Dissertations / Theses on the topic 'Transcranial Doppler ultrasound'

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2017.<br>This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.<br>Cataloged from student-submitted PDF version of thesis.<br>Includes bibliographical references (pages 183-190).<br>Transcranial Doppler (TCD) sonography is a specialized ultrasound technique that enables measurement of blood ow velocity from the basal intracerebral vessels. Use of TCD sonography is highly compelling as a diagnostic modality due to its safety in prolonged studies, high temporal resolution, and relative portability. Although TCD methods have been clinically indicated in a variety of cerebrovascular diagnostic applications, general acceptance by the medical community has been impeded by several critical deficiencies { including the need for a highly-trained TCD operator, operator dependent measurement results, and severe patient movement restrictions. This thesis seeks to mitigate such limitations through the development of a compact, wearable TCD ultrasound system, permitting untethered cerebrovascular monitoring with limited operator interaction. The prototype system incorporates a custom two-dimensional transducer array and multi-channel transceiver electronics, thereby facilitating acoustic focusing via phased array operation. Algorithmic vessel search and tracking further reduce operator dependencies by expediting vessel localization, systematizing vessel identification, and dynamically adapting to relative vessel position. Additionally, focal correction methods are presented, which improve acoustic beamformation capabilities in the presence of tissue inhomogeneities. Validation of the prototype hardware and embedded signal processing implementations under flow phantom and human subject testing yields high correlation with accepted velocimetry methods. Vessel search and tracking functionality are also verified experimentally. Circuit integration is explored to further reduce instrumentation dimensions and power consumption.<br>by Sabino Joseph Pietrangelo.<br>Ph. D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2013.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (p. 137-144).<br>This thesis details the design of a transcranial Doppler (TCD) ultrasound system to measure cerebral blood flow velocity (CBFV) at the middle cerebral artery (MCA). TCD sonography has been clinically indicated in a variety of neurovascular diagnostic applications. Acceptance of conventional TCD methods, however, has been primarily impeded by several constraints, including restrictive system form factors, measurement reliability concerns, and the need for a highly-skilled operator. The goal of this work is to reduce the effects of such limitations through the development of a highly-compact, wearable TCD ultrasound system for autonomous CBFV measurement. A first-generation, eight channel printed circuit board prototype system has been designed, fabricated, and experimentally tested. Characterization of the prototype system using a Doppler flow phantom resulted in a normalized root-mean-square error of < 3.5% over the range of expected in vivo MCA flow velocities. Extension of the initial prototype to higher channel count systems and the development of phased array beamformation and algorithmic vessel location are also examined in this work. The emergence of simple, robust, and non-invasive neurovascular diagnostic methods presents an enormous opportunity for the advancement of neurovascular monitoring, particularly in applications where - due to restrictions in current diagnostic modalities - standard monitoring procedures have not yet been established.<br>by Sabino Joseph Pietrangelo.<br>S.M.

The detection of micro-embolic signals (MES) is a mature application of transcranial Doppler (TCD) ultrasound. It involves the identification of abnormally highpitched signals within the arterial waveform as a method of diagnosis and prediction of embolic complications in stroke patients. More recently, algorithms have been developed to help characterise and classify MES using advanced signal processing techniques. These advances aim to improve our understanding of the causes of cereberovascular disease, helping to target the most appropriate interventions and quantifying the risk to patients of further stroke events. However, there are a number of limitations with current TCD systems which reduce their effectiveness. In particular, improvements in our understanding of the scattering effects in TCD ultrasound propagation channels will benefit our ability to develop algorithms that more robustly and reliably identify the consistency and material make-up of MES. This thesis explores TCD propagation channels in three related research areas. Firstly, a method of characterising TCD ultrasound propagation channels is proposed. Isotropic and non-isotropic three dimensional space (3-D) spherical scattering channel models are described in terms of theoretical reference models, simulation models, and sum of sinusoids (SoS) simulators, allowing the statistical properties to be analysed and reported. Secondly, a TCD ultrasound medical blood flow phantom is described. The phantom, designed to replicate blood flow in the middle cerebral arteries (MCA) for TCD ultrasound studies, is discussed in terms of material selection, physical construction and acoustic characteristics, including acoustic velocity, attenuation and backscatter coefficients. Finally, verification analysis is performed on the non-isotropic models against firstly, the blood flow phantom, and secondly, a patient recordings database. This analysis expands on areas of agreement and disagreement before assessing the usefulness of the models and describing their potential to improve signal processing approaches for detection of MES. The proposed non-isotropic channel reference model, simulation model, SoS simulator, and blood flow phantom are expected to contribute to improvements in the design, testing, and performance evaluation of future TCD ultrasound systems.

