"Magnetic resonance imaging (MRI) has emerged as the imaging modality of choice in a wide variety experimental and clinical applications. In this dissertation, I will describe novel MRI techniques for the characterization of neural and pulmonary vascular function in preclinical models of disease. In the first part of this dissertation, experimental results will be presented comparing the identification of ischemic lesions in experimental stroke using dynamic susceptibility contrast (DSC) and a well validated arterial spin labeling (ASL). We show that DSC measurements of an index of cerebral blood flow are sensitive to ischemia, treatment, and stroke subregions. Further, we derived a threshold of cerebral blood flow for ischemia as measured by DSC. Finally, we show that ischemic lesion volumes as defined by DSC are comparable to those defined by ASL. In the second part of this dissertation, a methodology of visualizing clots in experimental animal models of stroke is presented. Clots were rendered visible by MRI through the addition of a gadolinium based contrast agent during formation. Modified clots were used to induce an experimental embolic middle cerebral artery occlusion. Clots in the cerebral vasculature were visualized in vivo using MRI. Further, the efficacy of recombinant tissue plasminogen activator (r-tPA) and the combination of r-tPA and recombinant annexin-2 (rA2) was characterized by clot visualization during lysis. In the third part of this dissertation, we present results of the application of hyperpolarized helium (HP-He) in the characterization of new model of experimental pulmonary ischemia. The longitudinal relaxation time of HP-He is sensitive to the presence of paramagnetic oxygen. During ischemia, oxygen exchange from the airspaces of the lungs to the capillaries is hindered resulting in increased alveolar oxygen content which resulted in the shortening of the HP-He longitudinal relaxation time. Results of measurements of the HP-He relaxation time in both normal and ischemic animals are presented. In the final part of this dissertation, I will present results of a new method to measure pulmonary blood volume (PBV) using proton based MRI. A T1 weighted, inversion recovery spin echo sequence with cardiac and respiratory gating was developed to measure the changes in signal intensity of lung parenchyma before and after the injection of a long acting intravascular contrast agent. PBV is related to the signal change in the lung parenchyma and blood before and after contrast agent. We validate our method using a model of hypoxic pulmonary vasoconstriction in rats."

Neural systems are often stochastic, non-linear, and non-autonomous. The complex manifestation of these aspects hinders the interpretation of neuroscientific data. Neuroscience thus benefits from the inclusion of theoretical models in its methodology. Detailed biophysical models of neural systems, however, are often plagued by high-dimensional and poorly constrained parameter spaces. As an alternative, data-driven effective models can often explain the core dynamical features of a dataset with few underlying assumptions. By lumping high-dimensional fluctuations into low-dimensional stochastic terms, observed time-series can be well-represented by stochastic dynamical systems. Here, I apply this approach to two datasets from weakly electric fish. The rate of electrosensory sampling of freely behaving fish displays spontaneous transitions between two preferred values: an active exploratory state and a resting state. I show that, over a long timescale, this rate can be modelled with a stochastic double-well system where a slow external agent modulates the relative depth of the wells. On a shorter timescale, however, fish exhibit abrupt and transient increases in sampling rate not consistent with a diffusion process. I develop and apply a novel inference method to construct a jump-diffusion process that fits the observed fluctuations. This same technique is successfully applied to intrinsic membrane voltage noise in pyramidal neurons of the primary electrosensory processing area, which display abrupt depolarization events along with diffusive fluctuations. I then characterize a novel sensory acquisition strategy whereby fish adopt a rhythmic movement pattern coupled with stochastic oscillations of their sampling rate. Lastly, in the context of differentiating between self-generated and external electrosensory signals, I model the sensory signature of communication signals between fish. This analysis provides supporting evidence for the presence of a sensory ambiguity associated with these signals.

