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Neuroscientists rely on distributed spatio-temporal patterns of neural activity to understand how neural units contribute to cognitive functions and behavior. However, the extent to which neural activity reliably indicates a unit's causal contribution to the behavior is not well understood. To address this issue, we provide a systematic multi-site perturbation framework that captures time-varying causal contributions of elements to a collectively produced outcome. Applying our framework to intuitive toy examples and artificial neural networks revealed that recorded activity patterns of neural elements may not be generally informative of their causal contribution due to activity transformations within a network. Overall, our findings emphasize the limitations of inferring causal mechanisms from neural activities and offer a rigorous lesioning framework for elucidating causal neural contributions.
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Cognição , Neurônios , Causalidade , Intuição , Redes Neurais de ComputaçãoRESUMO
The aim of this work was to enhance the biological feasibility of a deep convolutional neural network-based in-silico model of neurodegeneration of the visual system by equipping it with a mechanism to simulate neuroplasticity. Therefore, deep convolutional networks of multiple sizes were trained for object recognition tasks and progressively lesioned to simulate neurodegeneration of the visual cortex. More specifically, the injured parts of the network remained injured while we investigated how the added retraining steps were able to recover some of the model's object recognition baseline performance. The results showed with retraining, model object recognition abilities are subject to a smoother and more gradual decline with increasing injury levels than without retraining and, therefore, more similar to the longitudinal cognition impairments of patients diagnosed with Alzheimer's disease (AD). Moreover, with retraining, the injured model exhibits internal activation patterns similar to those of the healthy baseline model when compared to the injured model without retraining. Furthermore, we conducted this analysis on a network that had been extensively pruned, resulting in an optimized number of parameters or synapses. Our findings show that this network exhibited remarkably similar capability to recover task performance with decreasingly viable pathways through the network. In conclusion, adding a retraining step to the in-silico setup that simulates neuroplasticity improves the model's biological feasibility considerably and could prove valuable to test different rehabilitation approaches in-silico.
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Intrinsic coupling modes (ICMs) can be observed in ongoing brain activity at multiple spatial and temporal scales. Two families of ICMs can be distinguished: phase and envelope ICMs. The principles that shape these ICMs remain partly elusive, in particular their relation to the underlying brain structure. Here we explored structure-function relationships in the ferret brain between ICMs quantified from ongoing brain activity recorded with chronically implanted micro-ECoG arrays and structural connectivity (SC) obtained from high-resolution diffusion MRI tractography. Large-scale computational models were used to explore the ability to predict both types of ICMs. Importantly, all investigations were conducted with ICM measures that are sensitive or insensitive to volume conduction effects. The results show that both types of ICMs are significantly related to SC, except for phase ICMs when using measures removing zero-lag coupling. The correlation between SC and ICMs increases with increasing frequency which is accompanied by reduced delays. Computational models produced results that were highly dependent on the specific parameter settings. The most consistent predictions were derived from measures solely based on SC. Overall, the results demonstrate that patterns of cortical functional coupling as reflected in both phase and envelope ICMs are both related, albeit to different degrees, to the underlying structural connectivity in the cerebral cortex.
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Córtex Cerebral , Furões , Humanos , Animais , Córtex Cerebral/diagnóstico por imagem , Encéfalo , Mapeamento Encefálico/métodos , EletrocorticografiaRESUMO
Neuroscientists rely on distributed spatio-temporal patterns of neural activity to understand how neural units contribute to cognitive functions and behavior. However, the extent to which neural activity reliably indicates a unit's causal contribution to the behavior is not well understood. To address this issue, we provide a systematic multi-site perturbation framework that captures time-varying causal contributions of elements to a collectively produced outcome. Applying our framework to intuitive toy examples and artificial neuronal networks revealed that recorded activity patterns of neural elements may not be generally informative of their causal contribution due to activity transformations within a network. Overall, our findings emphasize the limitations of inferring causal mechanisms from neural activities and offer a rigorous lesioning framework for elucidating causal neural contributions.