Cette thèse porte sur deux branches majeures de l'utilisation d'agents sensibles aux ultrasons: l'échographie ultrarapide du cerveau assistée par microbulles et la délivrance par ultrasons de médicaments pour la thérapie du cancer. Dans la première approche, des microbulles remplies de gaz fluoré ont été utilisés pour observer l'activation du cerveau à travers le crâne des rongeurs. Nous avons été en mesure de reconstituer de manière non invasive le réseau vasculaire du cerveau, puis de récupérer sa réponse hémodynamique avec une résolution spatio-temporelle élevée. La validation de cette approche d'imagerie fonctionnelle par échographie (FUS) a été facilitée par la grande sensibilité de la technique du Doppler ultrarapide ultrasensible. En effet, cette modalité d'imagerie permet de détecter les changements hémodynamiques dus au couplage neurovasculaire avec une grande résolution (1ms, 100pm). Ces résultats suggèrent que la combinaison des agents de contraste et l'imagerie ultrarapide peut aider à compenser entièrement l'atténuation par le crâne, et ce en préservant la résolution et en augmentant la profondeur de pénétration. L'injection d'agents de contraste ultrasonore a également conduit à des résultats remarquables en imagerie ultrasonore ultrarapide. La barrière de la diffraction a été contournée pour aller au-delà de la limite de demi-longueur d'onde de résolution. Nous avons démontré que des microvaisseaux cérébraux de 9pm de diamètre peuvent être distingués par microscopie échographie ultrarapide de localisation (uULM). Des millions de sources «clignotantes» sont localisées dans l'espace et dans le temps, conduisant à des images super-résolues (cartographie de densité de microbulles) de l'ensemble du réseau vasculaire du cerveau du rat avec une résolution spatiale de À / 10. En outre, les trajets des microbulles au cours du temps ont pu être relevés et ainsi permettre d'extraire les vitesses des flux sanguins avec une grande dynamique. Dans la seconde approche, nous avons exploité la manière dont nous pouvons contrôler, spatialement et temporellement, la vaporisation de micro gouttes composites de perfluorocarbone (PFC) lorsque leur activation est déclenchée par de courtes impulsions ultrasonore. Le concept de "chimie in-situ" est introduit dès lors que nous avons été en mesure de contrôler une réaction chimique spontanée in vitro. En outre, dans le cadre des applications in vivo de la chimie in situ, un nouveau dispositif microfluidique en verre a été proposé afin de permettre une production stable et rapide de gouttes monodisperses. Ce nouveau dispositif présente 128 générateurs en parallèles avec deux canaux sous pression. Finalement, de nouvelles séquences d'échographie de contrôle ultra-rapides ont été développées dans le but de contrôler et de surveiller la libération des gouttelettes composites<br>This thesis focuses on two main branches of the application of ultrasound contrast agents: microbubbles-aided ultrafast ultrasound imaging of the brain and ultrasound-triggered drug delivery for cancer therapy. At first, gas-filled microbubbles have been used to retrieve the brain activation through the skull in large animais. With this approach we have been able to non-invasively reconstruct the cerebral network of the brain, as well as retrieve its hemodynamic response to specific evoked tasks with high spatiotemporal resolution. The validation of this novel functional ultrasound (fUS) imaging approach was facilitated by the high sensitivity of the ultrasensitive Doppler technique able to detect subtle hemodynamic changes due to the neurovascular coupling. These resuits suggested that combining microbubbles injections with ultrafast imaging may help to fully compensate for the attenuation from the skull. Indeed, by combining both, we preserved resolution and increased penetration depth. The injection of ultrasound contrast agents has also