Dentre as inúmeras técnicas de conversão de voz utilizadas atualmente, aquelas baseadas em bancos de filtros wavelet, associadas com redes neurais artificiais,têm se destacado. Este trabalho se concentra em tais técnicas, realizando um estudo que relaciona qual a melhor wavelet para conversão de determinados padrões de voz, apresentando uma análise detalhada de quais são as características que levam a estes resultados. Os testes são realizados com vozes da base de dados TIMIT do Linguistic Data Consortium (LDC). / Dentre as inúmeras técnicas de conversão de voz utilizadas atualmente, aquelas baseadas em bancos de filtros wavelet, associadas com redes neurais artificiais, têm se destacado. Este trabalho se concentra em tais técnicas, realizando um estudo que relaciona qual a melhor wavelet para conversão de determinados padrões de voz, apresentando uma análise detalhada de quais são as características que levam a estes resultados. Os testes são realizados com vozes da base de dados TIMIT do Linguistic Data Consortium (LDC).

A key role in simplified models of neural circuitry (Wilson and Cowan, 1972) is played by the matrix of synaptic weights, also called connectivity matrix, whose elements describe the amount of influence the firing of one neuron has on another. Biologically, this matrix evolves over time whether or not sensory inputs are present, and symmetries possessed by the internal dynamics of the network may break up spontaneously, as found in the development of the visual cortex (Hubel and Wiesel, 1977). In this thesis, a full analytical treatment is provided for the simplest case of such a biological phenomenon, a single dendritic arbor driven by correlation-based dynamics (Linsker, 1988). Borrowing methods from the theory of Schrödinger operators, a complete study of the model is performed, analytically describing the break-up of rotational symmetry that leads to the functional specialization of cells. The structure of the eigenfunctions is calculated, lower bounds are derived on the critical value of the correlation length, and explicit expressions are obtained for the long-term profile of receptive fields, i.e. the dependence of neural activity on external inputs. The emergence of a functional architecture of orientation preferences in the cortex is another crucial feature of visual information processing. This is discussed through a model consisting of large neural layers connected by an infinite number of Hebb-evolved arbors. Ohshiro and Weiliky (2006), in their study of developing ferrets, found correlation profiles of neural activity in contradiction with previous theories of the phenomenon (Miller, 1994; Wimbauer, 1998). The theory proposed herein, based upon the type of correlations they measured, leads to the emergence of three different symmetry classes. The contours of a highly structured phase diagram are traced analytically, and observables concerning the various phases are estimated in every phase by means of perturbative, asymptotic and variational methods. The proper modeling of axonal competition proves to be key to reproducing basic phenomenological features. While these models describe the long-term effect of synaptic plasticity, plasticity itself makes the connectivity matrix highly dependent on particular histories, hence its stochasticity cannot be considered perturbatively. The problem is tackled by carrying out a detailed treatment of the spectral properties of synaptic-weight matrices with an arbitrary distribution of disorder. Results include a proof of the asymptotic compactness of random spectra, calculations of the shape of supports and of the density profiles, a fresh analysis of the problem of spectral outliers, a study of the link between eigenvalue density and the pseudospectrum of the mean connectivity, and applications of these general results to a variety of biologically relevant examples. The strong non-normality of synaptic-weight matrices (biologically engineered through Dale’s law) is believed to play important functional roles in cortical operations (Murphy and Miller, 2009; Goldman, 2009). Accordingly, a comprehensive study is dedicated to its effect on the transient dynamics of large disordered networks. This is done by adapting standard field-theoretical methods (such as the summation of ladder diagrams) to the non-Hermitian case. Transient amplification of activity can be measured from the average norm squared; this is calculated explicitly for a number of cases, showing that transients are typically amplified by disorder. Explicit expressions for the power spectrum of response are derived and applied to a number of biologically plausible networks, yielding insights into the interplay between disorder and non-normality. The fluctuations of the covariance of noisy neural activity are also briefly discussed. Recent optogenetic measurements have raised questions on the link between synaptic structure and the response of disordered networks to targeted perturbations. Answering to these developments, formulae are derived that establish the operational regime of networks through their response to specific perturbations, and a minimal threshold is found to exist for counterintuitive responses of an inhibitory-stabilized circuit such as have been reported in Ozeki et al. (2016), Adesnik (2016), Kato et al. (2017). Experimental advances are also bringing to light unsuspected differences between various neuron types, which appear to translate into different roles in network function (Pfeffer et al., 2013; Tremblay et al., 2016). Accordingly, the last part of the thesis focuses on networks with an arbitrary number of neuronal types, and predictions are provided for the response of networks with a multipopulation structure to targeted input perturbations.

