Cerebral hemodynamics monitoring is vital in the neuroscience intensive care unit to assess brain health. Diffuse optical methods using near-infrared light, e.g., near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS), allow for non-invasive prolonged monitoring of cerebral hemoglobin oxygenation and blood flow. For patients suffering from cerebral fluid or tissue volume buildup, intracranial pressure (ICP) is monitored invasively as its elevation compromises cerebral perfusion. The critical closing pressure (CrCP) is a transcranial doppler (TCD) derived non-invasive parameter that correlates with ICP; however, its use is limited due to discomfort during extended TCD measurement. I expanded on Sutin’s preliminary study using DCS to estimate CrCP and found high correlations between DCS obtained CrCP against TCD (R2: 0.77-0.83) in stroke patients. The use of DCS to monitor CrCP is advantageous because its sensors are comfortable to wear and easy to use continuously without the need of a specialized operator. However, the low DCS signal-to-noise ratio (SNR) limits the depth sensitivity and temporal resolution of CrCP measures. Following these encouraging results, I built a low-cost wireless cerebral oximeter based on multi-distance continuous wave NIRS called FlexNIRS, which exhibits high SNR (NEP < 70 fw/Hz0.5) and high sampling rate (266 Hz). This device not only quantifies cerebral oxygenation but resolves the pulsatile blood volume signal at large source-detector separations (33 mm). Using the relationship between blood flow and volume, I augmented pulsatile DCS blood flow measurements with FlexNIRS pulsatile signals. I experimentally demonstrated the high fidelity (R2: 0.98) and > 50-fold SNR improvement of the method, resulting in a one order of magnitude increase in the temporal resolution of CrCP estimates. / 2024-06-12T00:00:00Z

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Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation at high strain rates and then return to equilibrium following a brief negative pressure phase. This mechanical disruption of the tissue is known to cause oxidative stress and neuroinflammation in the brain, which can lead to neurodegeneration and consequently poor cognitive and behavioral outcomes. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure and there are currently no effective treatments. Thus, there is a need to investigate the acute molecular responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the acute molecular response, but how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the tissue-level biomechanics and the acute bTBI pathophysiology. In a rodent bTBI model, using adult rats, intracranial pressure was mapped throughout the brain during blast exposure where frequency contributions from skull flexure and wave dynamics were significantly altered between brain regions and were largely dependent on blast magnitude. These findings informed the subsequent spatial and temporal changes in neurometabolism. Amino acid molecular precursor concentrations decreased at four hours post-blast in the cortex and hippocampus regions. This motivates further investigation of amino acids as therapeutic targets aimed to reduce oxidative stress and prevent prolonged injury cascades. However, neurochemical changes were not consistent across blast magnitudes, which may be explained by the disparities in biomechanics at lower blast pressures. Lastly, we investigated the acute changes in metabolic regulators influencing excitotoxicity where it was found that astrocytes maintained normal clearance of excitatory and inhibitory neurotransmitters prior to astrocyte reactivity. Outcomes of this work provide improved understanding of blast mechanics and associated acute pathophysiology and inform future therapeutic and diagnostic approaches following bTBI. / Doctor of Philosophy / Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure wave rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation that can cause injury. This mechanical disruption of the tissue is known to trigger negative biological processes that lead to persistent cognitive and behavioral deficits. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure. There are currently no effective treatments that can help those afflicted, and biomarkers for injury diagnostics are limited. Thus, there is a great need to investigate the early biological responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the immediate responses, but also how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the brain biomechanics and the acute bTBI pathophysiology. Using a translational animal model, pressure inside the brain was measured with pressure sensors during blast exposure. Subsequent spatial and temporal changes in neurochemical concentrations were quantified. The results showed (1) significant disparities in the pressure dynamics inside the brain and it varied across brain regions, (2) neurochemical precursors may have therapeutic potential post-injury, and (3) biomechanical and neurochemical responses were dependent on blast severity. Outcomes of this work provide improved understanding of blast mechanics and associated pathophysiology and inform future therapeutic and diagnostic approaches to prevent prolonged injury cascades.

