Blast-induced mild traumatic brain injury (BImTBI) is one of the most common causes of traumatic brain injuries. BImTBI mechanisms are not well identified, as most previous blast-related studies were focused on the visible and fatal injuries. BImTBI is a hidden lesion and long-term escalation of related complications is considered a serious health care challenging due to lack of accurate data required for early diagnosis and intervention. The experimental studies presented in this thesis were performed to investigate aspects of blast shock wave mechanisms that might lead to mild traumatic brain injury. A compressed air-driven shock tube was designed and validated using finite element analysis (FEA) and experimental investigation. Two metal diaphragm types (steel and brass) with three thicknesses (0.127, 0.76, and 0.025mm) were utilized in the shock tube calibration experiment, as a new approach to generate shock wave. The consistency of generated shock waves was confirmed using a statistical assessment of the results by evaluating the shock waves parameters. The analysis results showed that the 0.127mm steel diaphragm induces a reliable shock waveform in the range of BImTB investigations. Evaluation of the shock wave impacts on the brain was examined using two sets of experiments. The first set was conducted using a gel brain model while the second set was performed using a physical head occupied with a gel brain model and supported by a neck model. The gel brain model in both the experimental studies was generated using silicone gel (Sylgard-527). The effects of tested models locations and orientations with respect to the shock tube exit were investigated by measuring the generated pressure wave within the brain model and acceleration. The results revealed that the pressure waveform and acceleration outcomes were greatly affected by the tested model orientations and locations in relation to the path of shock wave propagation. / Thesis / Doctor of Philosophy (PhD)

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.

Submitted by JOSIANE SANTOS DE OLIVEIRA (josianeso) on 2019-03-25T11:56:58Z No. of bitstreams: 1 Jeferson Cardoso do Rosario_.pdf: 3523684 bytes, checksum: 6d033c623e7ef74a93692efd6ca37e8e (MD5) / Made available in DSpace on 2019-03-25T11:56:58Z (GMT). No. of bitstreams: 1 Jeferson Cardoso do Rosario_.pdf: 3523684 bytes, checksum: 6d033c623e7ef74a93692efd6ca37e8e (MD5) Previous issue date: 2019-01-18 / Nenhuma / O traumatismo cranioencefálico (TCE) é atualmente a terceira maior causa de óbitos no âmbito mundial. Estudos recentes têm demonstrado que a monitorização de pressão intracraniana (PIC), como forma de cálculo da pressão de perfusão cerebral (PPC) é uma ferramenta importante para avaliação do fluxo sanguíneo cerebral (FSC), provocando sensível redução nas taxas de mortalidade. Além do TCE, outras patologias ou situações neurocirúrgicas tem utilizado a técnica de monitorização de PIC. A monitorização desse parâmetro foi proposta já na década de 50, onde um tubo com fluido em contato com o líquido cefalorraquidiano (LCR) era introduzido no espaço intracraniano e conectado a um transdutor de pressão externo. Com a evolução da indústria microeletrônica e dos sistemas microeletromecânicos, foi possível colocar os transdutores na ponta do cateter, permitindo uma monitorização menos invasiva, com menos riscos de infecções. Os cateteres atuais com micro transdutor na ponta podem ser divididos em três grupo: straingauge, fibra óptica e pneumático. Cada grupo possui suas características, entretanto o primeiro tem se demonstrado como solução mais robusta e confiável, com boa relação custo benefício. No presente trabalho foi proposto o desenvolvimento de um cateter implantável de monitorização de pressão intracraniana do tipo micro transdutor strain-gauge. Foram construídos protótipos funcionais e submetidos a ensaios de desempenho, especificados em norma técnica para monitorização de pressão sanguínea, a influência da temperatura na medição de pressão, bem como a exatidão das medições. Os processos empregados no trabalho são utilizados comumente na indústria de encapsulamento de semicondutores, porém foram levadas em consideração as especificidades da aplicação, adequando as técnicas disponíveis às geometrias e materiais empregados, considerando a necessidade de utilização de materiais biocompatíveis. / The traumatic brain injury (TBI) is nowadays the third cause of death in the world. Recent studies have shown the intracranial pressure (ICP) monitoring as an important tool for cerebral perfusion pressure (CPP) calculation and cerebral blood flow (CBF) assestment, reducing significantly the mortality statistics. Besides TBI, several others pathologies and neurosurgery conditions have been using the ICP monitoring technique. The proposal of ICP monitoring first appeared on the 50’s, where a tube fulfilled with fluid in contact with cerebrospinal fluid (CSF) was introduced into the intracranial space and connected to an external pressure transducer. With the waves of the microelectronics and microelectromechanical systems (MEMS) industry evolution, it was possible to put the transducer and all the electronics inside the catheter tip, allowing a less invasive monitoring, decreasing the risk of infection. The state of art catheters with micro transducer on the tip can be divided into three groups: strain-gauge, optical fiber and pneumatic. Each group has it’s own characteristics, however the first has been demonstrated as the rugged solution, being reliable, cost effective and with good accuracy. In the present work, it was proposed the development of an strain-gauge micro transducer implantable catheter for intracranial pressure monitoring. Functional prototypes were built and submitted to performance tests, according to the technical standards in the medical equipment area, the temperature influence over the pressure measurements was evaluated, as well as the accuracy. The adopted processes are commonly used in the semiconductor packaging industry, however it was considered the application special requirements, adapting the processes to the geometry and materials used, considering the needs of biocompatible materials.

