This dissertation describes the development, implementation, validation, optimization, and application, of a noninvasive and quantitative method for measuring cerebral blood volume changes with functional magnetic resonance imaging (fMRI) for mapping of neural activity changes. Since its inception over twenty years ago, the field of fMRI has grown in usage, sophistication, range of applications, and impact. Nevertheless it has yet to exploit its full potential regarding, spatiotemporal resolution, signal specificity, and quantifiability of hemodynamic changes. By utilization of a new MR pulse sequence, new concepts of radio frequency pulses, and high magnetic fields (7 T), a novel fMRI method named SS-SI VASO is presented here that overcomes sensitivity limitations of other noninvasive quantitative imaging methods. In order to validate that its signal represents changes in cerebral blood volume without other contaminations, SS-SI VASO is implemented in animal models for a close comparison with established, but invasive methods. A good agreement of blood volume sensitivity has been found with the new method compared to the established ones. After its validation, the SS-SI VASO method and its unprecedented sensitivity was used to localize and quantify hemodynamic changes in applications where conventional oxygenation based fMRI methods are limited. (A) SS-SI VASO was used to investigate biophysical aspects of actively controlled arteries and passive balloon-like veins during activity induced hemodynamic changes. (B) SS-SI VASO was used to provide insights whether the interplay of neural activity and resultant vascular response are the same for tasks that increase neural activity compared to tasks that suppress neural activity. (C) SS-SI VASO was used to calibrate conventional oxygenation based fMRI to quantify local changes in oxygen metabolism. (D) The high sensitivity of SS-SI VASO was further used to obtain sub-millimeter resolutions and estimate activity changes between cortical layers. This enables to address questions not only where the brain is activated but also how and whereby this activity is evoked. The implementation and application of this new SS-SI VASO fMRI method is a major step forward for the field of imaging neuroscience; it demonstrates that the current limitations of fMRI can be even overcome with respect to quantifiability, spatial specificity and distinguishing between vascular and neuronal phenomena.

Neurological and developmental disorders (NDDs) impose an enormous burden of disease on children throughout the world. Two of the most common are autism spectrum disorder (ASD) and epilepsy. ASD has recently been estimated to affect 1 in 68 children, making it the most common neurodevelopmental disorder in children. Epilepsy is also a spectrum disorder that follows a developmental trajectory, with an estimated prevalence of 1%, nearly as common as autism. ASD and epilepsy co-occur in approximately 30% of individuals with a primary diagnosis of either disorder. Although considered to be different disorders, the relatively high comorbidity suggests the possibility of common neuropathological mechanisms. Early interventions for NDDs lead to better long-term outcomes. But early intervention is predicated on early detection. Behavioral measures have thus far proven ineffective in detecting autism before about 18 months of age, in part because the behavioral repertoire of infants is so limited. Similarly, no methods for detecting emerging epilepsy before seizures begin are currently known. Because atypical brain development is likely to precede overt behavioral manifestations by months or even years, a critical developmental window for early intervention may be opened by the discovery of brain based biomarkers. Analysis of brain activity with EEG may be under-utilized for clinical applications, especially for neurodevelopment. The hypothesis investigated in this dissertation is that new methods of nonlinear signal analysis, together with methods from biomedical informatics, can extract information from EEG data that enables detection of atypical neurodevelopment. This is tested using data collected at Boston Children’s Hospital. Several results are presented. First, infants with a family history of ASD were found to have EEG features that may enable autism to be detected as early as 9 months. Second, significant EEG-based differences were found between children with absence epilepsy, ASD and control groups using short 30-second EEG segments. Comparison of control groups using different EEG equipment supported the claim that EEG features could be computed that were independent of equipment and lab conditions. Finally, the potential for this technology to help meet the clinical need for neurodevelopmental screening and monitoring in low-income regions of the world is discussed.

