A statistical model relating transcription factor concentrations to positional information in the early Drosophila embryo

The idea of morphogen gradients encoding positional information for a developing organism has long been discussed in the field of developmental biology, but only recently have quantitative models been proposed that relate measured transcription factor concentrations to enhancer activity. However, successful models are typically computationally time-consuming, thus limiting full exploration and interpretation of the data. This thesis addresses these problems using standard statistical techniques applied to a comprehensive data set with the even skipped (eve) locus as a test case. The first part of the thesis introduces the data set. This is the precellular Virtual Embryo from the Berkeley Drosophila Transcription Network project. It comprises expression measurements of almost 100 genes in more than 6,000 individual nuclei at six time points. Different modelling approaches are evaluated in the context of this data set leading to a justification of logistic regression and the methods used to prepare the data set for further analysis. The second part applies logistic regression to describe the response of the eve enhancers to known regulating transcription factors such as Hunchback. Predictions of behaviour under regulator perturbation are consistent with experimental results and the functional form is shown not to be arbitrarily flexible, both in terms of the regulators and regions of the embryo included. The third part uses the framework developed above to find minimal explanatory models in the context of statistical model selection. It is found that the best scoring models depend on well-known regulators. The model selection techniques are then extended by directing the process using previous biological observations to analyse the eve 2 and eve 3+7 enhancers. The results are consistent with published research, but suggest specific additional hypotheses for the enhancers’ regulation. Finally, the thesis concludes by proposing a general model of positional information and discussing the biological implications of the results. Overall, the results show how transcriptional control can be allocated to discrete enhancers and that characterising their activity in relatively simple terms is sufficient to explain their precise spatially-defined response to transcription factor concentrations

Modeling biophysical and neural circuit bases for core cognitive abilities evident in neuroimaging patterns: hippocampal mismatch, mismatch negativity, repetition positivity, and alpha suppression of distractors

This dissertation develops computational models to address outstanding problems in the domain of expectation-related cognitive processes and their neuroimaging markers in functional MRI or EEG. The new models reveal a way to unite diverse phenomena within a common framework focused on dynamic neural encoding shifts, which can arise from robust interactive effects of M-currents and chloride currents in pyramidal neurons. By specifying efficient, biologically realistic circuits that achieve predictive coding (e.g., Friston, 2005), these models bridge among neuronal biophysics, systems neuroscience, and theories of cognition. Chapter one surveys data types and neural processes to be examined, and outlines the Dynamically Labeled Predictive Coding (DLPC) framework developed during the research. Chapter two models hippocampal prediction and mismatch, using the DLPC framework. Chapter three presents extensions to the model that allow its application for modeling neocortical EEG genesis. Simulations of this extended model illustrate how dynamic encoding shifts can produce Mismatch Negativity (MMN) phenomena, including pharmacological effects on MMN reported for humans or animals. Chapters four and five describe new modeling studies of possible neural bases for alpha-induced information suppression, a phenomenon associated with active ignoring of stimuli. Two models explore the hypothesis that in simple rate-based circuits, information suppression might be a robust effect of neural saturation states arising near peaks of resonant alpha oscillations. A new proposal is also introduced for how the basal ganglia may control onset and offset of alpha-induced information suppression. Although these rate models could reproduce many experimental findings, they fell short of reproducing a key electrophysiological finding: phase-dependent reduction in spiking activity correlated with power in the alpha frequency band. Therefore, chapter five also specifies how a DLPC model, adapted from the neocortical model developed in chapter three, can provide an expectation-based model of alpha-induced information suppression that exhibits phase-dependent spike reduction during alpha-band oscillations. The model thus can explain experimental findings that were not reproduced by the rate models. The final chapter summarizes main theses, results, and basic research implications, then suggests future directions, including expanded models of neocortical mismatch, applications to artificial neural networks, and the introduction of reward circuitry

Event-Driven Technologies for Reactive Motion Planning: Neuromorphic Stereo Vision and Robot Path Planning and Their Application on Parallel Hardware