lead to outstanding resuits in ultrafast ultrasound imaging by breaking the diffraction barrier and move beyond the half-wavelength limit in resolution. We have demonstrated that cerebral microvessels of 9pm in diameter can me distinguished via ultrafast ultrasound localization microscopy (uULM). Millions of blinking sources were localized in space and in time in few seconds in a higher dimensional space, leading to super-resolved images (microbubble density map) of the whole rat brain with a spatial resolution of À/10. Moreover, a displacement vector allowed microbubbles-tracking within frames yielding to in-plane velocity measurements retrieving a large dynamic of cerebral blood velocities. Next, we have exploited how we can spatiotemporally control the vaporization of composite perfluorocarbon (PFC) microdroplets when their activation is triggered by short ultrasound pulses. The concept 'chemistry in-situ' is introduced as we have been able to control a spontaneous chemical reaction in-vitro. Moreover, a new microfluidic device in glass has been proposed to robustly produce monodisperse droplets for future in-vivo applications of the chemistry in situ. This new device presents 128-parallel generators with two pressurized rivers. Eventually, new ultrafast ultrasound monitoring sequences have been developed in order to control and monitor the release of composite droplets

Background: Stroke is a leading cause of significant physical, cognitive, and psychiatric morbidity. One risk factor for stroke is paradoxical embolization through a patent foramen ovale (PFO). In cardiac clinical practice, power M-mode Transcranial Doppler (TCD) evaluation is the gold standard for diagnosis of PFO, or right-to-left cardiac shunt (RLS). Brain micro-embolization due to diagnostic bubble contrast echocardiography may cause neurological symptoms in patients with PFO. However, the neurocognitive effects of TCD have not been studied. Objective: The purpose of this study was to evaluate cognitive outcomes in patients who undergo routine diagnostic bubble contrast TCD. The aims of the study were (1) to determine if cognitive function declines pre- to post-TCD evaluation and, (2) to assess the relationship between cognitive function and severity of the RLS measured using the Spencer Grading System. Methods: One hundred and four participants referred to Sorensen Cardiovascular Group for diagnosis of RLS were evaluated for changes in cognitive functioning at three time points. A dual baseline (pre-test and baseline test) was administered to mitigate practice effects between the first and second administrations. All pre and post-TCD comparisons were analyzed using the baseline test and post-TCD test, controlling for the effects of practice, if present. Results: Practice effects were observed for the working memory task, with significant improvement in working memory scores occurring between the first (pre-test) and second (baseline) administrations. The main effect for shunt group (no shunt vs. moderate-to-severe shunt) and the shunt group by time interactions were not significant for processing speed, attention, or working memory, adjusting for practice effects, age, and education. Migraine did not predict group status for mood or shunt variables. Conclusion: Cardiac patients with both small and large RLS did not experience a decline in processing speed, attention, or working memory ability following TCD, suggesting that TCD-induced microemboli do not result in immediate cognitive deficits in these domains. These findings support the use of TCD for routine evaluation of PFO, even in patients with severe RLS, although findings are limited to young (30s), medically healthy, predominately Caucasian individuals assessed immediately following TCD. Results do not exclude the possibility of cognitive impairment at follow-up, on other cognitive tests, or in other cognitive domains.