Orientador: Fernando Cendes / Dissertação (Mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T01:34:33Z (GMT). No. of bitstreams: 1 Campos_BrunnoMachadode_M.pdf: 2725354 bytes, checksum: 1b7b94986b97dca79114bf54aaabe11b (MD5) Previous issue date: 2013 / Resumo: Introdução: A técnica multimodal de eletroencefalografia (EEG) acoplada à ressonância magnética (RM) funcional (RMf) apresenta características físicas complementares. Este método permite não só avaliar atividades neurais fisiológicas, mas também a dinâmica de neuropatologias como a epilepsia. Dentro do grupo das epilepsias, as epilepsias de lobo temporal (ELT) são particularmente importantes pela sua elevada prevalência e morbidade. Objetivo: Investigar e comparar os padrões de alterações hemodinâmicas associados a descargas epilépticas interictais (DEIs) em pacientes com ELT com (ELT-EH) ou sem (ELT-NL) sinais de esclerose hipocampal em exames de RM, através do uso combinado das técnicas de EEG e RMf (EEG-RMf). Métodos: Foram submetidos a exames de EEG-RMf, 25 pacientes com diagnóstico de ELT, sendo 12 ELT-NL e 13 ELT-EH. As imagens de RM foram adquiridas em aparelho de 3T e o EEG amostrado com 64 eletrodos compatíveis com RM. O tempo das DEIs foi utilizado para avaliar as respostas BOLD positivas (BOLDpos) e negativas (BOLDneg). Foram realizadas análises de EEG-RMf individuais e para grupos, além de análise estrutural, com o software SPM8-VBM8. As análises funcionais foram realizadas com pico da função resposta hemodinâmicas (FRH) em 0 segundo (precoce) e 5 segundos (tardio) após as DEIs. Resultados: Os mapas BOLDpos no grupo ELT-EH mostraram alterações hemodinâmicas precoces no lobo temporal ipsilateral, ínsula e giro precentral contralateral, e tardia no putâmem ipsilateral, cíngulo anterior bilateral, ínsula e lobos temporais. No grupo ELT-NL, BOLDpos precoce difuso foi observado, com alterações mais significativas no giro medial frontais ipsilateral, enquanto BOLDpos tardio foi observado na ínsula ipsilateral e giro temporal superior. Em ambos os grupos a análise estrutural mostrou redução significativa de substância cinzenta em áreas que se estendem além do lobo temporal, porém sem sobreposição significativa com áreas de BOLDpos. Em ambos os grupos de pacientes, BOLDneg foi observado em áreas compatíveis com default mode network (DMN). Interpretação: As redes funcionais relacionadas às DEIs diferem entre ELT-EH e ELT-NL. As regiões com atrofia mais significativa de substância cinzenta não coincidem com estas redes funcionais. Há possível supressão da atividade em áreas da DMN relacionadas com as DEIs em pacientes com ELT com ou sem sinais de EH / Abstract: Introduction: The multimodal technique of electroencephalography (EEG) coupled to functional magnetic resonance imaging (fMRI) presents additional physical characteristics. This method allows not only evaluating physiological neural activities, but also the dynamics of neuropathologies as epilepsy. Within the group of epilepsy, temporal lobe epilepsy (TLE) is particularly important due to its high prevalence and morbidity. Objective: To investigate and compare the patterns of hemodynamic changes associated with interictal epileptiform discharges (IEDs) in patients with TLE with (TLE-HS) or without (TLE-NL) signs of hippocampal sclerosis in MRI, through the combined use of EEG and fMRI techniques (EEG-fMRI). Methods: Twenty five patients diagnosed with TLE underwent EEG-fMRI scans, 12 with TLE-NL and 13 TLE-HS. MR images were acquired on a 3T scanner and EEG recorded with 64 electrodes compatible with MRI. The time for IED was used to assess the BOLD positive (BOLDpos) and negative (BOLDneg) responses. Analysis of EEG-fMRI MRI structural analyses were performed with SPM8-VBM8 software. The functional analyses were performed with the peak of the hemodynamic response function (HRF) in 0 second (early) and 5 seconds (late) after IED. Results: The BOLDpos maps in TLE-HS group showed early hemodynamic changes in ipsilateral temporal lobe, contralateral insula and precentral gyrus and late hemodynamic changes in ipsilateral putamen, bilateral anterior cingulate, insula and temporal lobes. In TLE-NL, diffuse early BOLDpos was observed, with the most significant changes in the ipsilateral medial frontal gyrus, while late BOLDpos was observed in the ipsilateral insula and superior temporal gyrus. In both groups the structural analysis showed significant reduction of gray matter in areas that extend beyond the temporal lobe, but with no significant overlap with areas of BOLDpos. In both groups of patients BOLDneg was observed in areas consistent with default mode network (DMN). Interpretation: The functional networks related to the IED differ in TLE-HS and TLE-NL. The regions with the most significant gray matter atrophy do not coincide with these functional networks. There is possible suppression of activity in the DMN areas related to IED in TLE patients with or without signs of HS / Mestrado / Fisiopatologia Médica / Mestre em Ciências