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The connectivity of Artificial Neural Networks (ANNs) is different from the one observed in Biological Neural Networks (BNNs). Can the wiring of actual brains help improve ANNs architectures? Can we learn from ANNs about what network features support computation in the brain when solving a task? At a meso/macro-scale level of the connectivity, ANNs' architectures are carefully engineered and such those design decisions have crucial importance in many recent performance improvements. On the other hand, BNNs exhibit complex emergent connectivity patterns at all scales. At the individual level, BNNs connectivity results from brain development and plasticity processes, while at the species level, adaptive reconfigurations during evolution also play a major role shaping connectivity. Ubiquitous features of brain connectivity have been identified in recent years, but their role in the brain's ability to perform concrete computations remains poorly understood. Computational neuroscience studies reveal the influence of specific brain connectivity features only on abstract dynamical properties, although the implications of real brain networks topologies on machine learning or cognitive tasks have been barely explored. Here we present a cross-species study with a hybrid approach integrating real brain connectomes and Bio-Echo State Networks, which we use to solve concrete memory tasks, allowing us to probe the potential computational implications of real brain connectivity patterns on task solving. We find results consistent across species and tasks, showing that biologically inspired networks perform as well as classical echo state networks, provided a minimum level of randomness and diversity of connections is allowed. We also present a framework, bio2art, to map and scale up real connectomes that can be integrated into recurrent ANNs. This approach also allows us to show the crucial importance of the diversity of interareal connectivity patterns, stressing the importance of stochastic processes determining neural networks connectivity in general.
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Encéfalo , Conectoma , Redes Neurais de Computação , Aprendizado de MáquinaRESUMO
Connectomes represent comprehensive descriptions of neural connections in a nervous system to better understand and model central brain function and peripheral processing of afferent and efferent neural signals. Connectomes can be considered as a distinctive and necessary structural component alongside glial, vascular, neurochemical, and metabolic networks of the nervous systems of higher organisms that are required for the control of body functions and interaction with the environment. They are carriers of functional phenomena such as planning behavior and cognition, which are based on the processing of highly dynamic neural signaling patterns. In this study, we examine more detailed connectomes with edge weighting and orientation properties, in which reciprocal neuronal connections are also considered. Diffusion processes are a further necessary condition for generating dynamic bioelectric patterns in connectomes. Based on our precise connectome data, we investigate different diffusion-reaction models to study the propagation of dynamic concentration patterns in control and lesioned connectomes. Therefore, differential equations for modeling diffusion were combined with well-known reaction terms to allow the use of connection weights, connectivity orientation and spatial distances. Three reaction-diffusion systems Gray-Scott, Gierer-Meinhardt and Mimura-Murray were investigated. For this purpose, implicit solvers were implemented in a numerically stable reaction-diffusion system within the framework of neuroVIISAS. The implemented reaction-diffusion systems were applied to a subconnectome which shapes the mechanosensitive pathway that is strongly affected in the multiple sclerosis demyelination disease. It was found that demyelination modeling by connectivity weight modulation changes the oscillations of the target region, i.e. the primary somatosensory cortex, of the mechanosensitive pathway. In conclusion, a new application of reaction-diffusion systems to weighted and directed connectomes has been realized. Because the implementation was realized in the neuroVIISAS framework many possibilities for the study of dynamic reaction-diffusion processes in empirical connectomes as well as specific randomized network models are available now.
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Conectoma , Esclerose Múltipla , Humanos , Encéfalo/fisiologia , Imagem de Tensor de Difusão , Vias NeuraisRESUMO
Mice display signs of fear when neurons that express cFos during fear conditioning are artificially reactivated. This finding gave rise to the notion that cFos marks neurons that encode specific memories. Here we show that cFos expression patterns in the mouse dentate gyrus (DG) change dramatically from day to day in a water maze spatial learning paradigm, regardless of training level. Optogenetic inhibition of neurons that expressed cFos on the first training day affected performance days later, suggesting that these neurons continue to be important for spatial memory recall. The mechanism preventing repeated cFos expression in DG granule cells involves accumulation of ΔFosB, a long-lived splice variant of FosB. CA1 neurons, in contrast, repeatedly expressed cFos. Thus, cFos-expressing granule cells may encode new features being added to the internal representation during the last training session. This form of timestamping is thought to be required for the formation of episodic memories.
