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abstract: A direct Magnetic Resonance (MR)-based neural activity mapping technique with high spatial and temporal resolution may accelerate studies of brain functional organization. The most widely used technique for brain functional imaging is functional Magnetic Resonance Image (fMRI). The spatial resolution of fMRI is high. However, fMRI signals are highly influenced by the vasculature in each voxel and can be affected by capillary orientation and vessel size. Functional MRI analysis may, therefore, produce misleading results when voxels are nearby large vessels. Another problem in fMRI is that hemodynamic responses are slower than the neuronal activity. Therefore, temporal resolution is limited in fMRI. Furthermore, the correlation between neural activity and the hemodynamic response is not fully understood. fMRI can only be considered an indirect method of functional brain imaging. Another MR-based method of functional brain mapping is neuronal current magnetic resonance imaging (ncMRI), which has been studied over several years. However, the amplitude of these neuronal current signals is an order of magnitude smaller than the physiological noise. Works on ncMRI include simulation, phantom experiments, and studies in tissue including isolated ganglia, optic nerves, and human brains. However, ncMRI development has been hampered due to the extremely small signal amplitude, as well as the presence of confounding signals from hemodynamic changes and other physiological noise. Magnetic Resonance Electrical Impedance Tomography (MREIT) methods could have the potential for the detection of neuronal activity. In this technique, small external currents are applied to a body during MR scans. This current flow produces a magnetic field as well as an electric field. The altered magnetic flux density along the main magnetic field direction caused by this current flow can be obtained from phase images. When there is neural activity, the conductivity of the neural cell membrane changes and the current paths around the neurons change consequently. Neural spiking activity during external current injection, therefore, causes differential phase accumulation in MR data. Statistical analysis methods can be used to identify neuronal-current-induced magnetic field changes. / Dissertation/Thesis / Doctoral Dissertation Biomedical Engineering 2019

abstract: Electrical neural activity detection and tracking have many applications in medical research and brain computer interface technologies. In this thesis, we focus on the development of advanced signal processing algorithms to track neural activity and on the mapping of these algorithms onto hardware to enable real-time tracking. At the heart of these algorithms is particle filtering (PF), a sequential Monte Carlo technique used to estimate the unknown parameters of dynamic systems. First, we analyze the bottlenecks in existing PF algorithms, and we propose a new parallel PF (PPF) algorithm based on the independent Metropolis-Hastings (IMH) algorithm. We show that the proposed PPF-IMH algorithm improves the root mean-squared error (RMSE) estimation performance, and we demonstrate that a parallel implementation of the algorithm results in significant reduction in inter-processor communication. We apply our implementation on a Xilinx Virtex-5 field programmable gate array (FPGA) platform to demonstrate that, for a one-dimensional problem, the PPF-IMH architecture with four processing elements and 1,000 particles can process input samples at 170 kHz by using less than 5% FPGA resources. We also apply the proposed PPF-IMH to waveform-agile sensing to achieve real-time tracking of dynamic targets with high RMSE tracking performance. We next integrate the PPF-IMH algorithm to track the dynamic parameters in neural sensing when the number of neural dipole sources is known. We analyze the computational complexity of a PF based method and propose the use of multiple particle filtering (MPF) to reduce the complexity. We demonstrate the improved performance of MPF using numerical simulations with both synthetic and real data. We also propose an FPGA implementation of the MPF algorithm and show that the implementation supports real-time tracking. For the more realistic scenario of automatically estimating an unknown number of time-varying neural dipole sources, we propose a new approach based on the probability hypothesis density filtering (PHDF) algorithm. The PHDF is implemented using particle filtering (PF-PHDF), and it is applied in a closed-loop to first estimate the number of dipole sources and then their corresponding amplitude, location and orientation parameters. We demonstrate the improved tracking performance of the proposed PF-PHDF algorithm and map it onto a Xilinx Virtex-5 FPGA platform to show its real-time implementation potential. Finally, we propose the use of sensor scheduling and compressive sensing techniques to reduce the number of active sensors, and thus overall power consumption, of electroencephalography (EEG) systems. We propose an efficient sensor scheduling algorithm which adaptively configures EEG sensors at each measurement time interval to reduce the number of sensors needed for accurate tracking. We combine the sensor scheduling method with PF-PHDF and implement the system on an FPGA platform to achieve real-time tracking. We also investigate the sparsity of EEG signals and integrate compressive sensing with PF to estimate neural activity. Simulation results show that both sensor scheduling and compressive sensing based methods achieve comparable tracking performance with significantly reduced number of sensors. / Dissertation/Thesis / Ph.D. Electrical Engineering 2013