Die Höhe des optimalen zerebralen Perfusionsdruckes nach schwerem Schädel-Hirn-Trauma wird kontrovers diskutiert. Während im sogenannten Lund-Konzept ein niedriger Perfusionsdruck angestrebt und die Gabe von Katecholaminen aufgrund potentieller zerebraler vasokonstringierender und weiterer Nebeneffekte vermieden wird, befürwortet das CPP-Konzept nach Rosner eine Anhebung des zerebralen Perfusionsdruckes, wenn notwendig unter intravenöser Gabe von Katecholaminen. Vor diesem Hintergrund galt es, in einem experimentellen Schädel-Hirn-Trauma- Modell der Ratte (Controlled Cortical Impact Injury) den Bereich des optimalen zerebralen Perfusionsdruckes nach traumatischer Hirnkontusion zu ermitteln und den Effekt von Katecholaminen auf den posttraumatischen zerebralen Blutfluss und die Entwicklung des sekundären Hirnschadens zu untersuchen. Die wesentlichen Ergebnisse dieser Arbeit lassen sich wie folgt zusammenfassen: In der Akutphase nach Hirnkontusion liegt der Bereich des zerebralen Perfusionsdruckes, welcher die Entwicklung des Kontusionsvolumens nicht beeinflusst, zwischen 70 und 105 mm Hg. Eine Senkung des Perfusionsdruckes unterhalb bzw. Anhebung oberhalb dieser Schwellenwerte vergrößert das Kontusionsvolumen. Die Anhebung des Blutdruckes mittels intravenöser Infusion von Dopamin oder Noradrenalin führt sowohl in der Frühphase als auch in der Spätphase nach Trauma (4 Stunden bzw. 24 Stunden nach kortikaler Kontusion) zu einem signifikanten Anstieg im kortikalen perikontusionellen Blutfluss und in der Hirngewebe-Oxygenierung. Die durch Anhebung des zerebralen Perfusionsdruckes auf über 70 mm Hg induzierte Verbesserung des posttraumatischen zerebralen Blutflusses bewirkte jedoch keine Reduzierung der Hirnschwellung. Für eine Katecholamin-induzierte zerebrale Vasokonstriktion nach kortikaler Kontusion gibt es keinen Anhalt. Um die Entwicklung des sekundären Hirnschadens nach kortikaler Kontusion zu minimieren, sollte der zerebrale Perfusionsdruck nach traumatischem Hirnschaden nicht unterhalb 70 mm Hg liegen. Eine Anhebung des Perfusionsdruckes auf über 70 mm Hg erscheint nicht notwendig oder vorteilhaft zu sein. Wenn notwendig, kann sowohl in der Früh- als auch Spätphase nach Trauma der zerebrale Perfusionsdruck mittels intravenöser Gabe von Katecholaminen angehoben werden. / The optimum cerebral perfusion pressure after severe traumatic brain injury remains to be controversial. In the Lund concept a relatively low cerebral perfusion pressure is preferred, and administration of catecholamines is avoided due to potential catecholamine-mediated cerebral vasoconstriction and other side effects. In contrast, the CPP concept of Rosner recommends elevation of cerebral perfusion pressure, if needed by intravenous administration of catecholamines. Based on this, in an experimental model of traumatic brain injury of the rat (Controlled Cortical Impact Injury) the optimum range of cerebral perfusion pressure after traumatic brain contusion and the effects of catecholamines on posttraumatic cerebral perfusion and development of secondary brain injury were investigated. The most significant results can be summarized as follows: In the acute phase after brain contusion the range of cerebral perfusion pressure that does not affect the development of posttraumatic contusion volume was found to be between 70 and 105 mm Hg. Reduction of the cerebral perfusion pressure below or elevation above these thresholds increases contusion volume. Elevation of blood pressure by intravenous infusion of dopamine or norepinephrine during the early (4 hours) as well as late (24 hours) phase after trauma results in a significant increase in pericontusional blood flow and brain tissue oxygenation. The increase in cerebral blood flow by elevating cerebral perfusion pressure above 70 mm Hg did not decrease cerebral edema formation. There was no evidence of a catecholamine-induced cerebral vasoconstriction after cortical contusion. In order to minimize secondary brain injury after cortical contusion, cerebral perfusion pressure should not fall bellow 70 mm Hg. However, a further active elevation of cerebral perfusion pressure does not appear necessary or beneficial. If needed cerebral perfusion pressure can be elevated by administration of catecholamines in the early as well late phase after trauma.