<p> The purpose of this thesis was to design, build and test a prototype artifact suppressing electroencephalogram data acquisition system (AS-EEG-DAQ-S) to collect electroencephalogram (EEG) evoked potential (EP) data during repetitive transcranial magnetic stimulation (rTMS) without the EEG signal being masked by transcranial magnetic stimulation (TMS) artifact. A functional AS-EEG-DAQ-S capable of blocking TMS artifact would provide for the first time a quantitative measurement system to assist in optimal TMS coil positioning during the rTMS treatment of depression, an alternative to electroconvulsive therapy (ECT). This thesis provides the details for an AS-EEGDAQ-S. Preliminary TMS EP results on a human subject were collected. Results showed transcallosal conduction times of 12ms to 31ms, which are consistent with those predicted and collected by other researchers in the TMS field. </p> <p> The first portion of this work provides electrode heating data for modem rTMS Paradigms for the recording ofEEG during rTMS. The concern is that during rTMS EEG electrodes can heat to an unsafe temperature. Seven electrode types were tested: silver/silver chloride, silver cup, gold cup, notched gold cup, notched silver cup, notched gold-plated silver cup, and carbon. All electrodes tested are commercially available, including the carbon electrodes designed for MRI use. The three notched electrodes tested were standard electrodes notched using metal clippers to reduce induced currents. Induced currents are responsible for electrode heating during rTMS and can cause burns to the skin. The results ,of this study show that electrode heating is a concern when collecting BEG during rTMS. However, a number of standard electrodes or slightly modified standard electrodes are suitable for recording BEG during rTMS if certain stimulating parameters are adhered to. </p> <p> The second portion of this work provides the detailed development and design of the AS-EEG-DAQ-S. Four different approaches were tested and their ability to withstand a TMS pulse compared. </p> <p> Short circuiting the input pins of a commercially available EEG amplifier was the first approach tried and yielded only marginal results due to the switches used being designed for digital logic, transistor built, and creating an undesirable offset between input pins. </p> <p> The second approach tested involved continuing to work with a commercially available EEG amplifier and implementing a sample-and-hold circuit between the patient and the EEG machine inputs. This approach had the drawback of requiring that the BEG signal be attenuated back to EEG signal levels, which are near noise amplitude levels. </p> <p> The third approach involved using a high bandwidth amplification circuit to recover quicker from the baseline voltage offset created by the TMS artifact. However, increasing the bandwidth also allows the artifact to saturate the input amplifiers, which then require on the order of 500ms to recover fully. </p> <p> The fourth approach involved combining the second and third approaches to create a high bandwidth amplifier that incorporates a sample-and-hold circuit to prevent amplifier saturation when gain is increased. The fourth approach provide the high bandwidth and artifact blocking behavior desired. </p> / Thesis / Master of Applied Science (MASc)

Post-concussion syndrome (PCS) is a poorly understood sequela of mild traumatic brain injury (mTBI), more commonly referred to as concussion. While PCS is known to affect a subset of individuals following injury, it remains unclear how and why specific individuals incur chronic symptoms. Concussions disrupt normal neurophysiologic function within the brain, however the neurophysiologic underpinnings of PCS are unclear. Using transcranial magnetic stimulation (TMS), it is possible to non-invasively investigate neurotransmission in clinical populations such as those with PCS by stimulating the primary motor cortex (M1) and recording motor outputs in a contralateral hand muscle. A study was conducted using TMS to measure corticospinal excitability, intracortical facilitation and inhibition, and transcallosal inhibition in M1 of a group with PCS and a non-injured, healthy control