Introdução: O ultrassom transcraniano colorido (UTCC) é uma técnica ultrassonográfica que incorpora a imagem do parênquima cerebral à avaliação do fluxo sanguíneo dos vasos do polígono de Willis. Uma de suas maiores limitações é a necessidade de uma janela transtemporal adequada para insonação transcraniana, o que está ausente em cerca de 5-44% dos pacientes. A hiperostose da escama temporal tem sido fortemente associada a falência de janela transtemporal. Objetivamos neste estudo observacional analítico, avaliar a relação entre a a qualidade da janela transtemporal determinada com o UTCC e as características do osso temporal determinada com a tomografia computadorizada de crânio (TC). Materiais e métodos: Trata-se de estudo retrospectivo, analítico, observacional com avaliação de registros médicos onde foram incluídos para análise um total de 187 pacientes com acidente vascular cerebral ou AIT admitidos na Unidade de Emergência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto entre Julho de 2014 e Janeiro de 2015 que realizaram UTCC e TC de acordo com o protocolo institucional. Classificamos a qualidade das janelas dos pacientes com um escore validado em nosso serviço. A análise da espessura e densidade do osso temporal nos exames de TC foi realizada de forma cega para os demais dados clínicos e ultrassonográficos. Resultados: Ausência de Janela temporal bilateral foi encontrada em 21,93% dos pacientes da amostra e destes pacientes (78,05%) foram do sexo feminino p value < 0,0001. A média de idade dos pacientes com presença de Janela temporal foi de 59,9±13,9 anos e as medias de idade dos pacientes sem janela temporal foi de 70,5±12,7 anos com p value <0,001. A área sob a curva ROC para acurácia diagnóstica na detecção de ausência de janela a partir da espessura da escama temporal foi de 0,8232 (0,7504; 0,896) e para o ponto de corte de espessura da escama temporal na ROI de 2,23mm encontramos uma sensibilidade de 0,878 e especificidade de 0,537; Em uma regressão logística univariada, obtivemos que para cada 1 mm de aumento na espessura do osso temporal, obtivemos Odds Ratio (OR) de 4,16 em não se obter janela transtemporal pelo UTCC. Em uma regressão logística multivariada, a espessura da escama temporal em mm (OR : 3,04; IC95%: 1,73-5,35; p: 0,001) idade (OR de 1,07; IC95%: 1,03-1,11; p: 0,003) sexo feminino (OR: 5,99 IC95%:2,09-17,15; p: 0,009) se associaram com ausência da janela transtemporal e a presença de pneumatização óssea na escama do osso temporal (OR: 7,90; IC95%: 1,94-32,04; p: 0,003) se associou com presença da janela transtemporal. Discussão e conclusão: Em concordância com estudos prévios de DTC, os resultados encontrados com a técnica de UTCC sugerem que mulheres idosas possuem maior espessura da escama temporal e por consequência maior taxa de falência de janela transtemporal. Maior espessura do osso temporal e presença de pneumatização do osso temporal são fatores independentes que aumentam a chance de falência de janela transtemporal. A partir da espessura do osso temporal é possível prever a falência de janela transtemporal e assim identificar pacientes elegíveis para a realização do UTCC ou DTC<br>Introduction: Transcranial color Doppler ultrasound (TCDU) is an ultrasonographic technique that incorporates the image of the cerebral parenchyma to evaluate blood flow in the vessels of the Willis polygon. One of its major limitations is the need for a transtemporal window suitable for transcranial insonation, which is absent in about 5-44% of patients. Hyperostosis of the temporal scale has been strongly associated with transtemporal window failure. In this analytical observational study, we aimed to evaluate the association between the quality of the transtemporal window determined with the TCDU and the characteristics of the temporal bone determined by cranial computed tomography (CT). Materials and methods: This was a retrospective, analytical, observational study with evaluation of medical records where a total of 187 patients with stroke or TIA admitted to the Emergency Unit of the Hospital das Clínicas of the Medical School of Ribeirão Preto between July 2014 and January 2015 who underwent TCDU and CT according to the institutional protocol. We rated the quality of patients\' windows with a score validated at our service. Analysis of temporal bone thickness and density on CT scans was performed blindly for other clinical and ultrasonographic data. Results: Absence of bilateral temporal window was found in 21.93% of the patients in the sample and of these patients 78.05% were female p value <0.0001. The mean age of the patients with presence of temporal window was 59.9 ± 13.9 