<p>During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P>40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P>40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.</p>

A Pressão intracraniana (PIC) é um dos principais parâmetros fisiológicos em animais e humanos e sua morfologia é extremamente importante. Entretanto, todos os métodos de monitoramento existentes no mercado são invasivos, existindo uma ampla demanda por sistemas não invasivos, expandindo assim o campo de pesquisas acerca desse importante parâmetro neurológico, que só não é melhor estudado devido a forma invasiva de ser monitorado. A motivação é fazer com que o monitoramento da PIC seja tão comum e tão essencial quanto é hoje o monitoramento da pressão arterial, facilitando o diagnóstico e até prognóstico de diversas doenças. Este trabalho analisa e implementa melhorias de um sistema não invasivo de monitoramento da pressão intracraniana, baseado em extensometria. Um dos objetivos, no que tange o desenvolvimento do produto, é analisar o equipamento como um todo - Sensor, Hardware, Firmware e Software - e propor melhorias a partir dos testes realizados. Os testes realizados In vivo mostraram uma boa correlação do sinal com um sistema Gold Stardard, evidenciando o potencial promissor do método. / The intracranial pressure (ICP) is one of the main physiological parameters in animals and humans and its morphology is extremely important. However, all monitoring methods available in the market are invasive and there is a large demand for non-invasive systems, thus expanding the scope of research on this important neurological parameter, that just is not further studied because of the invasive method of monitoring. The motivation is to make monitoring the ICP as common and as essential, as monitoring the blood pressure is nowadays, facilitating diagnosis and even prognosis of various diseases. This work analyzes and implements improvements in a non-invasive intracranial pressure monitoring system based on extensometer. One of the goals, regarding product development, is to analyze the unit as a whole- Sensor, Hardware, Firmware and Software- and propose improvements from the tests. The in vivo tests showed a good correlation with a Gold Stardard system signal showing the promising potential of the method.

Made available in DSpace on 2017-07-21T14:35:54Z (GMT). No. of bitstreams: 1 Daniel da Silveira.pdf: 4620671 bytes, checksum: 940d0c2a58ed2267604a5ec3cb5752ba (MD5) Previous issue date: 2016-02-16 / Intracranial hypertension causes several complications when installed, it can severely affect the individual afflicted with permanent sequelae, besides the risk of death. In the case of pregnant women, the risk is even greater due to the high complexity involved in physiological pregnancy period. In this context, the evaluation of intracranial pressure (ICP) could provide important information that can detect these problems and thereby prevent these complications. However, the invasive method that this procedure is performed makes the use of this methodology very limited. It’s necessary the use of a method that is capable of generating this information while providing security to the patient, not generating complications such as infections or injuries resulting from its invasive form. The aim of this study was to evaluate a new technology for noninvasively ICP measuring in pregnant women in a municipal health center in Ponta Grossa, relating it to the clinical and laboratory data obtained at the time of the procedure. It was observed that low and high-risk pregnant women showed a high in ICP. There were also significant differences between groups for laboratory parameters, such as serum levels of alkaline phosphatase and ultra-sensitive C-reactive protein (hs-CRP). The existence of changes in the ICP and its relationship with clinical and laboratory data in the population studied, introduces in the monitoring of pregnant women, a parameter with unknown data due to technical limitations, which allows to identify changes even in the absence of symptoms and to prevent complications related to elevation in intracranial pressure. / A hipertensão intracraniana promove diversas complicações quando instalada, podendo afetar gravemente o indivíduo acometido com sequelas permanentes, além do risco