group. Greater corticospinal excitability, and specific reductions in intracortical and transcallosal inhibition were observed in the PCS group, providing evidence of impaired neurotransmitter receptor activity. Importantly, these findings differed from previous observations in recovered concussion groups using similar stimulation techniques. Furthermore, it was observed that these neurophysiological differences may relate specifically to the presence of depression symptoms rather than general concussion symptoms. The physiologic and clinical implications of the findings of this thesis are discussed, and novel research avenues warranting investigation are identified. / Thesis / Master of Science in Kinesiology

Yes / Two subdivisions of human V5/MT+; one located posteriorly (MT/TO-1), the other more anteriorly (MST/TO-2), were identified in human participants using functional magnetic resonance imaging (fMRI) on the basis of their representations of the ipsi- versus contra-lateral visual field. These subdivisions were then targeted for disruption by the application of repetitive transcranial magnetic stimulation (rTMS). rTMS was delivered to cortical areas whilst participants performed direction discrimination tasks involving three different types of moving stimuli defined by the translational, radial or rotational motion of dot patterns. For translational motion, performance was significantly reduced relative to baseline when rTMS was applied to both MT/TO-1 and MST/TO-2. For radial motion there was a differential effect between MT/TO-1 and MST/TO-2, with only disruption of the latter area affecting performance. rTMS failed to reveal a complete dissociation between MT/TO-1 and MST/TO-2 in terms of their contribution to the perception of rotational motion. On the basis of these results MT/TO-1 and MST/TO-2 appear to be functionally distinct subdivisions of hMT/V5+. Whilst both areas appear to be implicated in the processing of translational motion, only the anterior region (MST/TO-2) makes a causal contribution to the perception of radial motion. / BBSRC

This thesis investigated transcranial direct current stimulation (tDCS) as applied to the motor system, and its ability to modulate underlying cortical processes and resultant motor behaviours. Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) were employed to assess the extent to which tDCS induces quantifiable changes in neural structure and function in controls and stroke patients. Modifications in the connectivity of intrinsic functional networks following tDCS application were examined using resting state fMRI. Polarity-specific changes were found: cathodal (inhibitory) tDCS increased the strength of the default mode network and increased functional coupling between major nodes within the motor network. No significant effects were found following anodal (excitatory) tDCS. Although anodal tDCS elicited only subtle changes in resting activity, it is known to produce robust modifications of behaviour. Single and paired-pulse TMS were used to investigate the neurophysiological underpinnings of these changes. Consistent with the theory of homeostatic plasticity, anodal tDCS applied prior to task performance increased GABAA-mediated cortical inhibition and worsened behaviour. The specificity of these changes suggests a central role for the mechanism of surround inhibition. A longitudinal clinical trial in chronic stroke patients was conducted to determine the utility of tDCS as an adjunct in motor rehabilitation. Serial MRI scans revealed that, when combined with motor training, anodal tDCS increased functional activity and grey matter in primarily ipsilesional motor areas. These brain changes were correlated with behavioural improvements in the stroke-affected upper limb. The laterality of connectivity at baseline, as measured by resting state activity and corticospinal tract integrity, was predictive of response to the rehabilitation program, particularly in those stroke patients who received tDCS. Asymmetry favouring the contralesional hemisphere predicted greater behavioural gains. Such results underscore the importance of re-normalisation of structure and functional activity toward the lesioned hemisphere in stroke rehabilitation.

