Changes in cerebrovascular reactivity (CVR) to carbon dioxide (CO2) are reported in many neurological conditions. My aim was to validate a method for computerized prospective targeting of CO2 levels (RespiractTM) as a bedside tool for impaired CVR. I hypothesized that 1) The RespiractTM and TCD method can be used to detect impairment of CVR after SAH and that 2) CVR is impaired in SAH patients. In 18 SAH patients and 26 controls CVR index was calculated dividing the percentage change in middle cerebral artery blood flow velocity (MCAv) by the change in PETCO2. The absolute MCAv values were similar in both groups, but CVR was significantly different (hypercapnia: 0.044 ± 0.076 - controls; 0.014 ± 0.037 - SAH; p=0.0007). I showed that impaired CVR can be detected at the bedside using TCD and CO2 challenge with the RespiractTM, control of CO2 is precise and minimal changes are required.

Evidence suggests that cerebral blood flow patterns accompanying a mental activity are retained in many locked-in patients. Thus, real-time monitoring with functional transcranial Doppler (TCD) together with a specific mental task could control a brain-computer interface (BCI), thereby providing self-initiated interaction. The objective of this study was to create an automatic detection algorithm to differentiate hemodynamic responses coincident with one's performance of verbal fluency (VF) versus counting tasks. We recruited 10 healthy adults who each silently performed up to 30 VF tasks and counted between each. Both middle cerebral arteries were simultaneously imaged using TCD. Linear Discriminant Analyses (LDA) successfully differentiated between VF and both prior and post counting tasks. For every participant, LDA achieved the 70% classification accuracy sufficient for BCIs. Results demonstrate automatic detection of a VF task by TCD and warrant further investigation of TCD as a BCI.

Evidence suggests that cerebral blood flow patterns accompanying a mental activity are retained in many locked-in patients. Thus, real-time monitoring with functional transcranial Doppler (TCD) together with a specific mental task could control a brain-computer interface (BCI), thereby providing self-initiated interaction. The objective of this study was to create an automatic detection algorithm to differentiate hemodynamic responses coincident with one's performance of verbal fluency (VF) versus counting tasks. We recruited 10 healthy adults who each silently performed up to 30 VF tasks and counted between each. Both middle cerebral arteries were simultaneously imaged using TCD. Linear Discriminant Analyses (LDA) successfully differentiated between VF and both prior and post counting tasks. For every participant, LDA achieved the 70% classification accuracy sufficient for BCIs. Results demonstrate automatic detection of a VF task by TCD and warrant further investigation of TCD as a BCI.

In today’s aging population, cerebrovascular health plays a pivotal role in maintaining independence. The identification of early markers of change might help to plan more appropriate preventative and/or therapeutic measures. Recent focus has been placed on the relationship between peripheral vascular characteristics and cerebral hemodynamics. Given the compliant nature of the cerebral circulation, examination of passive properties, including critical closing pressure (CrCP) and resistance area product (RAP), might provide sensitive information about early functional changes. The purpose of this thesis was to provide a comprehensive view of peripheral vascular and cerebrovascular regulation in community-living older adults. In doing so, the thesis covered a spectrum, ranging from an examination of lifestyle factors, including habitual physical activity and sleep quality, to the impact of cerebrovascular health on functional status, characterized by gait speed. Key findings included the observation that while participants showed the ability to regulate cerebral blood flow (CBF) appropriately in most circumstances, the underlying mechanisms used to achieve this regulation was dependent on baseline vascular tone. During sit-to-stand transitions, individuals with lower baseline resistance relied primarily on fluctuations in RAP, which have been suggested to more closely reflect myogenic pathways. In contrast, individuals with elevated resistance had lower baseline CBF and relied relatively more on fluctuations in CrCP during the dynamic transition. The greater reliance on CrCP might indicate that these individuals were required to tap further into reserve pools to avoid hypoperfusion during the transition. Notably, those who exhibited a smaller dynamic RAP response during the posture change also had slower gait speed and higher occurrence of falls over the past year. These results provide evidence that passive cerebrovascular dynamics are sensitive markers linking peripheral and cerebrovascular properties with functional consequences for brain health in the elderly.