years and the mean age of patients without temporal window was 70.5 ± 12.7 years with p value <0.001. The area under the ROC curve for diagnostic accuracy in the detection of window absence, from the thickness of the temporal bone, was 0.8232 IC 95% (0.7504; 0.896) and for the cutoff point of the temporal scale thickness at ROI of 2.23mm we found a sensitivity of 0.878 and Specificity of 0.537; In a univariate logistic regression, we found that for each 1 mm of increase in temporal bone thickness, there was an odds ratio (OR) of 4.16 of not being able to obtain a transtemporal window by the TCDU. In a univariate logistic regression, we found that for each 1 mm increase in thickness of the temporal bone, obtained odds ratio (OR) of 4.16 to not obtain transtemporal window by the TCDU. In a multivariate logistic regression, the thickness in mm of the temporal scale (OR: 3.04; 95% CI: 1.73 to 5.35; p: 0.001), age (OR 1.07; 95% CI: 1,03 to 1.11, p: 0.003), being female (OR 5.99 95% CI: 2.09 to 17.15, P: 0.009) were associated with the absence of the transtemporal window, and the presence of bone pneumatized scale in the temporal region (OR: 7.90; 95% CI: 1.94 to 32.04, P: 0.003) was associated with the absence of the transtemporal window. Discussion and conclusion: In agreement with previous TCD studies, we have found that older women have a greater thickness of temporal scales and, consequently, a higher rate of transtemporal window failure on TCDU. From temporal bone thickness it is possible to predict transtemporal window failure and therefore to predict those patients with acute stroke that are suitable for UTCC or TCD exams.

Mes travaux de thèse portent sur l’application de l’imagerie fUS (functional ultrasound imaging) à l’imagerie cérébrale préclinique chez le petit animal. Le but était de transformer cette technique d’imagerie cérébrale récente en un véritable outil de quantification de l’état cérébral. Les objectifs principaux ont été de démontrer la faisabilité de l’imagerie fUS chez le petit animal non anesthésié ainsi que de passer du modèle rat au modèle souris - modèle de choix en imagerie préclinique en neurosciences - de surcroît de façon non invasive. J’ai tout d’abord mis au point une nouvelle séquence d’imagerie ultrasonore ultrarapide (Multiplane Wave imaging), permettant d’améliorer le rapport signal-à-bruit des images grâce à l’augmentation virtuelle de l’amplitude du signal émis, sans diminuer la cadence ultrarapide d’acquisition. Dans un deuxième temps j’ai démontré la possibilité d’imager le cerveau de la souris et du jeune rat anesthésiés par échographie Doppler ultrarapide, de manière transcrânienne et complètement non invasive, sans chirurgie ni injection d’agents de contraste. J’ai ensuite mis au point un montage expérimental, une séquence ultrasonore et un protocole expérimental permettant de réaliser de l’imagerie fUS de manière minimalement invasive chez des souris éveillées et libres de leurs mouvements. Enfin, j’ai démontré la possibilité d’utiliser le fUS pour étudier la connectivité fonctionnelle du cerveau au repos (sans stimulus) chez des souris éveillées ou sédatées. L’imagerie fUS et la combinaison « modèle souris » + « minimalement invasif » + « animal éveillé » + « connectivité fonctionnelle » constituent un outil précieux pour la communauté des neuroscientifiques travaillant sur des modèles animaux pathologiques ou de nouvelles molécules pharmacologiques<br>My work focuses on the application of fUS (functional ultrasound) imaging to preclinical brain imaging in small animals. The goal of my thesis was to turn this recent vascular brain imaging technique into a quantifying tool for cerebral state. The main objectives were to demonstrate the feasibility of fUS imaging in the non-anaesthetized small rodents and to move from rat model imaging to mouse model imaging –most used model for preclinical studies in neuroscience-, while developing the least invasive imaging protocols. First, I have developed a new ultrafast ultrasonic imaging sequence (Multiplane Wave imaging), improving the image signal-to-noise ratio by virtually increasing emitted signal amplitude, without reducing the ultrafast framerate. Then, I have demonstrated the possibility to use ultrafast Doppler ultrasound imaging to image both the mouse brain and the young rat brain, non-invasively and through the intact skull, without surgery or contrast agents injection. Next, I have developed an experimental setup, an ultrasound sequence and an experimental protocol to perform minimally invasive fUS imaging in awake and freely-moving mice. Finally, I have demonstrated the possibility to use fUS imaging to study the functional connectivity of the brain in a resting state in awake or sedated mice, still in a transcranial and minimally invasive way. fUS imaging and the combination of "mouse model" + "minimally invasive" + "awake animal" + "functional connectivity" represent a very promising tool for the neuroscientist community working on pathological animal models or new pharmacological molecules