An important aspect of cognitive neuroscience is to localise specific brain regions involved in cognitive tasks, and to determine the mediating brain processes. There are several investigative approaches towards this, but amongst them, only transcranial magnetic stimulation (TMS) is able to interfere with the brain in such a way as to show the critical involvement of a brain region in a particular behaviour. TMS can be applied in normal subjects during the performance of a cognitive task and the resulting disruption of activity in the targeted brain region leads to an alteration in, or suspension of, behaviour consequent upon that brain activity. More recently, another brain stimulation technique has emerged that may also be able to contribute to the investigation of human cognition. Transcranial direct current stimulation (tDCS) applies a weak direct current to a targeted brain region, modulating cortical excitability and thereby altering the behavioural output. tDCS may be able to provide information that complements TMS and other investigative techniques by modulating behaviour in a way that depends on the role the brain region is carrying out in the task. This thesis describes a series of experiments in which TMS and tDCS were applied to two well-studied cognitive behaviours, working memory (WM) and mental rotation (MR). WM is the temporary retention of information that can be manipulated in order to guide behaviour. The most popular psychological model of WM proposes a multi-modal central executive (CE) that acts upon information stored in dedicated buffers (Baddeley, 1986). The dorsolateral prefrontal cortex (DLPFC) is a strong candidate as a key CE node (D'Esposito & Postle, 2000; Petrides, 2000b; Smith & Jonides, 1997; Stuss & Knight, 2002). MR is a visuo-cognitive process by which an image can be mentally modified into an orientation other than the one in which it is displayed (Corballis & McLaren, 1984). The area centred around the intraparietal sulcus is a brain key region for MR (Alivisatos & Petrides, 1996; Harris et al., 2000; Jordan et al., 2001). The work presented in this thesis examines the roles of the DLPFC and posterior parietal cortex (PPC) in WM and MR, respectively, and also highlights some of the methodological issues that are necessary to consider in order to produce reliable virtual lesions. The studies were carried out in young healthy volunteers, and were approved by the institutional ethics committee. In one study, repetitive TMS (rTMS) was shown to disrupt the manipulation of verbal information held in WM when administered over the right DLPFC, a result which supports a process-based segregation of the human prefrontal cortex for WM. Low- and high-frequency rTMS did not disrupt performance on another popular test of executive processing, n-back, a result which suggests that specific stimulation and task conditions must be met in order to produce virtual lesions, but also questions the critical importance of recruitment of the DLPFC for a running span task. rTMS applied to the right PPC replicated results from a previous TMS investigation, supporting the critical role this region in the rotation of images (Harris & Miniussi, 2003). When the left PPC was stimulated, impairment was produced only for the rotation of inverted stimuli. A role for the left PPC in the rotation of objects-as-a-whole is proposed based on these findings. The use of tDCS in the investigation of WM and MR is amongst the first to be described. Stimulation of the left DLPFC led to decreased performance accuracy on a verbal WM task in a polarity-specific manner. The pattern of results produced supports the role of the DLPFC as a node of a CE. tDCS over the left DLPFC did not modulate n-back task performance, a result which supports the TMS results that the involvement of the left DLPFC is not critical to the successful performance of the n-back task, although methodological issues remain of concern in relation to this conclusion. MR was not affected by tDCS applied to the right PPC and this result is most likely a direct demonstration of the importance of electrode montage. In conclusion, these studies show that rTMS and tDCS can be usefully applied to create virtual cortical lesions or modulate cortical excitability during the performance of cognitive tasks in humans, and can play an important role in investigating cognitive neuropsychological models. More widespread use of these techniques to complement lesion studies and functional neuroimaging is recommended.

Anxiety and depression are highly prevalent and often comorbid disorders that cause significant personal and economic burdens (Lépine, 2001). Because a significant number of people with depression do not respond to therapy (Fava, 2003), the development of alternative treatment methods may lessen the burden of such mental disorders. Recent research has focused on brain stimulation methods, many of which require invasive surgery or have limited precision in targeting specific areas. Transcranial ultrasound (TUS) is an alternative, noninvasive brain stimulation method that has greater spatial precision than existing methods (Tufail, 2011). TUS has been found to excite neurons in animal brains (Tufail et. al, 2010) and increase positive mood in humans (Sanguinetti et al, 2013). The present study examined TUS, for the first time, as a potential mood intervention. Twenty-four college students with mild to moderate depressive symptoms were randomly assigned to TUS stimulation or TUS sham (no power administered). Participants completed one TUS session each day for five days. Although depression scores did not change differentially for TUS/Sham, trait worry decreased in the stimulation but not the sham condition. Additionally, those in the stimulation condition rated themselves significantly less tense ten minutes after stimulation compared to those in the sham condition. TUS stimulation did not impact a brain electrical activity index associated with approach motivation, frontal asymmetry. These results have significant implications for the potential utility of TUS as an intervention for anxiety disorders or worry-related psychopathology, warranting future investigation of implicated brain electrical activity and mood changes.