de óbito. Em se tratando de gestantes, o risco é maior ainda, devido à alta complexidade fisiológica envolvida no período gestacional. Nesse contexto, a avaliação da pressão intracraniana (PIC) pode fornecer informações importantes capazes de detectar esses problemas e com isso evitar essas complicações. No entanto, a forma invasiva como é realizado esse procedimento faz com que a utilização dessa metodologia seja bastante limitada. O uso de um método que seja capaz de gerar essas informações e ao mesmo tempo dar segurança ao paciente, não gerando complicações como infecções ou lesões decorrentes de sua forma invasiva, se faz necessário. O objetivo desse trabalho foi avaliar uma nova tecnologia para aferição da PIC de forma não invasiva em gestantes num centro municipal de saúde em Ponta Grossa, relacionando-a a dados clínicos e laboratoriais obtidos no momento da realização do procedimento. Observou-se que gestantes de baixo e alto risco apresentaram PIC elevada. Foram, ainda, encontradas diferenças significativas entre os grupos para os parâmetros laboratoriais, tais como nos níveis séricos de fosfatase alcalina e proteína C reativa -ultrassensível (PCR-us). A detecção da existência de alterações na PIC e sua relação com dados clínicos e laboratoriais, na população estudada, introduz no acompanhamento às gestantes, um parâmetro, com dados até então desconhecidos devido a limitações técnicas, que permite identificar alterações mesmo na ausência de sintomatologia e prevenir complicações relacionadas à elevação da pressão intracraniana.

A pressão intracraniana (PIC) é um dos principais parâmetros neurológicos em animais e humanos. A PIC é uma função da relação entre o conteúdo da caixa craniana (parênquima cerebral, líquido cefalorraquiano e sangue) e o volume do crânio. O aumento da PIC (hipertensão intracraniana) pode acarretar graves efeitos fisiológicos ou até mesmo o óbito em pacientes que não receberem rapidamente os devidos cuidados, os quais incluem o monitoramento em tempo real da PIC. Todos os métodos de monitoramento da PIC atualmente utilizados são invasivos, ou seja, é necessário introduzir um sensor de pressão no sistema nervoso central, acarretando aos pacientes riscos de infecções e traumas decorrentes do método. Neste trabalho desenvolvemos um método minimamente invasivo de monitoramento da pressão intracraniana, que consiste na utilização de sensores de deformação do tipo strain gauge fixados sobre a calota craniana. Os sinais oriundos deste sensor foram amplificados, filtrados e enviados para um computador com software apropriado para análise e armazenamento dos dados. O trabalho aqui apresentado objetivou os testes &quot;in vivo&quot; do sistema, onde foi utilizada mais de uma centena de animais em diversos testes, sendo que em todos os casos os resultados foram satisfatórios, apontando a eficácia do método. / The intracranial pressure (ICP) is one of the most important neurological parameter in animals and humans. The ICP is a function of the relation between the contents of the skull (brain parenchyma, cerebrospinal fluid and blood) and the volume of the skull. The increase in ICP (intracranial hypertension) may cause serious physiological effects and death in patients that do not receive appropriate care quickly, which includes real-time monitoring of ICP. All monitoring methods currently used in ICP are invasive, ie requiring invasion of the central nervous system by a pressure sensor, causing infections and traumas risks to patients. In this work we present a new minimally invasive method to monitor the intracranial pressure. This uses strain gauge deformation sensors, externally glued on the skull. The signal from this sensor is amplified, filtered and sent to a computer with appropriate software for analysis and data storage. &quot;In vitro&quot; and &quot;in vivo&quot; experiments let to the following results: (1) Our minimally invasive system is capable of adequately monitoring the ICP. (2) The measurements are in real and online time providing excellent signal and stability. (3) Simultaneous comparison with invasive methods not only validated our results but showed increased performance. The equipment cost effective will allow the use of our system in the Public Health System, with a important social aspect of our contribution.

