad. Por ello, se ha dedicado un capítulo a su estudio, y se han identificado varios factores que la involucran directamente en la actividad creativa del cerebro humano. Capítulo 5 Identificación y análisis de las bases neurocognitivas de la creatividad humana Se ha identificado el conjunto general de factores neurocognitivos que sustentan los procesos creativos en el cerebro humano. Capítulo 6 Paradigma neurocognitivo de la creatividad humana Se ha propuesto un modelo neurocognitivo del proceso creativo que reestructura, completa y detalla todos los modelos conceptuales propuestos hasta el momento. Capítulo 7 Paradigma computacional de la creatividad basado en la estructura neurocognitiva humana Analizando las diferentes bases neurocognitivas que sustentan la creatividad humana, se han establecido paralelismos computacionales y se han realizado diferentes sugerencias para el diseño de un sistema computacional creativo.In this Doctoral Thesis, the neurocognitive structure that supports human creativity has been identified based on the joint analysis of more than 800 bibliographical references that show the most important investigations carried out to date. Based on this structure, a neurocognitive paradigm of human creativity has been described, and a neurocognitive model of creative process has been proposed. Finally, a computational neurocognitive creative paradigm has been also proposed, and the structure of a creative computational multi-agent system has been designed. The research that has been carried out on the subject is very specialized and focuses on very specific aspects of creativity, and in many cases they have little relationship with each other. For this reason, and in order to have a joint and holistic idea of the neurocognitive processes of human creativity, it is necessary to study all these investigations in an interconnected way. This joint idea would allow directing more specific investigations in order to be more effective. For this reason, the first thing that has been done has been to classify, group, analyze, intertwine and structure, in an orderly manner, the most important investigations that have been carried out to date. However, the work carried out goes much further, since by structuring and intertwining the existing research it has been possible to identify certain patterns, correlations and parallelisms, and make certain deductions, which as a whole, have made it possible to identify the fundamental neurocognitive bases of human creativity. Chapter 2 Analysis of the main methods to stimulate creativity The main definitions of creativity are analyzed, and it has been decided that the best approach for its analysis is to structure it taxonomically, under the 4P model. A compilation and analysis of the most effective methods that stimulate human creativity has been carried out, showing the advantages and disadvantages of each one. Chapter 3 Functional structure of the human brain and its relationship with the creative process The general neurocognitive structure of the human brain that allows the generation of the fundamental and basic processes of its creative activity are identified. Chapter 4 The fundamental role of the DMN in the creative process It has been observed that the Default mode network (DMN) has a main role in creativity. For this reason, a chapter has been dedicated to its study, and several factors have been identified that directly involve it in the creative activity of the human brain. Chapter 5 Identification and analysis of the neurocognitive bases of human creativity The general set of neurocognitive factors that underpin creative processes in the human brain has been identified. Chapter 6 Neurocognitive paradigm of human creativity A neurocognitive model of the creative process has been proposed, which restructures, completes and details all the conceptual models proposed so far. Chapter 7 Computational paradigm of creativity based on the human neurocognitive structure Analyzing the different neurocognitive bases that support human creativity, computational parallels have been established and different suggestions have been made for the design of a creative computational system

The Role of Unimodal and Transmodal Cortex in Perceptually-Coupled and Decoupled Semantic Cognition: Evidence from fMRI

Semantic retrieval extends beyond the here-and-now, to draw on abstract knowledge that has been extracted across multiple experiences; for instance, we can easily bring to mind what a dog looks and sounds like, even when a dog is not present in our environment. However, a clear understanding of the neural substrates that support patterns of semantic retrieval that are not immediately driven by stimuli in the environment is lacking. This thesis sought to investigate the neural basis of semantic retrieval within unimodal and heteromodal networks, whilst manipulating the availability of information in the environment. Much of the empirical work takes inspiration from modern accounts of transmodal regions (Lambon Ralph et al. 2017; Margulies et al. 2016), which suggest the anterior temporal lobe (ATL) and default mode network (DMN) support both abstraction and perceptual decoupling. The first empirical chapter examines whether words and experiences activate common neural substrates in sensory regions and where, within the ATLs, representations are transmodal. The second empirical chapter investigates how perceptually-decoupled forms of semantic retrieval in imagination are represented across unimodal and transmodal regions. The third empirical chapter interrogates whether transmodal regions respond in a similar manner to conceptually-guided and perceptually-decoupled cognition, and whether these two factors interact. The data suggests ventrolateral ATL processes both abstract modality-invariant semantic representations (Chapter 3) and decoupled semantic processing during imagination (Chapter 4). In addition, this thesis found comparable networks recruited for both conceptual processing and perceptually-decoupled retrieval corresponding to the broader DMN (Chapter 5). Further interrogation of these sites confirmed lateral MTG and bilateral angular gyrus were pivotal in the combination of conceptual retrieval from memory. Collectively, this data suggests that brain regions situated farthest from sensory input systems in both functional and connectivity space are required for the most abstract forms of cognition

Brain structure and function in Huntington's disease gene carriers far from predicted disease onset