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Giro Denteado , Aprendizagem Espacial , Animais , Camundongos , Giro Denteado/fisiologia , Hipocampo , Neurônios/metabolismo , Memória EspacialRESUMO
Lesion inference analysis is a fundamental approach for characterizing the causal contributions of neural elements to brain function. This approach has gained new prominence through the arrival of modern perturbation techniques with unprecedented levels of spatiotemporal precision. While inferences drawn from brain perturbations are conceptually powerful, they face methodological difficulties. Particularly, they are challenged to disentangle the true causal contributions of the involved elements, since often functions arise from coalitions of distributed, interacting elements, and localized perturbations have unknown global consequences. To elucidate these limitations, we systematically and exhaustively lesioned a small artificial neural network (ANN) playing a classic arcade game. We determined the functional contributions of all nodes and links, contrasting results from sequential single-element perturbations with simultaneous perturbations of multiple elements. We found that lesioning individual elements, one at a time, produced biased results. By contrast, multi-site lesion analysis captured crucial details that were missed by single-site lesions. We conclude that even small and seemingly simple ANNs show surprising complexity that needs to be addressed by multi-lesioning for a coherent causal characterization.
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Encéfalo , Redes Neurais de ComputaçãoRESUMO
Brain functions rely on the communication network formed by axonal fibers. However, the number of axons connecting different brain regions is unknown. A study in PLoS Biology addresses this question and finds that most areas of the human cerebral cortex are linked by an astoundingly small number of fibers.
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Axônios , Encéfalo , Córtex Cerebral , HumanosRESUMO
The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation.
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Encéfalo , Computação em Nuvem , Animais , Teorema de Bayes , Encéfalo/diagnóstico por imagem , Simulação por Computador , Humanos , Imageamento por Ressonância Magnética/métodos , Camundongos , SoftwareRESUMO
What structural and connectivity features of the human brain help to explain the extraordinary human cognitive abilities? We recently proposed a set of relevant connectomic fundamentals, some of which arise from the size scaling of the human brain relative to other primate brains, while others of these fundamentals may be uniquely human. In particular, we suggested that the remarkable increase of the size of the human brain due to its prolonged prenatal development has brought with it an increased sparsification, hierarchical modularization, as well as increased depth and cytoarchitectonic differentiation of brain networks. These characteristic features are complemented by a shift of projection origins to the upper layers of many cortical areas as well as the significantly prolonged postnatal development and plasticity of the upper cortical layers. Another fundamental aspect of cortical organization that has emerged in recent research is the alignment of diverse features of evolution, development, cytoarchitectonics, function, and plasticity along a principal, natural cortical axis from sensory ("outside") to association ("inside") areas. Here we highlight how this natural axis is integrated in the characteristic organization of the human brain. In particular, the human brain displays a developmental expansion of outside areas and a stretching of the natural axis such that outside areas are more widely separated from each other and from inside areas than in other species. We outline some functional implications of this characteristic arrangement.
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Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor 'language and consciousness' was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function. Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks.