Chronic non-specific low back pain (CNSLBP) is a widespread but poorly understood condition that places a substantial burden on the sufferer, health services and the wider economy. Existing approaches to management do not demonstrate impressive levels of effectiveness. There is growing evidence that CNSLBP is associated with significant alterations in central nervous system (CNS) structure and function, suggesting a possible role for the brain in the aetiology of the condition, and presenting a case for novel therapies which aim to treat CNSLBP by affecting brain function. One such potential therapeutic approach is non-invasive brain stimulation (NIBS). Following a literature review discussing the epidemiology and management of low back pain, the evidence for altered CNS function and the potential role of brain stimulation in CNSLBP and chronic pain generally this thesis includes 3 original scientific studies: (i) A Cochrane systematic review of the effectiveness of NIBS techniques for the treatment of chronic pain; (ii) A randomised double-blind exploratory study of transcranial direct current stimulation of the motor cortex in the treatment of CNSLBP; (iii) Is blinding to the stimulation condition maintained in trials comparing 2mA tDCS with sham stimulation? A randomised cross-over study. Results: There is limited existing evidence that some forms of NIBS may have a beneficial effect on chronic pain, though caution is warranted. Exploratory data from study 2 is not suggestive that tDCS to the motor cortex is effective for treating CNSLBP. Commonly used sham controls in trials of tDCS do not ensure adequate blinding, and so introduce a potential source of bias to the existing evidence base. Conclusion: Further research is required to establish the value of NIBS as a treatment for chronic pain and CNSLBP. Future research in tDCS will need to develop and employ fully validated sham controls to ensure adequate blinding. NIBS cannot currently be recommended for the treatment of CNSLBP.

A Neuronavegação é uma técnica de visualização computacional da localização de instrumentos em relação às estruturas neuronais. A estimulação magnética transcraniana (EMT) é uma ferramenta para estimulação cerebral não-invasiva, que tem sido utilizada em aplicações clínicas, para o tratamento de algumas patologias, e também em pesquisas. Entretanto, a EMT é uma técnica altamente dependente de parâmetros como o posicionamento e orientação da bobina de estimulação em relação às estruturas neuronais. Para auxiliar no posicionamento da bobina, uma combinação entre neuronavegação e EMT é utilizada, chamada de EMTnavegada (EMTn). Essa técnica permite o monitoramento em tempo real da bobina de EMT em relação às neuroimagens. Porém, a utilização da EMTn ainda é pouco explorada, tanto na pesquisa quanto no ambiente clínico, devido ao alto custo, exigência da imagem de ressonância magnética, complexidade e baixa portabilidade dos sistemas de EMTn comerciais. O neuronavegador de código aberto e livre, InVesalius Navigator, vem sendo desenvolvido para ajudar a suprir essa necessidade. Assim, o objetivo desta dissertação foi desenvolver ferramentas para o sistema de neuronavegação InVesalius Navigator. As funcionalidades adicionadas foram: i) suporte para três tipos de rastreadores espaciais; ii) sincronização da EMT com o neuronavegador; iii) guia para o reposicionamento da bobina. Além disso, com intuito de contornar a necessidade de utilizar a imagem de ressonância magnética foram realizados estudos para a substituição por uma imagem padrão. Na parte de desenvolvimento, experimentos de caracterização foram realizados para validação das ferramentas. O sistema de neuronavegação apresentou-se intuitivo e de fácil portabilidade. Além disso, a precisão obtida foi semelhante à de sistemas comerciais. Os erros de localização foram inferiores a 3 mm, considerados aceitáveis para aplicações clínicas. Na segunda