abstract: Neural activity tracking using electroencephalography (EEG) and magnetoencephalography (MEG) brain scanning methods has been widely used in the field of neuroscience to provide insight into the nervous system. However, the tracking accuracy depends on the presence of artifacts in the EEG/MEG recordings. Artifacts include any signals that do not originate from neural activity, including physiological artifacts such as eye movement and non-physiological activity caused by the environment. This work proposes an integrated method for simultaneously tracking multiple neural sources using the probability hypothesis density particle filter (PPHDF) and reducing the effect of artifacts using feature extraction and stochastic modeling. Unique time-frequency features are first extracted using matching pursuit decomposition for both neural activity and artifact signals. The features are used to model probability density functions for each signal type using Gaussian mixture modeling for use in the PPHDF neural tracking algorithm. The probability density function of the artifacts provides information to the tracking algorithm that can help reduce the probability of incorrectly estimating the dynamically varying number of current dipole sources and their corresponding neural activity localization parameters. Simulation results demonstrate the effectiveness of the proposed algorithm in increasing the tracking accuracy performance for multiple dipole sources using recordings that have been contaminated by artifacts. / Dissertation/Thesis / Masters Thesis Electrical Engineering 2014

Axons are injured after stroke, spinal cord injury, or neurodegenerative disease such as ALS. Most axons do not regenerate. A recent report suggests that not all neurons are poor regenerators, but rather a small subset can regenerate robustly. What intrinsic property of these regenerating neurons allows them to regenerate, but not their neighbors, remains a mystery. This subtype-specific regeneration has also been observed in Drosophila larvae sensory neurons. We exploited this powerful genetic system to unravel the intrinsic mechanism of subtype-specific neuron regeneration. We found that neuron bursting activity after axotomy correlates with regeneration ability. Furthermore, neuron bursting activity is necessary for regeneration of a regenerative neuron subtype, and sufficient for regeneration of a non-regenerative neuron subtype. This optogenetically-induced regeneration is dependent on a bursting pattern, not simply overall activity increase. We conclude that neuron bursting activity is an intrinsic mechanism of subtype-specific regeneration. We then discovered through a reverse genetic screen that an L-type voltage gated calcium channel (VGCC) promotes neuron bursting and subsequent regeneration. This VGCC has high expression in the regenerative neuron and weak expression in the non-regenerative neuron. This suggests that VGCC expression level is the molecular mechanism of subtype-specific neuron regeneration. Together, our findings identify a cellular and molecular intrinsic mechanism of subtype-specific regeneration, which is why some neurons are able to regenerate while the majority of neurons do not. Perhaps VGCC activation or neuron activity pattern modulation could be used therapeutically for patients with nerve injury.

Event-related brain potentials (ERPs) in electroencephalography are manifestations at the scalp of neural activity that is triggered by, and is involved in, the processing of specific events. This chapter focuses on braincomputer interfaces (BCIs) that use P300, an endogenous ERP component. The P300 is a positive potential that occurs over central-parietal scalp 250- 700 msec after a rare event occurs in the context of the oddball paradigm. This paradigm has three essential attributes: a subject is presented with a series of events (i.e., stimuli), each of which falls into one of two classes; the events that fall into one of the classes are less frequent than those that fall into the other class; and the subject performs a task that requires classifying each event into one of the two classes.