Die Robotik wird immer mehr zu einem Schlüsselfaktor des technischen Aufschwungs. Trotz beeindruckender Fortschritte in den letzten Jahrzehnten, übertreffen Gehirne von Säugetieren in den Bereichen Sehen und Bewegungsplanung noch immer selbst die leistungsfähigsten Maschinen. Industrieroboter sind sehr schnell und präzise, aber ihre Planungsalgorithmen sind in hochdynamischen Umgebungen, wie sie für die Mensch-Roboter-Kollaboration (MRK) erforderlich sind, nicht leistungsfähig genug. Ohne schnelle und adaptive Bewegungsplanung kann sichere MRK nicht garantiert werden. Neuromorphe Technologien, einschließlich visueller Sensoren und Hardware-Chips, arbeiten asynchron und verarbeiten so raum-zeitliche Informationen sehr effizient. Insbesondere ereignisbasierte visuelle Sensoren sind konventionellen, synchronen Kameras bei vielen Anwendungen bereits überlegen. Daher haben ereignisbasierte Methoden ein großes Potenzial, schnellere und energieeffizientere Algorithmen zur Bewegungssteuerung in der MRK zu ermöglichen. In dieser Arbeit wird ein Ansatz zur flexiblen reaktiven Bewegungssteuerung eines Roboterarms vorgestellt. Dabei wird die Exterozeption durch ereignisbasiertes Stereosehen erreicht und die Pfadplanung ist in einer neuronalen Repräsentation des Konfigurationsraums implementiert. Die Multiview-3D-Rekonstruktion wird durch eine qualitative Analyse in Simulation evaluiert und auf ein Stereo-System ereignisbasierter Kameras übertragen. Zur Evaluierung der reaktiven kollisionsfreien Online-Planung wird ein Demonstrator mit einem industriellen Roboter genutzt. Dieser wird auch für eine vergleichende Studie zu sample-basierten Planern verwendet. Ergänzt wird dies durch einen Benchmark von parallelen Hardwarelösungen wozu als Testszenario Bahnplanung in der Robotik gewählt wurde. Die Ergebnisse zeigen, dass die vorgeschlagenen neuronalen Lösungen einen effektiven Weg zur Realisierung einer Robotersteuerung für dynamische Szenarien darstellen. Diese Arbeit schafft eine Grundlage für neuronale Lösungen bei adaptiven Fertigungsprozesse, auch in Zusammenarbeit mit dem Menschen, ohne Einbußen bei Geschwindigkeit und Sicherheit. Damit ebnet sie den Weg für die Integration von dem Gehirn nachempfundener Hardware und Algorithmen in die Industrierobotik und MRK

Towards building a more complex view of the lateral geniculate nucleus: Recent advances in understanding its role

The lateral geniculate nucleus (LGN) has often been treated in the past as a linear filter that adds little to retinal processing of visual inputs. Here we review anatomical, neurophysiological, brain imaging, and modeling studies that have in recent years built up a much more complex view of LGN . These include effects related to nonlinear dendritic processing, cortical feedback, synchrony and oscillations across LGN populations, as well as involvement of LGN in higher level cognitive processing. Although recent studies have provided valuable insights into early visual processing including the role of LGN, a unified model of LGN responses to real-world objects has not yet been developed. In the light of recent data, we suggest that the role of LGN deserves more careful consideration in developing models of high-level visual processing

Models and Algorithms for Sorting Permutations with Tandem Duplication and Random Loss