parte, procedimentos que não exigem extrema precisão, como a localização e digitalização do hotspot, a variabilidade foi considerada aceitável. Portanto, a utilização da imagem média mostrou-se uma possível alternativa para as imagens de ressonância magnética. / Neuronavigation is a computer image-guided technique to locate surgical instruments related to brain structures. The transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method, it has been used for clinical purposes, treating neurological disorders, and also for research purpose, studying cortical brain function. However, the use of TMS is highly dependent on coil position and orientation related to brain structures. The navigated TMS (nTMS) is a combined technique of neuronavigation system and TMS, this technique allows tracking TMS coil by image guidance. Yet, nTMS is not widely used, either in research and in the clinical environment, due to the high cost, magnetic resonance imaging requirement, complexity, and low portability of commercial TMS systems. Thus, the aim of this dissertation was to develop tools for the neuronavigator system InVesalius Navigator, such as: i) support for three types of spatial trackers; ii) synchronization of the TMS with the neuronavigator; iii) guide for coil repositioning. In addition, in order to overcome the magnetic resonance imaging requirement, studies were made to replace it with a standard brain image. In the development part, characterization experiments were done to validate the new functionalities. Therefore, the accuracy obtained was similar to commercial systems. Localization errors were less than 3 mm considered acceptable for clinical applications. In the second part, for procedures that do not require extreme accuracy, such as the location and scanning of the hotspot, the variability was considered acceptable. Therefore, the use of the standard brain image was a possible alternative for magnetic resonance imaging.

Gao Shan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 191-194). / Abstracts in English and Chinese. / Abstract in English --- p.i / Abstract in Chinese --- p.iii / Acknowledgement --- p.v / Introduction --- p.vi / Contents --- p.viii / List of tables --- p.xiv / List of figures --- p.xv / Chapter Chapter One --- Literature Review / Chapter 1.1 --- Middle Cerebral Artery (MCA) Stenos --- p.is / Chapter 1.1.1 --- Prevalence of atherosclerotic MCA stenosis --- p.2 / Chapter 1.1.2 --- Methods for diagnosis of MCA stenosis --- p.3 / Chapter 1.1.3 --- Possible mechanism and course of stroke with MCA stenosis --- p.4 / Chapter 1.1.4 --- Treatment and prevention of stroke in patients with MCA stenosis --- p.5 / Chapter 1.2 --- Microembolic Signal (MES) Detection / Chapter 1.2.1 --- Introduction --- p.9 / Chapter 1.2.2 --- Technology --- p.9 / Characteristics of MES / Factors that affect MES detection / Problems of technology / Chapter 1.2.3 --- Clinical application --- p.15 / MES originating from atherosclerotic carotid artery stenosis / MES detection in internal carotid endarterectomy (CEA) / MES detection in patients with MCA stenosis / Predicting value and application in therapeutic trial / References --- p.19 / Chapter Chapter Two --- General Methodology / Chapter 2.1 --- Transcranial Doppler (TCD) Diagnosis for Intracranial Artery Stenosis / Chapter 2.1.1 --- TCD spectrum and common parameters --- p.29 / Chapter 2.1.2 --- Emitting and receiving transducers --- p.29 / Chapter 2.1.3 --- Pulsitility index (PI) --- p.31 / Chapter 2.1.4 --- Insonation depth and flow direction --- p.31 / Chapter 2.1.5 --- Continuous wave (CW) and pulsed wave (PW) --- p.33 / Chapter 2.1.6 --- Normal intracranial arteries through temporal and suboccipital window --- p.33 / Chapter 2.1.7 --- Normal intracranial arteries through orbital window --- p.36 / Chapter 2.1.8 --- Normal extracranial arteries --- p.36 / Chapter 2.1.9 --- TCD diagnosis for intracranial artery