In today’s aging population, cerebrovascular health plays a pivotal role in maintaining independence. The identification of early markers of change might help to plan more appropriate preventative and/or therapeutic measures. Recent focus has been placed on the relationship between peripheral vascular characteristics and cerebral hemodynamics. Given the compliant nature of the cerebral circulation, examination of passive properties, including critical closing pressure (CrCP) and resistance area product (RAP), might provide sensitive information about early functional changes. The purpose of this thesis was to provide a comprehensive view of peripheral vascular and cerebrovascular regulation in community-living older adults. In doing so, the thesis covered a spectrum, ranging from an examination of lifestyle factors, including habitual physical activity and sleep quality, to the impact of cerebrovascular health on functional status, characterized by gait speed. Key findings included the observation that while participants showed the ability to regulate cerebral blood flow (CBF) appropriately in most circumstances, the underlying mechanisms used to achieve this regulation was dependent on baseline vascular tone. During sit-to-stand transitions, individuals with lower baseline resistance relied primarily on fluctuations in RAP, which have been suggested to more closely reflect myogenic pathways. In contrast, individuals with elevated resistance had lower baseline CBF and relied relatively more on fluctuations in CrCP during the dynamic transition. The greater reliance on CrCP might indicate that these individuals were required to tap further into reserve pools to avoid hypoperfusion during the transition. Notably, those who exhibited a smaller dynamic RAP response during the posture change also had slower gait speed and higher occurrence of falls over the past year. These results provide evidence that passive cerebrovascular dynamics are sensitive markers linking peripheral and cerebrovascular properties with functional consequences for brain health in the elderly.

Normal pressure hydrocephalus (NPH), a CSF circulation disorder, is important as a reversible cause of gait and cognitive disturbance in an aging population. The inconsistent response to CSF shunting is usually attributed to difficulties in differential diagnosis or co-morbidity. Improving outcome depends on an increased understanding of the pathophysiology of NPH. Specifically, this thesis examines the contribution of, and inter-relationship between, the brain parenchyma and CSF circulation in the pathophysiology of NPH. Of the four core studies of the thesis, the first quantifies the characteristics of the CSF circulation and parenchyma in NPH using CSF infusion studies to measure the resistance to CSF absorption and brain compliance. The second study assesses cerebral blood flow (CBF) was using O15-labelled positron emission tomography (PET) with MR co-registration. By performing CSF infusion studies in the PET scanner, CBF at baseline CSF pressure and at a higher equilibrium pressure is measured. Regional changes and autoregulatory capacity are assessed. The final study examines the microstructural integrity of the parenchyma using MR diffusion tensor imaging. These studies confirm the importance of the inter-relationship of the brain parenchyma and CSF circulation. NPH symptomatology and its relationship to the observed regional CBF reductions in the basal ganglia and thalamus are discussed. Regional CBF reductions with increased CSF pressure and the implications for autoregulatory capacity in NPH are considered. The reduction in CBF when CSF was increased was most striking in the periventricular regions. In addition, periventricular structures demonstrated increased diffusivity and decreased anisotropy. The relationship between these changes and mechanisms such as transependymal CSF passage are reviewed. The findings of this thesis support a role of both the CSF circulation and the brain parenchyma in the pathophysiology of NPH. The results have implications for the approach to the management of patients with NPH.