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Biological neuronal networks (BNNs) are a source of inspiration and analogy making for researchers that focus on artificial neuronal networks (ANNs). Moreover, neuroscientists increasingly use ANNs as a model for the brain. Despite certain similarities between these two types of networks, important differences can be discerned. First, biological neural networks are sculpted by evolution and the constraints that it entails, whereas artificial neural networks are engineered to solve particular tasks. Second, the network topology of these systems, apart from some analogies that can be drawn, exhibits pronounced differences. Here, we examine strategies to construct recurrent neural networks (RNNs) that instantiate the network topology of brains of different species. We refer to such RNNs as bio-instantiated. We investigate the performance of bio-instantiated RNNs in terms of: (i) the prediction performance itself, that is, the capacity of the network to minimize the cost function at hand in test data, and (ii) speed of training, that is, how fast during training the network reaches its optimal performance. We examine bio-instantiated RNNs in working memory tasks where task-relevant information must be tracked as a sequence of events unfolds in time. We highlight the strategies that can be used to construct RNNs with the network topology found in BNNs, without sacrificing performance. Despite that we observe no enhancement of performance when compared to randomly wired RNNs, our approach demonstrates how empirical neural network data can be used for constructing RNNs, thus, facilitating further experimentation with biologically realistic network topologies, in contexts where such aspect is desired.
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Redes Neurais de Computação , Neurobiologia , Algoritmos , NeurôniosRESUMO
Structural connections between cortical areas form an intricate network with a high degree of specificity. Many aspects of this complex network organization in the adult mammalian cortex are captured by an architectonic type principle, which relates structural connections to the architectonic differentiation of brain regions. In particular, the laminar patterns of projection origins are a prominent feature of structural connections that varies in a graded manner with the relative architectonic differentiation of connected areas in the adult brain. Here we show that the architectonic type principle is already apparent for the laminar origins of cortico-cortical projections in the immature cortex of the macaque monkey. We find that prenatal and neonatal laminar patterns correlate with cortical architectonic differentiation, and that the relation of laminar patterns to architectonic differences between connected areas is not substantially altered by the complete loss of visual input. Moreover, we find that the degree of change in laminar patterns that projections undergo during development varies in proportion to the relative architectonic differentiation of the connected areas. Hence, it appears that initial biases in laminar projection patterns become progressively strengthened by later developmental processes. These findings suggest that early neurogenetic processes during the formation of the brain are sufficient to establish the characteristic laminar projection patterns. This conclusion is in line with previously suggested mechanistic explanations underlying the emergence of the architectonic type principle and provides further constraints for exploring the fundamental factors that shape structural connectivity in the mammalian brain.
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Córtex Cerebral , Macaca , Animais , Encéfalo , Mapeamento Encefálico , Diferenciação Celular , Vias NeuraisRESUMO
Transmitter receptors constitute a key component of the molecular machinery for intercellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distill these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density); excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density); and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.
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Encéfalo/metabolismo , Comunicação Celular/genética , Córtex Cerebral/metabolismo , Receptores de Neurotransmissores/genética , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/ultraestrutura , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/ultraestrutura , Humanos , Receptores de AMPA/genética , Receptores de AMPA/isolamento & purificação , Receptores de GABA-A/genética , Receptores de GABA-A/isolamento & purificação , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/isolamento & purificação , Receptores de Neurotransmissores/química , Receptores de Neurotransmissores/classificação , Receptores de Neurotransmissores/ultraestruturaRESUMO
High-resolution functional 2-photon microscopy of neural activity is a cornerstone technique in current neuroscience, enabling, for instance, the image-based analysis of relations of the organization of local neuron populations and their temporal neural activity patterns. Interpreting local image intensity as a direct quantitative measure of neural activity presumes, however, a consistent within- and across-image relationship between the image intensity and neural activity, which may be subject to interference by illumination artifacts. In particular, the so-called vignetting artifact-the decrease of image intensity toward the edges of an image-is, at the moment, widely neglected in the context of functional microscopy analyses of neural activity, but potentially introduces a substantial center-periphery bias of derived functional measures. In the present report, we propose a straightforward protocol for single image-based vignetting correction. Using immediate-early gene-based 2-photon microscopic neural image data of the mouse brain, we show the necessity of correcting both image brightness and contrast to improve within- and across-image intensity consistency and demonstrate the plausibility of the resulting functional data.