This thesis focuses on my work using optical techniques to study different brain regions in vivo. The ability to optically study neurons and the circuits they comprise in vivo is an important method to better understand their role in the healthy brain and their dysfunction in disease. The first part of my thesis focuses on my work using on a collaborative project using a new optical probe to study norepinephrine synapses in vivo. In this work we were able to observe the effects of amphetamine on norepinephrine release in vivo and observed some evidence of potential silent synapses. I also describe a new method of cranial window surgery I developed for optical imaging. This technique called PHASOR, is faster, and has a higher success rate, than traditional surgical methods. The improvements demonstrated in this new surgical technique may enable more widespread use of optical imaging methods. In the second part of my thesis, I used optical techniques to study the dorsal striatum in vivo in awake behaving mice. The direct and indirect paths of the dorsal striatum play an important role in motor behavior and motor learning. Dysfunction in these paths has been implicated in motor diseases as well as in mood disorders. In this thesis, I provide a review of the anatomy and physiology of the neurons that comprise the dorsal striatum, and the circuits that they form. The next chapters describe my work using optical techniques to record from these neurons in vivo. In my first set of experiments, I recorded from the direct and indirect paths during a behavioral task of anxiety and observed differential firing depending on the anxiety state of the mouse. Finally, in a preliminary set of experiments, I record from the direct and indirect paths during tasks of motor learning. I found that both paths show changes in firing during motor learning and that these changes differ between the dorsolateral and dorsomedial striatum.

No description available.

Appropriately organized synaptic connections are essential for proper neural circuit function. Prior to forming and refining synaptic connections, axons of projection neurons must first navigate long distances to their targets. Research in the axon guidance field has generated a great deal of knowledge about how axons successfully navigate through intermediate choice points and form initial connections with their synaptic targets. One aspect of neural circuit development that has been less well studied is whether axons are organized within their tracts. Axons could be highly ordered, or arranged haphazardly, to be sorted out within their destination target zone. Findings from several systems indicate that axon tracts are organized and, furthermore, that pre-target organization is important for accurate targeting. Chapter 1 will survey these findings as an introduction to my thesis. The remaining chapters present my research in the mouse retinogeniculate pathway, in which I examine three aspects of pre-target axon organization: the organization of cohorts of retinal ganglion cell (RGC) axons in the optic nerve and tract; the role of axon self association in tract organization; and the relationship between tract order and targeting. RGC axons project either ipsi- or contralaterally at the optic chiasm. In the first thalamic target, the dorsal lateral geniculate nucleus (dLGN), RGC axon terminals are organized based on retinotopy and laterality (i.e., into ipsi- and contralateral zones). Chapter 2 presents my findings on the organization of ipsilateral (ipsi) and contralateral (contra) RGC axons in the optic nerve and tract. Ipsilateral RGC axons cluster together in the optic nerve, are less tightly bundled in the optic chiasm, and once in the optic tract, again bundle together and are segregated from contralateral axons. Topographic and ipsi/contra axon order in the optic tract are largely in register, although ipsi- and contralateral axons from the same topographic region maintain distinct ipsi/contra segregation in the tract. Chapter 3 explores one potential mechanism involved in creating the organization between ipsi and contra RGC axons in the tract: differential fasciculation behavior between RGC axon cohorts. I used in vitro retinal explant culture systems to test the hypothesis that ipsilateral RGC axons have a greater preference to self-fasciculate than contralateral axons. Ipsilateral neurites display greater self-association/fasciculation than contralateral neurites, indicating an axon-intrinsic mechanism of ipsilateral-specific self-association. Chapter 4 examines tract organization and fasciculation in the EphB1 mutant retinogeniculate pathway. EphB1 is expressed exclusively by ipsilateral RGCs, and loss of EphB1 leads to a reduced ipsilateral projection and increased contralateral projection. However, aberrantly crossing axons project to the ipsilateral zone in the dLGN. Given its combination of an aberrant decussation phenotype with a grossly normal targeting phenotype, I used this mutant to explore the relationship between midline choice, tract organization, and targeting. First, remaining ipsilateral axons in the EphB1-/- optic tract largely retain their position in the lateral optic tract, but appear splayed apart, suggestive of aberrant fasciculation. In vitro, EphB1-/- ipsilateral neurites still bundle more than EphB1-/- contralateral neurites, although the magnitude of this difference is less striking than in wild-type retinal explants. Thus, EphB1 may be involved in preferential ipsilateral RGC axon fasciculation. In vivo, the aberrantly crossing axons in the EphB1 mutant grossly maintain their position in the ipsilateral zone of the optic tract (i.e., the lateral aspect), indicating a preservation of ipsilateral segregation in the tract. This is in line with a model in which bundling partners in the tract may help guide axons to the correct zone in the target. The data presented in this thesis detail two organizational modes of RGC axons in the developing optic nerve and tract, eye-specific (typographic) and topographic, and suggest that axon-intrinsic factors mediate ipsilateral-specific self-association. Axon-intrinsic factors likely act alongside extrinsic cellular and molecular cues in the developing retinogeniculate pathway to facilitate pre-target axon organization, which may in turn facilitate accurate formation of synaptic connections in the dLGN.