It is well known now that there exists a coupling between functional brain activity and regional blood flow response in the somatosensory cortex and other cortical areas. Various modalities, including functional magnetic resonance imaging and optical imaging (intrinsic signals as well as fluorescence), have been developed in the past to map functional brain activity. The complexity and fundamental physical constraints of the instruments preclude functional imaging in awake, behaving small animals. This thesis presents the method of Laser Speckle Imaging (LSI) of brain with high spatial and temporal resolution, and potential for imaging awake and behaving animals. The method has the potential to map brain activation with high sensitivity and spatiotemporal resolution without using any exogenous contrast agents. In LSI, scattered laser light with different paths produces a random interference pattern known as speckle, fluctuations of which contain information about the motion of particles in the underlying medium. A post-processing step is needed to extract information out of the speckle images, two of which we introduce in details. Our first method is based on Laser speckle contrast analysis (LASCA), which has been demonstrated as a full-field method for imaging the cerebral blood flow (CBF). However, conventional LASCA is limited to extremely low dynamic range because of the ambient background field, dark current and anomalies in the circuits of CCD camera, which makes it difficult to analyze the spatiotemporal variabilities in CBF. In this study, we propose an enhanced laser speckle contrast analysis (eLASCA) method to improve the dynamic range of LASCA based on monotonic point transformation (MPT). In addition, eLASCA greatly improves the CBF visualization, which is very helpful in demonstrating the details of CBF change. Our second method involves the second order features (SOFs) of the image; they are derived from the cooccurrence matrix that in turn was calculated over the same spatial and temporal window than for the contrast. The image quality metrics - equivalent number of looks, entropy and objective quality – showed superior performance of the SOFs comparing to the contrast analysis. / --

Cerebral small vessel disease (SVD) is associated with increased risks of stroke and dementia, however the mechanisms remain unclear. Low cerebral blood flow (CBF) has long been suggested and accepted, but clinical evidence is conflicting. On the other hand, growing evidence suggests that increased intracranial pulsatility due to vascular stiffening might be an alternative mechanism. Pulse-gated phase-contrast MRI is an imaging technique that allows measuring of CBF contemporaneously with pulsatility in multiple vessels and cerebrospinal fluid (CSF) spaces. The overall aim of this thesis was to provide an overview of existing clinical evidence on both hypotheses, to test the reproducibility of CBF and pulsatility measures in phase-contrast MRI, and to explore the relationship between CBF and intracranial pulsatility and SVD features in a group of patients with minor stroke and SVD changes on brain imaging. I first systematically reviewed and meta-analysed clinical studies that have assessed CBF or intracranial pulsatility in SVD patients. There were 38 studies (n=4006) on CBF and 27 (n=3356) on intracranial pulsatility. Most were cross-sectional, and longitudinal studies were scarce. There were large heterogeneities in patient characteristics and indices used particularly for measuring and calculating pulsatility. Methods to reduce bias such as blinding and the expertise of structural image readers were generally poorly reported, and many studies did not account for the impact of confounding factors (e.g. age, vascular risk factors and disease severity) on CBF or pulsatility. Evidence for falling CBF predating SVD was not supported by longitudinal studies; high pulsatility in one large artery such as internal carotid arteries (ICA) or middle cerebral arteries might be related to SVD, but studies that measured arteries, veins and CSF in the same patients were very limited and the reliability of some pulsatility measures, especially in CSF, needs to be tested. In order to test the reproducibility of the CBF and intracranial pulsatility measures, I repeated 2D phase-contrast MRI scans of vessels and CSF on healthy volunteers during two visits. I also compared the ICA pulsatility index derived from the MRI flow waveform to that from the Doppler ultrasound velocity waveform in patients with minor stroke and SVD features. In 10 heathy volunteers (age 35.2±9.78 years), the reproducibility of CBF and vascular pulsatility indices was good, with within-subject coefficients of variability (CV) less than 10%; whereas CSF flow and pulsatility measures were generally less reproducible (CV > 20%). In 56 patients (age 67.8±8.27 years), the ICA pulsatility indices in Doppler ultrasound and MRI were acceptably well-correlated (r=0.5, p < 0.001) considering the differences in the two techniques. We carried out a cross-sectional study aiming to recruit 60 patients with minor stroke and SVD features. We measured CBF and intracranial pulsatility using phase-contrast MRI, as well as aortic augmentation index (AIx) using a SphygmoCor device. I first investigated the relationship between intracranial measures, and systemic blood pressure or aortic AIx, and then focused on how the intracranial haemodynamic measures related to two main SVD features (white matter hyperintensities (WMH) and perivascular spaces (PVS)). We obtained usable data from 56/60 patients (age 67.8±8.27 years), reflecting a range of SVD burdens. After the adjustment for age, gender, and history of hypertension, higher pulsatility in the venous sinuses was associated with lower diastolic blood pressure and lower mean arterial pressure (e.g. diastolic blood pressure on straight sinus pulsatility index (PI): β=-0.005, P=0.029), but not with aortic AIx. Higher aortic AIx was associated with low ICA PI (β=-0.011, P=0.040). Increased pulsatility in the venous sinuses, not low CBF, was associated with greater WMH volume (e.g. superior sagittal sinus PI: β=1.29, P=0.005) and more basal ganglia PVS (e.g. odds ratio=1.379 per 0.1 increase in superior sagittal sinus PI) after the adjustment for age, gender and blood pressure. The thesis is the first to summarise the literature on CBF and intracranial pulsatility in SVD patients, addressed the major limitations of current clinical studies of SVD, and also assessed CBF and intracranial pulsatility contemporaneously in well-characterised patients with SVD features. The overall results of the thesis challenge the traditional hypothesis of the cause and effect between low CBF and SVD, and suggest that increased cerebrovascular pulsatility, which might be due to intrinsic cerebral small vessel pathologies rather than just aortic stiffness, is important for SVD. More importantly, this pilot study also provides a reliable methodology for measuring intracranial pulsatility using phase-contrast MRI for future longitudinal or larger multicentre studies, and shows that intracranial pulsatility could be used as a secondary outcome in clinical trials of SVD. However, future research is required to elucidate the implication of venous pulsatility and to fully explore the passage of pulse wave transmission in the brain. Overall, this thesis advances knowledge and suggest potential targets for future SVD studies in terms of mechanisms, prevention and treatment.

Intracranial monitoring after severe traumatic brain injury offers the possibility for early detection and amelioration of physiological insults. In this thesis, I explore cerebral insults due raised intracranial pressure, decreased cerebral perfusion pressure and impaired cerebral pressure reactivity after traumatic brain injury. In chapter 2, the importance of intracranial pressure, cerebral perfusion pressure and pressure reactivity in regulating the cerebral circulation is elucidated along with a summary of the existing evidence supporting intracranial monitoring in traumatic brain injury. In chapter 4, intracranial pressure, cerebral perfusion pressure, and pressure reactivity insults are demonstrated to be common, prognostically important, and responsive to long-term changes in management policies. Further, while these insults often occur independently, coexisting insults portend worse prognosis. In chapter 5, I examine possible imaging antecedents of raised intracranial pressure and demonstrate that initial subarachnoid haemorrhage is associated with the subsequent development of elevated intracranial pressure. In addition, elevated glucose during the intensive care stay is associated with worse pressure reactivity. Cortical blood flow and brain tissue oxygenation are demonstrated to be sensitive to increases in intracranial pressure in chapter 6. In chapter 7, a method is proposed to estimate the cerebral perfusion pressure limits of reactivity in real-time, which may allow for more nuanced intensive care treatment. Finally, I explore a recently developed visualisation technique for intracranial physiological insults and apply it to the cerebral perfusion pressure limits of reactivity. Taken together, this thesis outlines the scope, risk factors and consequences of intracranial insults after severe traumatic brain injury. Novel signal processing applications are presented that may serve to facilitate a physiological, personalised and precision approach to patient therapy.