ABSTRACT: Cognitive functions rely on the extensive use of information stored in the brain, and the searching for the relevant information for solving some problem is a very complex task. Human cognition largely uses biological search engines, and we assume that to study cognitive function we need to understand the way these brain search engines work. The approach we favor is to study multi-modular network models, able to solve particular problems that involve searching for information. The building blocks of these multimodular networks are the context dependent memory models we have been using for almost 20 years. These models work by associating an output to the Kronecker product of an input and a context. Input, context and output are vectors that represent cognitive variables. Our models constitute a natural extension of the traditional linear associator. We show that coding the information in vectors that are processed through association matrices, allows for a direct contact between these memory models and some procedures that are now classical in the Information Retrieval field. One essential feature of context-dependent models is that they are based on the thematic packing of information, whereby each context points to a particular set of related concepts. The thematic packing can be extended to multimodular networks involving input-output contexts, in order to accomplish more complex tasks. Contexts act as passwords that elicit the appropriate memory to deal with a query. We also show toy versions of several 'neuromimetic' devices that solve cognitive tasks as diverse as decision making or word sense disambiguation. The functioning of these multimodular networks can be described as dynamical systems at the level of cognitive variables.
Project description:Mathematical modeling is seen as a key step to understand, predict, and control the temporal dynamics of interacting systems in such diverse areas like physics, biology, medicine, and economics. However, for large and complex systems we usually have only partial knowledge about the network, the coupling functions, and the interactions with the environment governing the dynamic behavior. This incomplete knowledge induces structural model errors which can in turn be the cause of erroneous model predictions or misguided interpretations. Uncovering the location of such structural model errors in large networks can be a daunting task for a modeler. Here, we present a data driven method to search for structural model errors and to confine their position in large and complex dynamic networks. We introduce a coherence measure for pairs of network nodes, which indicates, how difficult it is to distinguish these nodes as sources of an error. By clustering network nodes into coherence groups and inferring the cluster inputs we can decide, which cluster is affected by an error. We demonstrate the utility of our method for the C. elegans neural network, for a signal transduction model for UV-B light induced morphogenesis and for synthetic examples.
Project description:In our daily lives, we use eye movements to actively sample visual information from our environment ("active vision"). However, little is known about how the underlying mechanisms are affected by goal-directed behavior. In a study of 31 participants, magnetoencephalography was combined with eye-tracking technology to investigate how interregional interactions in the brain change when engaged in two distinct forms of active vision: freely viewing natural images or performing a guided visual search. Regions of interest with significant fixation-related evoked activity (FRA) were identified with spatiotemporal cluster permutation testing. Using generalized partial directed coherence, we show that, in response to fixation onset, a bilateral cluster consisting of four regions (posterior insula, transverse temporal gyri, superior temporal gyrus, and supramarginal gyrus) formed a highly connected network during free viewing. A comparable network also emerged in the right hemisphere during the search task, with the right supramarginal gyrus acting as a central node for information exchange. The results suggest that all four regions are vital to visual processing and guiding attention. Furthermore, the right supramarginal gyrus was the only region where activity during fixations on the search target was significantly negatively correlated with search response times. Based on our findings, we hypothesize that, following a fixation, the right supramarginal gyrus supplies the right supplementary eye field (SEF) with new information to update the priority map guiding the eye movements during the search task.
Project description:Primary hyperoxaluria type 1 (PHT1) treatment is mainly focused on inhibiting the enzyme glycolate oxidase, which plays a pivotal role in the production of glyoxylate, which undergoes oxidation to produce oxalate. When the renal secretion capacity exceeds, calcium oxalate forms stones that accumulate in the kidneys. In this respect, detailed QSAR analysis, molecular docking, and dynamics simulations of a series of inhibitors containing glycolic, glyoxylic, and salicylic acid groups have been performed employing different regression machine learning techniques. Three robust models with less than 9 descriptors-based on a tenfold cross (Q2 CV) and external (Q2 EXT) validation-were found i.e., MLR1 (Q2 CV = 0.893, Q2 EXT = 0.897), RF1 (Q2 CV = 0.889, Q2 EXT = 0.907), and IBK1 (Q2 CV = 0.891, Q2 EXT = 0.907). An ensemble model was built by averaging the predicted pIC50 of the three models, obtaining a Q2 EXT = 0.933. Physicochemical properties such as charge, electronegativity, hardness, softness, van der Waals volume, and polarizability were considered as attributes to build the models. To get more insight into the potential biological activity of the compouds studied herein, docking and dynamic analysis were carried out, finding the hydrophobic and polar residues show important interactions with the ligands. A screening of the DrugBank database V.5.1.7 was performed, leading to the proposal of seven commercial drugs within the applicability domain of the models, that can be suggested as possible PHT1 treatment.