Introdução: A hanseníase é a principal causa infecciosa de neuropatia periférica e consequentes incapacidades em todo o mundo. Seu diagnóstico, na maioria das vezes é simples, especialmente quando as clássicas lesões cutâneas estão presentes. No entanto, alguns pacientes apresentam apenas envolvimento neural (forma neural pura - PNL) transformando o seu diagnóstico em um grande desafio. Nesses casos, mesmo quando essa possibilidade é aventada, sua confirmação pode ser extremamente difícil e muitos pacientes só serão corretamente diagnosticados tardiamente, quando uma neuropatia grave e irreversível já está estabelecida. Objetivos: Analisar as características de uma série de pacientes com diagnóstico definitivo ou provável de PNL seguidos no setor de doenças neuromusculares e dermatologia no HCRP em um período de 12 anos e reconhecer o padrão de apresentação mais frequente, suas manifestações clínicas e o padrão eletroneuromiográfico. Métodos: Estudo retrospectivo, observacional, cujos critérios de inclusão foram: evidência clínica de comprometimento de nervos periféricos na ausência de lesões de pele. O diagnóstico definitivo foi estabelecido quando o Mycobacterium leprae foi identificado na biópsia de nervo, e provável quando um quadro clínico sugestivo foi associado a pelo menos um dos seguintes: anti PGL1 positivo, padrão sugestivo na biópsia (neurite granulomatosa epitelióide, infiltrado linfomomononuclear, fibrose) e/ou padrão eletroneuromiográfico sugestivo. Para avaliar a importância da duração da doença na apresentação clínica, foram considerados dois grupos de acordo com o tempo da doença, 12 meses ou menos (grupo 1) e mais de 12 meses (grupo 2). Foram comparados os sinais, os sintomas, a gravidade da doença e o padrão da EMG para delinear o quadro de apresentação. Resultados: Dos 34 pacientes incluídos no estudo, 7 tinham diagnóstico definitivo e 24 diagnóstico provável. Os sintomas de início mais frequentes foram alterações sensitivas (91,2%), em 70,6% dos casos iniciaram nos membros superiores, sendo o nervo ulnar o local mais frequente. O padrão de distribuição intradérmico exclusivo foi observado apenas no grupo 1. A alteração da sensibilidade vibratória (p=0,07), a presença de alterações motoras (p=0,03) e hipo ou areflexia em 1 ou mais nervos (p=0,03) foram mais frequentemente observadas no grupo 2. Os nervos sensitivos mais frequentemente envolvidos foram o ulnar e fibular superficial. O nervo motor mais frequentemente afetado foi o ulnar. O padrão eletroneuromiográfico mais frequente foi de uma neuropatia sensitivo motora assimétrica com reduções focais da velocidade de condução e franco predomínio sensitivo. Conclusões: A PNL se apresenta invariavelmente de maneira assimétrica e com franco predomínio sensitivo. Na maioria das vezes o início ocorre nos membros superiores, especificamente no território do nervo ulnar. Há uma predisposição ao acometimento das fibras finas nos estágios iniciais e com a evolução da doença as fibras grossas passam a também serem afetadas. Os nervos sensitivos mais frequentemente envolvidos são o ulnar seguido pelo fibular superficial. / Backgrounds: Leprosy is the main infectious cause of peripheral neuropathy and disabilities in the world. Its diagnosis is straightforward when the classical skin lesions are present. However, some patients present only neural involvement (pure neural form-PNL) turning its diagnosis on a great challenge. Additionally, even when this possibility is suspected, confirmation may be extremely difficult and many patients are only correctly diagnosed late on the clinical course of the disease when a severe and irreversible neuropathy is already established. Objectives: To review the characteristics of a series of PNL patients followed in our institution in the last 12 years and recognize the clinical manifestations. Methods: Inclusion criteria: Clinical evidence of peripheral nerve impairment with no skin lesions. PNL diagnose were classified as definitive when the Mycobacterium leprae was identified under nerve biopsy, and probable when a suggestive clinical picture was associated to at least one of the following: positive anti PGL1, suggestive pattern biopsy represented by the presence of epithelioid granulomatous neuritis, mononuclear cell endoneuritis and fibrose and/or an EMG pattern showing a predominantly sensory mononeuritis multiplex pattern. Exclusion criteria: Two patients were excluded because of associated diabetes mellitus, one because had CMT1A and another had HNPP. To evaluate the importance of disease duration in clinical presentation, we considered two groups according to the time course, first that disease duration of 12 or fewer months (group 1) and those with disease duration over 12 months (group 2). Results: We reviewed 34 patients with PNL, including 7 with a definite and 24 with probable diagnosis. The most common onset symptoms were sensory (91.2 %), in 70.6 % of cases symptoms started in the upper limbs, the ulnar nerve being the most frequent site. Intradermal pattern was observed only in group 1. Vibration was altered more frequent in group 2 (p=0.07), the presence of motor abnormalities (p = 0.03) and deep tendon reflexes reduced or absent in 1 or more nerves (p = 0.03) were more frequently observed in group 2. Sensory nerves most frequently involved were the ulnar and superficial peroneal. The motor nerve most often affected was the ulnar. The most frequent EMG pattern was an asymmetrical sensory and motor neuropathy with focal slowing of conduction velocity. Conclusions: PNL is an asymmetrical sensory or sensory motor neuropathy. Upper limbs are most frequent affected with frequent ulnar nerve territory involvement. Small fibers seem to be affected at early stages. Larger fibers are affected with disease progression. It is unclear whether the PNL represents a stage prior to the appearance of typical skin lesions or whether it represents a different and more aggressive leprosy type. Phenotype characterization from early signs and symptoms its a powerful tool to PNL early diagnosis.