stenosis --- p.39 / Chapter 2.1.10 --- Example of multiple intracranial arteries stenosis --- p.39 / Chapter 2.2 --- Microembolic Signal (MES) Detection / Chapter 2.2.1 --- Device of MES monitoring --- p.41 / Chapter 2.2.2 --- Insonated artery and depth --- p.41 / Chapter 2.2.3 --- Axis length of the sample volume --- p.43 / Chapter 2.2.4 --- Fast Fourier Transform (FFT) time window overlap --- p.43 / Chapter 2.2.5 --- Distinguishing embolic signal and artifact with two-gate transducer --- p.45 / Chapter 2.2.6 --- Measurements of embolic signal and threshold --- p.47 / References --- p.45 / Chapter Chapter Three --- Prevalence and Clinical Significance of Microembolic Signal (MES) in Patients with Middle Cerebral Artery (MCA) Stenosis / Chapter 3.1 --- Abstract --- p.50 / Chapter 3.2 --- Introduction --- p.51 / Chapter 3.3 --- Methodology --- p.51 / Patients / Severity of stroke and clinical course / Diagnosis for middle cerebral artery (MCA) stenosis / Microembolic signal (MES) detection / Statistical analysis / Chapter 3.4 --- Results --- p.55 / Baseline information of patients / Prevalence of MES / Relationship between presence of MES and severity of MCA stenosis / Correlation between presence of MES and clinical course in 85 symptomatic patients / Correlation between the count of MES and clinical course in 85 symptomatic patients / Correlation between the presence of MES and further ischemic stroke / Chapter 3.5 --- Discussion --- p.63 / Prevalence of MES / Association between severity of stroke and presence or the number of MES / Predictive value of MES for further stroke / References --- p.66 / Chapter Chapter Four --- Mechanisms of Acute Cerebral Infarction in Patients with Cerebral Artery Stenosis: a Diffusion-weighted Imaging and Microemboli Monitoring study / Chapter 4.1 --- Abstract / Chapter 4.2 --- Introduction --- p.72 / Chapter 4.3 --- Methodology --- p.73 / Patients / Microembolic signal (MES) detection by transcranial Doppler (TCD) / "Magnetic resonance imaging (DWI, MRI and MRA)" / Statistical analysis / Chapter 4.4 --- Results --- p.77 / Severity of MCA stenosis on MRA and pattern of infarct on DWI / Frequency and count of MES and its relationship with multiple and borderzone infarction on DWI / Chapter 4.5 --- Discussion --- p.79 / Frequency of MES / Pattern of cerebral infarcts on DWI / Relationship between MES and multiple infarcts on DWI / References --- p.83 / Chapter Chapter Five / Chapter Chapter Five-I --- Novel Observations of the Characteristics of Real Time Genesis of Thromboembolism in Middle Cerebral Artery Stenosis Detected by Transcranial Doppler / Chapter 5.1.1 --- Abstract --- p.90 / Chapter 5.1.2 --- Introduction --- p.91 / Chapter 5.1.3 --- Methodology --- p.91 / Characteristics of patients / "MRA, DWI and conventional TCD data" / MES monitoring method and overall data / Neuroimaging and MES monitoring data in all five patients / Signal analysis in off-line / Confirmation test for the origin of MES / Chapter 5.1.4 --- Results --- p.104 / Frequency of three special phenomena / Characteristics of three special phenomena / Results of confirmation test for embolic source / Chapter 5.1.5 --- Discussion --- p.133 / Occurrence of MES with flow velocity change simultaneously / MES splatter / Bi-directional low frequency (S-velocity) vibration / Testing for source of MES detected from MCA stenosis / References --- p.139 / Chapter Chapter Five-II --- Characteristics of Microembolic Signals Detected near Its Origin from the Middle Cerebral Artery Stenosis / Chapter 5.2.1 --- Abstract --- p.143 / Chapter 5.2.2 --- Introduction --- p.144 / Chapter 5.2.3 --- Methodology --- p.144 / Patients / Microembolic signal (MES) detection / Classification of MES / Chapter 5.2.4 --- Results --- p.145 / Types of MES detected from MCA stenosis / Characteristics of three types of MES / Chapter 5.2.5 --- Discussion --- p.157 / Emboli moving from vessel wall to the