Introdução: a pressão intracraniana pode ser monitorada por meio de vários métodos que podem ser invasivos ou não invasivos. A ultrassonografia do nervo óptico é uma técnica não invasiva que permite mensurar a bainha deste nervo e detectar possíveis variações no seu diâmetro. O nervo óptico faz parte do sistema nervoso central de maneira contígua e é envolvido por uma bainha. Sendo assim, elevações ou reduções da pressão intracraniana podem ser transpostas à bainha deste nervo com consequente variação do seu diâmetro. Essas variações podem ser observadas pela ultrassonografia. Objetivo: determinar, por meio da ultrassonografia, o diâmetro da bainha do nervo óptico normal e avaliar os possíveis efeitos das drogas neste diâmetro durante a indução anestésica em suínos hígidos com pressão intracraniana normal. Métodos: foram selecionados 118 suínos híbridos saudáveis (64 fêmeas) de aproximadamente 20 kg e faixa etária similar. Todos os suínos foram submetidos à anestesia geral e foram devidamente monitorados. Os animais foram divididos em três grupos conforme os medicamentos utilizados: Grupo A: utilizando medicamento pré-anestésico xilazina e quetamina; Grupo B: utilizando xilazina (X), quetamina (Q) mais Propofol (P), e Grupo C: anestesiados com xilazina, quetamina e tiopental [tionembutal (T)]. As coletas das medidas nos três grupos foram feitas pelo aparelho de ultrassom em triplicata de cada olho, com os animais em posição laterolateral. Resultados: não houve diferenças estatisticamente significantes entre sexo e peso. O Diâmetro médio da bainha do nervo óptico em ambos os lados de cada grupo foram de 0,394±0,048 cm (X/Q), 0,407±0,029 cm (X/Q/P) e 0,378±0,042 cm (X/Q/T). Considerando todos os grupos, o diâmetro da bainha do nervo óptico variou de 0,287 cm a 0,512 cm (média 0,302 ± 0,039 cm). Houve diferenças estatisticamente significativas entre os grupos P e T (P > T, p = 0,003). Não foram detectadas diferenças significativas quando outros grupos foram comparados entre si. Conclusão: o diâmetro médio da bainha do nervo óptico, considerando todos os grupos, foi 0,302 ± 0,039 cm (0,287 cm - 0,512 cm) e 0,344 cm ± 0,048 cm nos indivíduos sedados apenas com X/Q / Introduction: the intracranial pressure can be monitored by various methods that may be invasive or non-invasive. Ultrasonography of the optic nerve is a technique non-invasive that allows measurement of the nerve sheath and detection of possible variations in its diameter noninvasively. The optic nerve is part of the central nervous system continuously and is surrounded by a sheath. Thus, with the increase or reduction of intracranial pressure, it can be transposed to the sheath of this nerve with consequent variation of its diameter. These variations can be observed through the ultrasound image. Objective: determine the normal optical nerve sheath diameter and to evaluate the possible effects of drugs on optical nerve sheath diameter during anesthetic induction in healthy pigs with normal intracranial pressure through ultrasound image. Methods:118 Healthy hybrid piglets from (64 female) the weighing approximately 20 kg each and of similar ages. All pigs underwent general anesthesia and were duly monitored. The animals were divided into three groups according to the medications used. Group A received preanesthetic xylazine and ketamine; Grupo B received xylazine, ketamine and propofol, and Grupo C received xylazine, ketamine, and thiopental (thionembutal). Measurements in the three groups were done by the ultrasound device in triplicate of each eye from the left and right sides. Results: There were no statistically significant differences between sex and weight. The mean optical nerve sheath sizes on both sides in each group were 0.394±0.048 cm (X/K), 0.407±0.029 cm (X/K/P) and 0.378±0.042 cm (X/K/T). Considering all the groups, the diameter of the optic nerve sheath varied from 0.287-0.512 cm (mean of 0.302±0.039 cm). There were statistically significant differences between the groups P and T (P > T, p=0.003). No statistically significant differences were detected when other groups were compared each other. Conclusion: The mean diameter of the optic nerve sheath considering all groups was 0.302±0.039 cm (0.287-0.512 cm) and 0.394±0.048 cm in the subjects only sedated with X/K