A central topic of evolutionary biology is the inference of phylogeny, i. e., the evolutionary history of species. A powerful tool for the inference of such phylogenetic relationships is the arrangement of the genes in mitochondrial genomes. The rationale is that these gene arrangements are subject to different types of mutations in the course of evolution. Hence, a high similarity in the gene arrangement between two species indicates a close evolutionary relation. Metazoan mitochondrial gene arrangements are particularly well suited for such phylogenetic studies as they are available for a wide range of species, their gene content is almost invariant, and usually free of duplicates. With these properties gene arrangements of mitochondrial genomes are modeled by permutations in which each element represents a gene, i. e., a specific genetic sequence. The mutations that shape the gene arrangement of genomes are then represented by operations that rearrange elements in permutations, so-called genome rearrangements, and thereby bridge the gap between evolutionary biology and optimization. Many problems of phylogeny inference can be formulated as challenging combinatorial optimization problems which makes this research area especially interesting for computer scientists. The most prominent examples of such optimization problems are the sorting problem and the distance problem. While the sorting problem requires a minimum length sequence of rearrangements that transforms one given permutation into another given permutation, i. e., it aims for a hypothetical scenario of gene order evolution, the distance problem intends to determine only the length of such a sequence. This minimum length is called distance and used as a (dis)similarity measure quantifying the evolutionary relatedness. Most evolutionary changes occurring in gene arrangements of mitochondrial genomes can be explained by the tandem duplication random loss (TDRL) genome rearrangement model. A TDRL consists of a duplication of a consecutive set of genes in tandem followed by a random loss of one copy of each duplicated gene. In spite of the importance of the TDRL genome rearrangement in mitochondrial evolution, its combinatorial properties have rarely been studied. In addition, models of genome rearrangements which include all types of rearrangement that are relevant for mitochondrial genomes, i. e., inversions, transpositions, inverse transpositions, and TDRLs, while admitting computational tractability are rare. Nevertheless, especially for metazoan gene arrangements the TDRL rearrangement should be considered for the reconstruction of phylogeny. Realizing that a better understanding of the TDRL model is indispensable for the study of mitochondrial gene arrangements, the central theme of this thesis is to broaden the horizon of TDRL genome rearrangements with respect to mitochondrial genome evolution. For this purpose, this thesis provides combinatorial properties of the TDRL model and its variants as well as efficient methods for a plausible reconstruction of rearrangement scenarios between gene arrangements. The methods that are proposed consider all types of genome rearrangements that predominately occur during mitochondrial evolution. More precisely, the main points contained in this thesis are as follows: The distance problem and the sorting problem for the TDRL model are further examined in respect to circular permutations, a formal concept that reflects the circular structure of mitochondrial genomes. As a result, a closed formula for the distance is provided. Recently, evidence for a variant of the TDRL rearrangement model in which the duplicated set of genes is additionally inverted have been found. Initiating the algorithmic study of this new rearrangement model on a certain type of permutations, a closed formula solving the distance problem is proposed as well as a quasilinear time algorithm that solves the corresponding sorting problem. The assumption that only one type of genome rearrangement has occurred during the evolution of certain gene arrangements is most likely unrealistic, e. g., at least three types of rearrangements on top of the TDRL rearrangement have to be considered for the evolution metazoan mitochondrial genomes. Therefore, three different biologically motivated constraints are taken into account in this thesis in order to produce plausible evolutionary rearrangement scenarios. The first constraint is extending the considered set of genome rearrangements to the model that covers all four common types of mitochondrial genome rearrangements. For this 4-type model a sharp lower bound and several close additive upper bounds on the distance are developed. As a byproduct, a polynomial-time approximation algorithm for the corresponding sorting problem is provided that guarantees the computation of pairwise rearrangement scenarios that deviate from a minimum length scenario by at most two rearrangement operations. The second biologically motivated constraint is the relative frequency of the different types of rearrangements occurring during the evolution. The frequency is modeled by employing a weighting scheme on the 4-type model in which every rearrangement is weighted with respect to its type. The resulting NP-hard sorting problem is then solved by means of a polynomial size integer linear program. The third biologically motivated constraint that has been taken into account is that certain subsets of genes are often found in close proximity in the gene arrangements of many different species. This observation is reflected by demanding rearrangement scenarios to preserve certain groups of genes which are modeled by common intervals of permutations. In order to solve the sorting problem that considers all three types of biologically motivated constraints, the exact dynamic programming algorithm CREx2 is proposed. CREx2 has a linear runtime for a large class of problem instances. Otherwise, two versions of the CREx2 are provided: The first version provides exact solutions but has an exponential runtime in the worst case and the second version provides approximated solutions efficiently. CREx2 is evaluated by an empirical study for simulated artificial and real biological mitochondrial gene arrangements

A biologically plausible embodied model of action discovery

During development, animals can spontaneously discover action-outcome pairings enabling subsequent achievement of their goals. We present a biologically plausible embodied model addressing key aspects of this process. The biomimetic model core comprises the basal ganglia and its loops through cortex and thalamus. We incorporate reinforcement learning (RL) with phasic dopamine supplying a sensory prediction error, signalling “surprising” outcomes. Phasic dopamine is used in a cortico-striatal learning rule which is consistent with recent data. We also hypothesized that objects associated with surprising outcomes acquire “novelty salience” contingent on the predicability of the outcome. To test this idea we used a simple model of prediction governing the dynamics of novelty salience and phasic dopamine. The task of the virtual robotic agent mimicked an in vivo counterpart (Gancarz et al., 2011) and involved interaction with a target object which caused a light flash, or a control object which did not. Learning took place according to two schedules. In one, the phasic outcome was delivered after interaction with the target in an unpredictable way which emulated the in vivo protocol. Without novelty salience, the model was unable to account for the experimental data. In the other schedule, the phasic outcome was reliably delivered and the agent showed a rapid increase in the number of interactions with the target which then decreased over subsequent sessions. We argue this is precisely the kind of change in behavior required to repeatedly present representations of context, action and outcome, to neural networks responsible for learning action-outcome contingency. The model also showed cortico-striatal plasticity consistent with learning a new action in basal ganglia. We conclude that action learning is underpinned by a complex interplay of plasticity and stimulus salience, and that our model contains many of the elements for biological action discovery to take place