center / Emboli vibration / About calculating the time delay between two channels / References --- p.160 / Chapter Chapter Five-III --- "Hemodynamic change,microembolic signal counts and use of antithrombotic treatments" / Chapter 5.3.1 --- Abstract --- p.163 / Chapter 5.3.2 --- Introduction --- p.164 / Chapter 5.3.3 --- Methodology --- p.164 / Chapter 5.3.4 --- Results / "The relationship among flow velocity, the number of MES and time since symptom onset" --- p.165 / Patient one / Patient two / Patient three / Chapter 5.3.5 --- Discussion / Association between flow velocity or MES change and different anticoagulants in acute stage / Progression of MCA stenosis after acute stage / Stability of MCA atherosclerotic stenosis / References --- p.173 / Chapter Chapter Six --- The Optimal Values of Flow Velocity on Transcranial Dopplerin Grading Severity of Middle Cerebral Artery Stenosis in Comparison With Magnetic Resonance Angiography / Chapter 6.1 --- Abstract --- p.179 / Chapter 6.2 --- Introduction --- p.180 / Chapter 6.3 --- Methodology --- p.180 / Patients / TCD examination / Grading of MCA stenosis on MRA / Statistical analysis / Chapter 6.4 --- Results --- p.182 / Detection of >50% MCA stenosis according to flow velocity / Grading severity of MCA stenosis by flow velocity / Chapter 6.5 --- Discussion --- p.186 / Reliability of TCD diagnosis for MCA stenosis / Grading MCA stenosis according to flow velocity on TCD / References / Abbreviations --- p.189 / Publications --- p.191

Intracranial pressure (ICP) is an important monitoring modality in the clinical management of several neurological diseases carrying the risk of fatal intracranial hypertension. However, this parameter is not always considered due to its invasive assessment. In this scenario, a non-invasive estimation of ICP (nICP) may be essential, and indeed it has become a Holy Grail in Clinical Neurosciences: extensively searched, albeit never found. This thesis is devoted to the assessment, applications and development of transcranial Doppler (TCD)-based non-invasive methods for ICP and cerebral perfusion pressure (CPP) monitoring. The thesis is divided into three sections: I) The accuracy of existing TCD-based nICP estimators in various scenarios of varying ICP (traumatic brain injury, rise of ICP during plateau waves, and rise in ICP induced by infusion of cerebrospinal fluid during infusion test). The estimators of nICP consisted of a mathematical black box model, methods based on non-invasive CPP, and a method based on TCD pulsatility index. II) The feasibility of the best performing nICP estimator in clinical practice, including patients with closed TBI and brain midline shift, patients with acute liver failure during liver transplant surgery, and patients during non-neurosurgical surgery in the beach chair position. III) The description and assessment of a novel methodology for non-invasive assessment of cerebral perfusion pressure (nCPP) based on spectral arterial blood volume accounting. As main results, TCD-based non-invasive methods could replicate changes in direct ICP across time confidently, and could provide reasonable accuracy in comparison to the standard invasive techniques. Furthermore, in feasibility studies, nICP in association with other TCD physiological parameters provided a comprehensive interpretation of cerebral haemodynamics in conditions presenting impairment of cerebral blood flow circulation. The new method of nCPP estimation could identify changes in CPP across time reliably in conditions of decreasing and increasing CPP. These findings support the use of TCD-based nICP methods in a variety of clinical conditions requiring management of ICP and brain perfusion. More importantly, the low costs associated with nICP methods, since TCD is a widely available medical device, could contribute to its widespread use as a reliable alternative for ICP monitoring in everyday clinical practice.