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Cognitive abilities of the human brain, including language, have expanded dramatically in the course of our recent evolution from nonhuman primates, despite only minor apparent changes at the gene level. The hypothesis we propose for this paradox relies upon fundamental features of human brain connectivity, which contribute to a characteristic anatomical, functional, and computational neural phenotype, offering a parsimonious framework for connectomic changes taking place upon the human-specific evolution of the genome. Many human connectomic features might be accounted for by substantially increased brain size within the global neural architecture of the primate brain, resulting in a larger number of neurons and areas and the sparsification, increased modularity, and laminar differentiation of cortical connections. The combination of these features with the developmental expansion of upper cortical layers, prolonged postnatal brain development, and multiplied nongenetic interactions with the physical, social, and cultural environment gives rise to categorically human-specific cognitive abilities including the recursivity of language. Thus, a small set of genetic regulatory events affecting quantitative gene expression may plausibly account for the origins of human brain connectivity and cognition.
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Evolução Biológica , Encéfalo/fisiologia , Conectoma , Regulação da Expressão Gênica no Desenvolvimento/genética , Animais , Encéfalo/crescimento & desenvolvimento , Cognição , Genoma Humano , Humanos , Idioma , Tamanho do Órgão , Fenótipo , PrimatasRESUMO
The architectonic type principle conceptualizes structural connections between brain areas in terms of the relative architectonic differentiation of connected areas. It has previously been shown that spatio-temporal interactions between the time and place of neurogenesis could underlie multiple features of empirical mammalian connectomes, such as projection existence and the distribution of projection strengths. However, so far no mechanistic explanation for the emergence of typically observed laminar patterns of projection origins and terminations has been tested. Here, we expand an in silico model of the developing cortical sheet to explore which factors could potentially constrain the development of laminar projection patterns. We show that manipulations which rely solely on spatio-temporal interactions, namely the relative density of laminar compartments, a delay in the neurogenesis of infragranular layers relative to layer 1, and a delay in the neurogenesis of supragranular layers relative to infragranular layers, do not result in the striking correlation between supragranular contribution to projections and the relative differentiation of areas that is typically observed in the mammalian cortex. In contrast, we find that if we introduce systematic variation in cell-intrinsic properties, coupling them with architectonic differentiation, the resulting laminar projection patterns closely mirror the empirically observed patterns. We also find that the spatio-temporal interactions posited to occur during neurogenesis are necessary for the formation of the characteristic laminar patterns. Hence, our results indicate that the specification of the laminar patterns of projection origins may result from systematic variation in a number of cell-intrinsic properties, superimposed on the previously identified spatio-temporal interactions which are sufficient for the emergence of the architectonic type principle on the level of inter-areal connectivity in silico.
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Córtex Cerebral , Modelos Neurológicos , Rede Nervosa , Neurogênese/fisiologia , Animais , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/fisiologia , Biologia Computacional , Simulação por Computador , Conectoma , Humanos , Camundongos , Rede Nervosa/crescimento & desenvolvimento , Rede Nervosa/fisiologiaRESUMO
Behavioral effects of transcranial magnetic stimulation (TMS) often show substantial differences between subjects. One factor that might contribute to these inter-individual differences is the interaction of current brain states with the effects of local brain network perturbation. The aim of the current study was to identify brain regions whose connectivity before and following right parietal perturbation affects individual behavioral effects during a visuospatial target detection task. 20 subjects participated in an fMRI experiment where their brain hemodynamic response was measured during resting state, and then during a visuospatial target detection task following 1 Hz rTMS and sham stimulation. To select a parsimonious set of associated brain regions, an elastic net analysis was used in combination with a whole-brain voxel-wise functional connectivity analysis. TMS-induced changes in accuracy were significantly correlated with the pattern of functional connectivity during the task state following TMS. The functional connectivity of the left superior temporal, angular, and precentral gyri was identified as key explanatory variable for the individual behavioral TMS effects. Our results suggest that the brain must reach an appropriate state in which right parietal TMS can induce improvements in visual target detection. The ability to reach this state appears to vary between individuals.