Whilst there are currently no available disease modifying therapies for Huntington’s Disease (HD), recent progress in huntingtin-lowering strategies hold great promise. Initiating therapies early in the disease course will be important and a complete characterisation of the premanifest period will help inform when to initiate disease modifying therapies and the biomarkers that may be useful in such trials. Previous research has characterised the premanifest period up to approximately 15 years from predicted onset, but even at this early stage the disease process is already underway as evidenced by striatal and white matter atrophy, reductions in structural connectivity within brain networks, rising biofluid biomarkers of neuronal dysfunction, elevations in psychiatric symptoms and emerging subtle cognitive impairments. In order to understand how early neurodegeneration can be detected and which measures are most sensitive to the early disease processes, we need to look even earlier in the disease course. This thesis documents the recruitment and analysis of the HD Young Adult Study: a premanifest cohort further from predicted clinical onset than previously studied with an average of 24 years prior to predicted onset. Differences between gene carriers and controls were examined across a range of imaging, cognitive, neuropsychiatric and biofluid measures. The structural and functional brain connectivity in this cohort is then investigated in further detail. By providing a detailed characterisation of brain structure and function in the early premanifest period along with the most sensitive biomarkers at this stage, this work will inform future treatment strategies that may seek to delay the onset of functional impairments in HD

On Arousal and the Internal Regulation of Brain Function: Theory and Evidence across Modalities and Species

The brain is an organ. It is subject to the same physiological regulatory processes that engage the rest of the body’s organs, sculpted over hundreds of millions of years to sustain life so effectively. The central message of this thesis is that the holistic functioning of the brain, rather than operating at some level above or independent from these systemic regulatory processes, is deeply related to them. In short, as our limited attention spans might suggest: brain function is internally regulated. I propose that this internal regulation is a primary function of intrinsic brain activity. Chapter 2 provides a theoretical treatment of this issue, recasting intrinsic activity as an internal regulatory process operating on the brain’s temporal “states” and spatial “networks”. After establishing this framework, Chapters 3 and 4 provide tests of specific predictions. Thus, Chapter 3 confirms, in humans and macaque monkeys, the presence of topographically organized traveling waves occurring in synchrony with ongoing arousal fluctuations, with propagation occurring in parallel within the neocortex, striatum, thalamus, and cerebellum. This process is argued to provide a heretofore lacking physiological account of “resting-state functional connectivity” and related phenomenology. Chapter 4 extends this observation by demonstrating a continuous and tightly coordinated temporal evolution of brain, body, and behavioral states along a latent arousal cycle. Across multiple recording techniques and species, this cyclic trajectory is shown to be coupled to the traveling wave process described in Chapter 3, thus providing a parsimonious and integrative account of intrinsic brain activity and its spatiotemporal dynamics. Taken together, this thesis argues for the existence of an intrinsic regulatory process for global brain function

Analyzing hierarchical multi-view MRI Data With StaPLR An Application to Alzheimer's disease classification: an application to Alzheimer's disease classification

Multi-view data refers to a setting where features are divided into feature sets, for example because they correspond to different sources. Stacked penalized logistic regression (StaPLR) is a recently introduced method that can be used for classification and automatically selecting the views that are most important for prediction. We introduce an extension of this method to a setting where the data has a hierarchical multi-view structure. We also introduce a new view importance measure for StaPLR, which allows us to compare the importance of views at any level of the hierarchy. We apply our extended StaPLR algorithm to Alzheimer's disease classification where different MRI measures have been calculated from three scan types: structural MRI, diffusion-weighted MRI, and resting-state fMRI. StaPLR can identify which scan types and which derived MRI measures are most important for classification, and it outperforms elastic net regression in classification performance. Horizon 2020(H2020)101041064Multivariate analysis of psychological dat

ApoE4 effects on the structural covariance brain networks topology in Mild Cognitive Impairment

The Apolipoprotein E isoform E4 (ApoE4) is consistently associated with an elevated risk of developing late-onset Alzheimer's Disease (AD). However, little is known about his potential genetic modulation on the structural covariance brain networks during prodromal stages like Mild Cognitive Impairment (MCI). The covariance phenomenon is based on the observation that regions correlating in morphometric descriptors are often part of the same brain system. In a first study, I assessed the ApoE4-related changes on the brain network topology in 256 MCI patients, using the regional cortical thickness to define the covariance network. The cross-sectional sample selected from the ADNI database was subdivided into ApoE4-positive (Carriers) and negative (non-Carriers). At the group-level, the results showed a significant decrease in characteristic path length, clustering index, local efficiency, global connectivity, modularity, and increased global efficiency for Carriers compared to non-Carriers. Overall, I found that ApoE4 in MCI shaped the topological organization of cortical thickness covariance networks. In the second project, I investigated the impact of ApoE4 on the single-subject gray matter networks in a sample of 200 MCI from the ADNI database. The patients were classified based on clinical outcome (stable MCI versus converters to AD) and ApoE4 status (Carriers versus non-Carriers). The effects of ApoE4 and disease progression on the network measures at baseline and rate of change were explored. The topological network attributes were correlated with AD biomarkers. The main findings showed that gray matter network topology is affected independently by ApoE4 and the disease progression (to AD) in late-MCI. The network measures alterations showed a more random organization in Carriers compared to non-Carriers. Finally, as additional research, I investigated whether a network-based approach combined with the graph theory is able to detect cerebrovascular reactivity (CVR) changes in MCI. Our findings suggest that this experimental approach is more sensitive to identifying subtle cerebrovascular alterations than the classical experimental designs. This study paves the way for a future investigation on the ApoE4-cerebrovascular interaction effects on the brain networks during AD progression. In summary, my thesis results provide evidence of the value of the structural covariance brain network measures to capture subtle neurodegenerative changes associated with ApoE4 in MCI. Together with other biomarkers, these variables may help predict disease progression, providing additional reliable intermediate phenotypes