The use of transcranial Doppler (TCD) ultrasound for the assessment of cerebral blood flow velocity (CBFV) provides an indication of cerebral blood flow assuming the diameter of the insonated vessel remains constant. Studies using TCD have traditionally described cerebrovascular hemodynamics with respect to CBFV and cerebrovascular resistance (CVRi); however, a more complete assessment of the cerebral circulation can be gleaned from the analysis of within beat characteristic of the TCD velocity waveform for the determination of cerebrovascular tone. Therefore, the general purpose of the presented studies was to assess CBFV responses and within beat characteristic for the description of cerebrovascular hemodynamics after long duration spaceflight, with sustained orthostasis, in response to changes in the partial pressure of end tidal carbon dioxide (PETCO2), and with NG stimulation. After long duration spaceflight, cerebrovascular autoregulation was found to be impaired along with a reduction in cerebrovascular CO2 reactivity (Study 1). Additionally, critical closing pressure (CrCP) was found to be increased suggesting potential remodelling of the cerebrovasculature contributing to an increase in cerebrovascular tone (Study 2). With sustained orthostasis, CBFV was found to progressively decrease and to be related to reductions in PETCO2 and increases in CrCP suggesting the contribution of changes in cerebrovascular tone leading to the development of syncope (Study 4). The CBFV reduction with the progression towards syncope was also associated with changes in waveform morphology such that the dicrotic notch point was less than the end diastolic value (Study 3). Mathematical modelling (RCKL) was used to further assess changes in cerebrovascular hemodynamics for physiological interpretation of changes in CBFV waveform morphology and found that the amplitude of the dicrotic notch and the calculation of the augmentation index were both significantly related to vascular compliance before and after stimulation with NG (Study 5). The use of quantitative assessments of common carotid artery (CCA) blood flow as an indicator of cerebral blood flow suggested the dilation of the middle cerebral artery (MCA) with NG (Study 5 and 6) and changes in MCA diameter with acute alterations in PETCO2 (Study 6). CCA and MCA velocity wave morphology were assessed showing that with changes in PETCO2, changes in CBFV velocity wave were not reflected in the CCA trace (Study 7). In addition, further assessment of the CBFV velocity trace and the calculation of CrCP and the augmentation index suggested that with changes in PETCO2 cerebrovascular compliance and cerebrovascular tension, both thought to be components of cerebrovascular tone, change independently (Study 7). Combined, the results of the presented studies suggest that changes in cerebrovascular hemodynamics can be determined from alterations in the CBFV velocity waveform morphology. However, further work is required to determine how these variations relate to specific components of cerebrovascular tone, including alterations in cerebrovascular compliance and vascular tension, and how these variables change with acute and chronic alterations in cerebrovascular hemodynamics.

We investigated an emerging brain-computer interface (BCI) modality, namely, transcranial Doppler ultrasonography (TCD), which measures cerebral blood flow velocity. We hypothesized that a bilateral TCD-driven online BCI would be able to dichotomously classify a user’s intentions with at least 70% accuracy. To test this hypothesis, we had three objectives: (1) to develop a signal classifier that yielded high (>80%) offline accuracies; (2) to develop an online TCD-BCI system with an onscreen keyboard; and, (3) to determine the achievable online accuracy with able-bodied participants. With a weighted, forward feature selection and a Naïve Bayes classifier, sensitivity and specificity of 81.44 ± 8.35% and 82.30 ± 7.39%, respectively, were achieved in the online differentiation of two mental tasks. The average information transfer rate and throughput of the system were 0.87 bits/min and 0.35 ± 0.18 characters/min, respectively. These promising online results encourage future testing of TCD-BCI systems with the target population.