Computational role of disinhibition in brain function

Neurons are connected to form functional networks in the brain. When neurons are combined in sequence, nontrivial effects arise. One example is disinhibition; that is, inhibition to another inhibitory factor. Disinhibition may be serving an important purpose because a large number of local circuits in the brain contain disinhibitory connections. However, their exact functional role is not well understood. The objective of this dissertation is to analyze the computational role of disinhibition in brain function, especially in visual perception and attentional control. My approach is to propose computational models of disinhibition and then map the model to the local circuits in the brain to explain psychological phenomena. Several computational models are proposed in this dissertation to account for disinhibition. (1) A static inverse difference of Gaussian filter (IDoG) is derived to account explicitly for the spatial effects of disinhibition. IDoG can explain a number of complex brightness-contrast illusions, such as the periphery problem in the Hermann grid and the White's effect. The IDoG model can also be used to explain orientation perception of multiple lines as in the modified version of Poggendorff illusion. (2) A spatio-temporal model (IDoGS) in early vision is derived and it successfully explains the scintillating grid illusion, which is a stationary display giving rise to a striking, dynamic, scintillating effect. (3) An interconnected Cohen-Grossberg neural network model (iCGNN) is proposed to address the dynamics of disinhibitory neural networks with a layered structure. I derive a set of sufficient conditions for such an interconnected system to reach asymptotic stability. (4) A computational model combining recurrent and feed-forward disinhibition is designed to account for input-modulation in temporal selective attention. The main contribution of this research is that it developed a unified framework of disinhibition to model several different kinds of neural circuits to account for various perceptual and attentional phenomena. Investigating the role of disinhibition in the brain can provide us with a deeper understanding of how the brain can give rise to intelligent and complex functions

Machine Learning and Statistical Analysis of Complex Mathematical Models: An Application to Epilepsy

The electroencephalogram (EEG) is a commonly used tool for studying the emergent electrical rhythms of the brain. It has wide utility in psychology, as well as bringing a useful diagnostic aid for neurological conditions such as epilepsy. It is of growing importance to better understand the emergence of these electrical rhythms and, in the case of diagnosis of neurological conditions, to find mechanistic differences between healthy individuals and those with a disease. Mathematical models are an important tool that offer the potential to reveal these otherwise hidden mechanisms. In particular Neural Mass Models (NMMs), which describe the macroscopic activity of large populations of neurons, are increasingly used to uncover large-scale mechanisms of brain rhythms in both health and disease. The dynamics of these models is dependent upon the choice of parameters, and therefore it is crucial to be able to understand how dynamics change when parameters are varied. Despite they are considered low-dimensional in comparison to micro-scale neural network models, with regards to understanding the relationship between parameters and dynamics NMMs are still prohibitively high dimensional for classical approaches such as numerical continuation. We need alternative methods to characterise the dynamics of NMMs in high dimensional parameter spaces. The primary aim of this thesis is to develop a method to explore and analyse the high dimensional parameter space of these mathematical models. We develop an approach based on statistics and machine learning methods called decision tree mapping (DTM). This method is used to analyse the parameter space of a mathematical model by studying all the parameters simultaneously. With this approach, the parameter space can efficiently be mapped in high dimension. We have used measures linked with this method to determine which parameters play a key role in the output of the model. This approach recursively splits the parameter space into smaller subspaces with an increasing homogeneity of dynamics. The concepts of decision tree learning, random forest, measures of importance, statistical tests and visual tools are introduced to explore and analyse the parameter space. We introduce formally the theoretical background and the methods with examples. The DTM approach is used in three distinct studies to: • Identify the role of parameters on the dynamic model. For example, which parameters have a role in the emergence of seizure dynamics? • Constrain the parameter space, such that regions of the parameter space which give implausible dynamic are removed. • Compare the parameter sets to fit different groups. How does the thalamocortical connectivity of people with and without epilepsy differ? We demonstrate that classical studies have not taken into account the complexity of the parameter space. DTM can easily be extended to other fields using mathematical models. We advocate the use of this method in the future to constrain high dimensional parameter spaces in order to enable more efficient, person-specific model calibration

Dynamic causal modelling shows a prominent role of local inhibition in alpha power modulation in higher visual cortex

During resting-state EEG recordings, alpha activity is more prominent over the posterior cortex in eyes-closed (EC) conditions compared to eyes-open (EO). In this study, we characterized the difference in spectra between EO and EC conditions using dynamic causal modelling. Specifically, we investigated the role of intrinsic and extrinsic connectivity-within the visual cortex-in generating EC-EO alpha power differences over posterior electrodes. The primary visual cortex (V1) and the bilateral middle temporal visual areas (V5) were equipped with bidirectional extrinsic connections using a canonical microcircuit. The states of four intrinsically coupled subpopulations-within each occipital source-were also modelled. Using Bayesian model selection, we tested whether modulations of the intrinsic connections in V1, V5 or extrinsic connections (or a combination thereof) provided the best evidence for the data. In addition, using parametric empirical Bayes (PEB), we estimated group averages under the winning model. Bayesian model selection showed that the winning model contained both extrinsic connectivity modulations, as well as intrinsic connectivity modulations in all sources. The PEB analysis revealed increased extrinsic connectivity during EC. Overall, we found a reduction in the inhibitory intrinsic connections during EC. The results suggest that the intrinsic modulations in V5 played the most important role in producing EC-EO alpha differences, suggesting an intrinsic disinhibition in higher order visual cortex, during EC resting state