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第18919号 / 薬科博第33号 / 新制||薬||4(附属図書館) / 31870 / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 中山 和久, 教授 金子 周司, 教授 竹島 浩 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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INTRODUÇÃO: Frente às evidências de que a depressão associa-se a eventos cardíacos, morte súbita, desenvolvimento de coronariopatia, e maior mortalidade por causas cardiovasculares, torna-se muito importante estudar as possíveis causas das alterações cardiovasculares na depressão. Alterações de sistema nervoso autonômico (SNA) vêm sendo descritas em pacientes deprimidos. Os estudos sobre funcionamento do SNA têm utilizado a dosagem de catecolaminas séricas e urinárias e análise de VFC, que são avaliações indiretas do funcionamento do SNA. Avaliações diretas, como a microneurografia, aparentemente ainda não foram utilizadas no estudo do funcionamento do SNA em pacientes com depressão maior. MÉTODOS: Neste estudo o comportamento do sistema nervoso simpático em indivíduos deprimidos, em período basal e após teste de estresse mental, foi comparado com controles. Realizaram as avaliações: 19 pacientes com depressão maior e 15 controles, com 18 a 45 anos de idade. Indivíduos que apresentassem condições médicas e/ou uso de medicamentos que pudessem interferir com o comportamento do sistema nervoso autonômico não foram incluídos. A avaliação psiquiátrica incluiu a administração da Escala de avaliação para depressão de Montgomery e Asberg (MADRS) e Entrevista Clínica Estruturada para o DSM-IV - Transtornos do Eixo I - Versão 2.0 (SCID-I /P). Atividade nervosa simpática muscular (ANMS) foi medida pela microneurografia. Fluxo sangüíneo muscular (FSM) no antebraço foi medido pela técnica de peltismografia de oclusão venosa. A pressão arterial (PA) foi monitorizada de forma não invasiva por um manguito inflado automaticamente, e a freqüência cardíaca (FC) foi medida por eletrocardiograma. O registro basal foi realizado por 3 minutos, seguido de teste de cores, que foi realizado por 4 minutos. RESULTADOS: Os grupos de pacientes deprimidos e controles não diferiram significativamente em relação a idade, peso e índice de massa corpórea. Os grupos de pacientes deprimidos e controles não apresentaram diferenças significativas nos valores de ANSM, PA sistólica, PA diastólica, PA média, FC, FSM e condutância vascular no antebraço no período basal. Não houve diferença significativa na reatividade ao estresse mental entre os grupos. Houve correlação positiva e significativa (0,84; p=0,0001) entre os valores de MADRS e de ANSM média no período basal dos pacientes com depressão. Houve correlação positiva e significativa (0,70; p=0,01) entre os valores do item tensão da MADRS e de ANSM média no período basal dos pacientes com depressão. CONCLUSÕES: Não foram encontradas diferenças nas medidas basais de atividade simpática entre indivíduos deprimidos e controles. Também não foram encontradas diferenças na reatividade cardiovascular a teste de estresse mental entre os grupos. Houve uma correlação positiva e significativa entre sintomas depressivos e atividade nervosa simpática muscular (ANSM), medida por microneurografia. Houve também uma correlação positiva e significativa entre sintomas ansiosos e ANSM. / INTRODUCTION: It is well established that depression is associated with cardiac events, sudden death, higher cardiovascular mortality and higher incidence of coronary artery disease (CAD). A number of biological mechanisms linking depression and CAD have been identified, including dysregulation of autonomic nervous system (ANS). Studies with heart rate variability and catecholamines measures have been perfomed in depressed patients. Microneurography is a direct and efficient method to measure sympathetic nerve traffic in humans. To our knowledge, there is no previous study with microneurography in depressed patients. METHODS: ANS functioning, during rest and mental stress, in depressed patients was compared to controls. Nineteen depressed patients and 15 controls (18 to 45 years old) were involved in the study. Subjects with medical conditions and/or use of medications that could interfere on ANS were not included. Psychiatric evaluation included the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P, Version 2.0) and the Montgomery and Asberg Depression Rating Scale (MADRS). Muscle sympathetic nervous activity (MSNA) was directly measured from the peroneal nerve using microneurography. Forearm blood flow (FBF) was measured by venous occlusion pletysmography. Blood pressure (BP) was monitored noninvasively by an automatic BP cuff, and heart rate (HR) was measured by electrocardiogram. Baseline register was performed by 3 minutes and Stroop color word test was performed for 4 minutes. RESULTS: There was no difference in age, weight and body mass index between the two groups studied. No significant difference was found between groups in regard to systolic BP (SBP), diastolic BP (DBP), mean BP (MBP), HR, MSNA, FBF and forearm vascular conductance at baseline. All parameters significantly increased during mental stress in the two groups. The reactivity to mental stress showed no difference between groups. There was a significant positive correlation between MADRS total scores and mean baseline MSNA (0,84; p=0,0001) among depressed patients. There was also a significant positive correlation between MADRS tension scores and mean baseline MSNA (0,70; p=0,01) among depressed patients. CONCLUSIONS: There were no differences in baseline measures of sympathetic activity between depressed patients and controls. The reactivity to mental stress between the groups did not differ as well. There was a positive significant correlation between depressive symptoms and mean baseline MSNA. There was a positive significant correlation between anxiety symptoms and mean baseline MSNA.