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Measurements of respiratory mechanics, very important to conduct the patient with mechanical ventilation, are obtained with the relaxation of respiratory muscle in sedated or paralyzed patients or through a brief period of hyperventilation (HV), which is possible to decrease the drive ventilation of patient. However, it´s known that the hyperventilation decreases the carbon dioxide arterial pressure (PaCO2) and can induce changes in the cerebral blood flow. Then, this study proposes to verify the effects of this brief period of HV on the gasometric parameters, cerebral and systemic hemodynamic in 15 mechanically ventilated patients, with ventilation drive and different pathologies, except cerebral pathology, admitted in Intensive Care Unit of Vita Hospital in Curitiba-PR; being 12 males (80%) and three females (20%), mean age of 61,29 (± 18,97), eight clinical and seven surgical diagnosis. The protocol consisted of a brief HV with increase by 50% from previous minute volume of patient for two minutes. The variables were recorded before, on the first minute of HV (HV1), on the second minute (HV2) and five minutes after the end of maneuver. The parameters recorded were mean blood flow velocity and pulsatility index through transcranial doppler of the middle cerebral arteries, blood gas parameters (pH, PaCO2, EtCO2, HCO3, BE, PaO2, SatO2 e SpO2), besides heart rate and mean arterial pressure. The data were averaged statistically by ANOVA, Newman-Keuls and Wilcoxon tests. The normality condition of data were averaged by Kolmogorov-Smirnov. Values of p<0,05, indicate statistically significant. The results show a decrease of mean blood flow velocity of the right (p=0,18888) and left (p=0,0071) middle cerebral arteries, mainly on the first minute of HV, estimating a decrease of cerebral blood flow (4,12% e 6,51%, of the right and left middle cerebral arteries, bespectively). Five minutes after HV, there was a return to baseline values. In relation to gasometric parameters, there were a significant variation of EtCO2 and PaCO2 during the HV, with smaller changes of PaCO2 in relation to EtCO2. The pulsatility index, another gasometric parameters, heart rate and mean arterial pressure remained stable during HV. Concluding, based on results of this study, that the maneuver of HV may be security applied and does not promote cerebral and systemic repercussion in studied patients. / Cálculos da mecânica respiratória, tão importantes para a condução do paciente sob ventilação mecânica (VM), são obtidos com o relaxamento da musculatura respiratória através de sedação, curarização ou breve período de hiperventilação (HV), em que é possível diminuir o drive ventilatório do paciente. Porém, sabe-se que a HV reduz a pressão arterial de dióxido de carbono (PaCO2) e pode levar a alterações do fluxo sanguíneo cerebral (FSC). Com isso, este trabalho se propôs a verificar os efeitos deste breve período de HV na hemodinâmica cerebral, sistêmica e variáveis gasométricas em 15 pacientes sob VM apresentando drive ventilatório, com patologias diversas, exceto patologias cerebrais, internados na Unidade de Terapia Intensiva do Hospital Vita na cidade de Curitiba-PR; sendo 12 pacientes do sexo masculino (80%) e três do sexo feminino (20%), com média de idade de 61,29 (±18,97), sendo oito diagnósticos cirúrgicos e sete clínicos. O protocolo consistia de uma HV breve com aumento de 50% do volume minuto prévio do paciente por dois minutos. A coleta dos dados foi feita antes, no primeiro minuto de HV (HV1), no segundo minuto (HV2) e cinco minutos após o final da manobra. Foram colhidos dados de Velocidade Média (Vm) do FSC e Índice de Pulsatilidade (IP) ao Doppler Transcraniano (DTC) das artérias cerebrais médias (ACMs), dados gasométricos (pH, PaCO2, EtCO2, HCO3, BE, PaO2, SatO2 e SpO2), bem como freqüência cardíaca (FC) e pressão arterial média (PAM). Os dados foram avaliados estatisticamente pelos testes ANOVA, Newman-Keuls e teste não-paramétrico de Wilcoxon. A condição de normalidade dos dados foi avaliada pelo teste de Kolmogorov-Smirnov. Valores de p<0,05 indicaram significância estatística. Como resultados, observou-se que houve uma diminuição da velocidade média (Vm) do FSC das ACMs direita (p=0,18888) e esquerda (p=0,0071), mais evidente no primeiro minuto de HV, estimando uma diminuição do FSC (4,12% e 6,51%, nas ACMs direita e esquerda, respectivamente). Após 5 minutos do final da manobra, encontrou-se retorno da Vm e do FSC aos valores iniciais. Quanto às variáveis gasométricas observou-se que o EtCO2 e PaCO2 alteram com a manobra de HV breve, porém com menores mudanças da PaCO2 em relação à EtCO2. O IP, as demais variáveis gasométricas, a FC e a PAM permaneceram estáveis durante a HV. Conclui-se, portanto, a partir dos dados obtidos neste estudo, que a manobra de HV pode ser realizada de forma segura, sem repercussão hemodinâmica cerebral e sistêmica dos pacientes estudados.