Project description:Neuroimaging data can be represented as networks of nodes and edges that capture the topological organization of the brain connectivity. Graph theory provides a general and powerful framework to study these networks and their structure at various scales. By way of example, community detection methods have been widely applied to investigate the modular structure of many natural networks, including brain functional connectivity networks. Sparsification procedures are often applied to remove the weakest edges, which are the most affected by experimental noise, and to reduce the density of the graph, thus making it theoretically and computationally more tractable. However, weak links may also contain significant structural information, and procedures to identify the optimal tradeoff are the subject of active research. Here, we explore the use of percolation analysis, a method grounded in statistical physics, to identify the optimal sparsification threshold for community detection in brain connectivity networks. By using synthetic networks endowed with a ground-truth modular structure and realistic topological features typical of human brain functional connectivity networks, we show that percolation analysis can be applied to identify the optimal sparsification threshold that maximizes information on the networks' community structure. We validate this approach using three different community detection methods widely applied to the analysis of brain connectivity networks: Newman's modularity, InfoMap and Asymptotical Surprise. Importantly, we test the effects of noise and data variability, which are critical factors to determine the optimal threshold. This data-driven method should prove particularly useful in the analysis of the community structure of brain networks in populations characterized by different connectivity strengths, such as patients and controls.
Project description:A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.
Project description:The substitution rate in a gene can provide valuable information for understanding its functionality and evolution. A widely used method to estimate substitution rates is the maximum-likelihood method implemented in the CODEML program in the PAML package. A limited number of branch models, chosen based on a priori information or an interest in a particular lineage(s), are tested, whereas a large number of potential models are neglected. A complementary approach is also needed to test all or a large number of possible models to search for the globally optional model(s) of maximum likelihood. However, the computational time for this search even in a small number of sequences becomes impractically long. Thus, it is desirable to explore the most probable spaces to search for the optimal models. Using dynamic programming techniques, we developed a simple computational method for searching the most probable optimal branch-specific models in a practically feasible computational time. We propose three search methods to find the optimal models, which explored O(n) (method 1) to O(n(2)) (method 2 and method 3) models when the given phylogeny has n branches. In addition, we derived a formula to calculate the number of all possible models, revealing the complexity of finding the optimal branch-specific model. We show that in a reanalysis of over 50 previously published studies, the vast majority obtained better models with significantly higher likelihoods than the conventional hypothesis model methods.
Project description:The extent to which brain functions are localized or distributed is a foundational question in neuroscience. In the human brain, common fMRI methods such as cluster correction, atlas parcellation, and anatomical searchlight are biased by design toward finding localized representations. Here we introduce the functional searchlight approach as an alternative to anatomical searchlight analysis, the most commonly used exploratory multivariate fMRI technique. Functional searchlight removes any anatomical bias by grouping voxels based only on functional similarity and ignoring anatomical proximity. We report evidence that visual and auditory features from deep neural networks and semantic features from a natural language processing model, as well as object representations, are more widely distributed across the brain than previously acknowledged and that functional searchlight can improve model-based similarity and decoding accuracy. This approach provides a new way to evaluate and constrain computational models with brain activity and pushes our understanding of human brain function further along the spectrum from strict modularity toward distributed representation.
Project description:Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI.
Project description:Protein phosphorylation is the most common post-translational modification that regulates several pivotal functions in cells. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase which is mostly active in the nervous system. It regulates several biological processes such as neuronal migration, cytoskeletal dynamics, axonal guidance and synaptic plasticity among others. In search for novel substrates of Cdk5 in the brain we performed quantitative phosphoproteomics analysis, isolating phosphoproteins from whole brain derived from E18.5 Cdk5+/+ and Cdk5-/- embryos, using an Immobilized Metal-Ion Affinity Chromatography (IMAC), which specifically binds to phosphorylated proteins. The isolated phosphoproteins were eluted and isotopically labeled for relative and absolute quantitation (iTRAQ) and mass spectrometry identification. We found 40 proteins that showed decreased phosphorylation at Cdk5-/- brains. In addition, out of these 40 hypophosphorylated proteins we characterized two proteins, :MARCKS (Myristoylated Alanine-Rich protein Kinase C substrate) and Grin1 (G protein regulated inducer of neurite outgrowth 1). MARCKS is known to be phosphorylated by Cdk5 in chick neural cells while Grin1 has not been reported to be phosphorylated by Cdk5. When these proteins were overexpressed in N2A neuroblastoma cell line along with p35, serine phosphorylation in their Cdk5 motifs was found to be increased. In contrast, treatments with roscovitine, the Cdk5 inhibitor, resulted in an opposite effect on serine phosphorylation in N2A cells and primary hippocampal neurons transfected with MARCKS. In summary, the results presented here identify Grin 1 as novel Cdk5 substrate and confirm previously identified MARCKS as a a bona fide Cdk5 substrate.