INTRODUÇÃO: Frente às evidências de que a depressão associa-se a eventos cardíacos, morte súbita, desenvolvimento de coronariopatia, e maior mortalidade por causas cardiovasculares, torna-se muito importante estudar as possíveis causas das alterações cardiovasculares na depressão. Alterações de sistema nervoso autonômico (SNA) vêm sendo descritas em pacientes deprimidos. Os estudos sobre funcionamento do SNA têm utilizado a dosagem de catecolaminas séricas e urinárias e análise de VFC, que são avaliações indiretas do funcionamento do SNA. Avaliações diretas, como a microneurografia, aparentemente ainda não foram utilizadas no estudo do funcionamento do SNA em pacientes com depressão maior. MÉTODOS: Neste estudo o comportamento do sistema nervoso simpático em indivíduos deprimidos, em período basal e após teste de estresse mental, foi comparado com controles. Realizaram as avaliações: 19 pacientes com depressão maior e 15 controles, com 18 a 45 anos de idade. Indivíduos que apresentassem condições médicas e/ou uso de medicamentos que pudessem interferir com o comportamento do sistema nervoso autonômico não foram incluídos. A avaliação psiquiátrica incluiu a administração da Escala de avaliação para depressão de Montgomery e Asberg (MADRS) e Entrevista Clínica Estruturada para o DSM-IV - Transtornos do Eixo I - Versão 2.0 (SCID-I /P). Atividade nervosa simpática muscular (ANMS) foi medida pela microneurografia. Fluxo sangüíneo muscular (FSM) no antebraço foi medido pela técnica de peltismografia de oclusão venosa. A pressão arterial (PA) foi monitorizada de forma não invasiva por um manguito inflado automaticamente, e a freqüência cardíaca (FC) foi medida por eletrocardiograma. O registro basal foi realizado por 3 minutos, seguido de teste de cores, que foi realizado por 4 minutos. RESULTADOS: Os grupos de pacientes deprimidos e controles não diferiram significativamente em relação a idade, peso e índice de massa corpórea. Os grupos de pacientes deprimidos e controles não apresentaram diferenças significativas nos valores de ANSM, PA sistólica, PA diastólica, PA média, FC, FSM e condutância vascular no antebraço no período basal. Não houve diferença significativa na reatividade ao estresse mental entre os grupos. Houve correlação positiva e significativa (0,84; p=0,0001) entre os valores de MADRS e de ANSM média no período basal dos pacientes com depressão. Houve correlação positiva e significativa (0,70; p=0,01) entre os valores do item tensão da MADRS e de ANSM média no período basal dos pacientes com depressão. CONCLUSÕES: Não foram encontradas diferenças nas medidas basais de atividade simpática entre indivíduos deprimidos e controles. Também não foram encontradas diferenças na reatividade cardiovascular a teste de estresse mental entre os grupos. Houve uma correlação positiva e significativa entre sintomas depressivos e atividade nervosa simpática muscular (ANSM), medida por microneurografia. Houve também uma correlação positiva e significativa entre sintomas ansiosos e ANSM. / INTRODUCTION: It is well established that depression is associated with cardiac events, sudden death, higher cardiovascular mortality and higher incidence of coronary artery disease (CAD). A number of biological mechanisms linking depression and CAD have been identified, including dysregulation of autonomic nervous system (ANS). Studies with heart rate variability and catecholamines measures have been perfomed in depressed patients. Microneurography is a direct and efficient method to measure sympathetic nerve traffic in humans. To our knowledge, there is no previous study with microneurography in depressed patients. METHODS: ANS functioning, during rest and mental stress, in depressed patients was compared to controls. Nineteen depressed patients and 15 controls (18 to 45 years old) were involved in the study. Subjects with medical conditions and/or use of medications that could interfere on ANS were not included. Psychiatric evaluation included the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P, Version 2.0) and the Montgomery and Asberg Depression Rating Scale (MADRS). Muscle sympathetic nervous activity (MSNA) was directly measured from the peroneal nerve using microneurography. Forearm blood flow (FBF) was measured by venous occlusion pletysmography. Blood pressure (BP) was monitored noninvasively by an automatic BP cuff, and heart rate (HR) was measured by electrocardiogram. Baseline register was performed by 3 minutes and Stroop color word test was performed for 4 minutes. RESULTS: There was no difference in age, weight and body mass index between the two groups studied. No significant difference was found between groups in regard to systolic BP (SBP), diastolic BP (DBP), mean BP (MBP), HR, MSNA, FBF and forearm vascular conductance at baseline. All parameters significantly increased during mental stress in the two groups. The reactivity to mental stress showed no difference between groups. There was a significant positive correlation between MADRS total scores and mean baseline MSNA (0,84; p=0,0001) among depressed patients. There was also a significant positive correlation between MADRS tension scores and mean baseline MSNA (0,70; p=0,01) among depressed patients. CONCLUSIONS: There were no differences in baseline measures of sympathetic activity between depressed patients and controls. The reactivity to mental stress between the groups did not differ as well. There was a positive significant correlation between depressive symptoms and mean baseline MSNA. There was a positive significant correlation between anxiety symptoms and mean baseline MSNA.