This dissertation describes the development, implementation, validation, optimization, and application, of a noninvasive and quantitative method for measuring cerebral blood volume changes with functional magnetic resonance imaging (fMRI) for mapping of neural activity changes. Since its inception over twenty years ago, the field of fMRI has grown in usage, sophistication, range of applications, and impact. Nevertheless it has yet to exploit its full potential regarding, spatiotemporal resolution, signal specificity, and quantifiability of hemodynamic changes. By utilization of a new MR pulse sequence, new concepts of radio frequency pulses, and high magnetic fields (7 T), a novel fMRI method named SS-SI VASO is presented here that overcomes sensitivity limitations of other noninvasive quantitative imaging methods. In order to validate that its signal represents changes in cerebral blood volume without other contaminations, SS-SI VASO is implemented in animal models for a close comparison with established, but invasive methods. A good agreement of blood volume sensitivity has been found with the new method compared to the established ones. After its validation, the SS-SI VASO method and its unprecedented sensitivity was used to localize and quantify hemodynamic changes in applications where conventional oxygenation based fMRI methods are limited. (A) SS-SI VASO was used to investigate biophysical aspects of actively controlled arteries and passive balloon-like veins during activity induced hemodynamic changes. (B) SS-SI VASO was used to provide insights whether the interplay of neural activity and resultant vascular response are the same for tasks that increase neural activity compared to tasks that suppress neural activity. (C) SS-SI VASO was used to calibrate conventional oxygenation based fMRI to quantify local changes in oxygen metabolism. (D) The high sensitivity of SS-SI VASO was further used to obtain sub-millimeter resolutions and estimate activity changes between cortical layers. This enables to address questions not only where the brain is activated but also how and whereby this activity is evoked. The implementation and application of this new SS-SI VASO fMRI method is a major step forward for the field of imaging neuroscience; it demonstrates that the current limitations of fMRI can be even overcome with respect to quantifiability, spatial specificity and distinguishing between vascular and neuronal phenomena.

One of the most powerful and important applications that the brain accomplishes is solving the sensory "cocktail party problem:" to adaptively suppress extraneous signals in an environment. Theoretical studies suggest that the solution to the problem involves an adaptive filter, which learns to remove the redundant noise. However, neural learning is also in its infancy and there are still many questions about the stability and application of synaptic learning rules for neural computation. In this thesis, the implementation of an adaptive filter in the brain of a weakly electric fish, A. Leptorhynchus, was studied. It was found to require a cerebellar architecture that could supply independent frequency channels of delayed feedback and multiple burst learning rules that could shape this feedback. This unifies two ideas about the function of the cerebellum that were previously separate: the cerebellum as an adaptive filter and as a generator of precise temporal inputs.

One of the most powerful and important applications that the brain accomplishes is solving the sensory "cocktail party problem:" to adaptively suppress extraneous signals in an environment. Theoretical studies suggest that the solution to the problem involves an adaptive filter, which learns to remove the redundant noise. However, neural learning is also in its infancy and there are still many questions about the stability and application of synaptic learning rules for neural computation. In this thesis, the implementation of an adaptive filter in the brain of a weakly electric fish, A. Leptorhynchus, was studied. It was found to require a cerebellar architecture that could supply independent frequency channels of delayed feedback and multiple burst learning rules that could shape this feedback. This unifies two ideas about the function of the cerebellum that were previously separate: the cerebellum as an adaptive filter and as a generator of precise temporal inputs.

One of the most powerful and important applications that the brain accomplishes is solving the sensory "cocktail party problem:" to adaptively suppress extraneous signals in an environment. Theoretical studies suggest that the solution to the problem involves an adaptive filter, which learns to remove the redundant noise. However, neural learning is also in its infancy and there are still many questions about the stability and application of synaptic learning rules for neural computation. In this thesis, the implementation of an adaptive filter in the brain of a weakly electric fish, A. Leptorhynchus, was studied. It was found to require a cerebellar architecture that could supply independent frequency channels of delayed feedback and multiple burst learning rules that could shape this feedback. This unifies two ideas about the function of the cerebellum that were previously separate: the cerebellum as an adaptive filter and as a generator of precise temporal inputs.

One of the most powerful and important applications that the brain accomplishes is solving the sensory "cocktail party problem:" to adaptively suppress extraneous signals in an environment. Theoretical studies suggest that the solution to the problem involves an adaptive filter, which learns to remove the redundant noise. However, neural learning is also in its infancy and there are still many questions about the stability and application of synaptic learning rules for neural computation. In this thesis, the implementation of an adaptive filter in the brain of a weakly electric fish, A. Leptorhynchus, was studied. It was found to require a cerebellar architecture that could supply independent frequency channels of delayed feedback and multiple burst learning rules that could shape this feedback. This unifies two ideas about the function of the cerebellum that were previously separate: the cerebellum as an adaptive filter and as a generator of precise temporal inputs.