This thesis considers the neural network learning control of a variable-geometry automotive active suspension system which combines most of the benefits of active suspension systems with low energy consumption. Firstly, neural networks are applied to the control of various simplified automotive active suspensions, in order to understand how a neural network controller can be integrated with a physical dynamic system model. In each case considered, the controlled system has a defined objective and the minimisation of a cost function. The neural network is set up in a learning structure, such that it systematically improves the system performance via repeated trials and modifications of parameters. The learning efficiency is demonstrated by the given system performance in agreement with prior results for both linear and non-linear systems. The above simulation results are generated by MATLAB and the Neural Network Toolbox. Secondly, a half-car model, having one axle and an actuator on each side, is developed via the computer language, AUTOSIM. Each actuator varies the ratio of the spring/damper unit length change to wheel displacement in order to control each wheel rate. The neural network controller is joined with the half-car model and learns to reduce the defined cost function containing a weighted sum of the squares of the body height change, body roll and actuator displacements. The performances of the neurocontrolled system are compared with those of passive and proportional-plusdifferential controlled systems under various conditions. These involve various levels of lateral force inputs and vehicle body weight changes. Finally, energy consumption of the variable-geometry system, with either the neurocontrol or proportional-plus-differential control, is analysed using an actuator model via the computer simulation package, SIMULINK. The simulation results are compared with those of other actively-controlled suspension systems taken from the literature.

No description available.