Brain diseases including neurological disorders and tumors remain undertreated due to the challenge in accessing the brain, and blood-brain barrier (BBB) restricting drug delivery, which also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with acoustic agents including microbubbles and nanodroplets remains as the only method to open the BBB noninvasively, locally, and transiently to assist drug delivery. For an ideal medical system to serve a broad patient population, it requires precise and flexible targeting with simulation to personalize treatment, real-time monitoring to ensure safety and effectiveness, and rapid application, as repetitive pharmacological treatment is often required. Since none of current systems fulfills all the requirements, here we designed a neuronavigation-guided FUS system with protocol assessed in in vivo mice, in vivo non-human primates, and human skulls from in silico preplanning, online FUS treatment and real-time acoustic monitoring and mapping, to post-treatment assessment using MRI. Both sedate and awake non-human primates were evaluated with total treatment time averaging 30 min and 3-mm targeting accuracy in cerebral cortex and subcortical structures. The FUS system developed would enable transcranial FUS in patients with high accuracy and independent of MRI guidance.

Research Doctorate - Doctor of Philosophy (PhD)<br>In the last two decades there have been substantial advances in the development of virtual reality (VR) technology for various applications such as entertainment, education and training. However, limited knowledge is available about the side effects of this technology including cybersickness - a form of motion sickness that is caused by immersion in VR. My present study is aimed at providing an insight into cybersickness in order to better understand the physiological characteristics of this averse phenomenon. In this study, a total of 79 healthy volunteers (41 females, 38 males) were exposed to cybersickness provoking VR content (virtual ride on a rollercoaster using Oculus Rift head-mounted display) in four independent research experiments. In the first experiment (described in Chapter 2), we investigated the symptom profile of cybersickness and explored if desensitization can occur with repetitive exposure. We found that gastrointestinal symptoms such as nausea are the most common symptoms associated with cybersickness followed by other - central, peripheral and sopite-like symptoms. We found that these symptoms can last over 3 hours after exposure. Our results clearly demonstrate that repetitive exposure to virtual environments can result in habituation to cybersickness. Our findings demonstrate that forehead sweating increases significantly with increasing nausea and therefore, forehead sweating can be a reliable biomarker for cybersickness in general and nausea in particular. In the second experiment (described in Chapter 3), we examined the effects of visual content on the intensity of cybersickness symptoms. We found that changes in the direction of visual flow of the same VR content has a significant effect on the severity of sickness such that moving forward in a virtual environment is more provocative than moving backward. In the third experiment (described in Chapter 4), two different imaging modalities were used to analyse brain hemodynamic during cybersickness. We found that cybersickness is associated with variations in brain activity (region-specific increases and decreases) in a complex network in numerous cortical regions related to the cognitive, evaluative and sensory discriminative aspects of this syndrome. Our results demonstrate that overall sensitivity to cybersickness was significantly higher in females than males. In the fourth experiment (described in Chapter 5), we compared the subjective symptoms and physiological effects of cybersickness induced by virtual reality and “classic” motion sickness triggered by vestibular stimulation (Coriolis cross-coupling). We found that despite fundamental differences in provoking stimuli, cybersickness and motion sickness are clinically identical. We conclude that cybersickness is a complex syndrome, and that its symptoms and physiological effects are far beyond the common gastrointestinal symptoms. My work represents detailed characterisation of symptoms and physiological changes that accompany cybersickness. The major impact of my work is, firstly, in the identification of a selective and sensitive biomarker that will allow detection, monitoring and quantification of cybersickness in future studies. Secondly, my finding of similarity between cybersickness and “classical” motion sickness opens opportunity for translational work, namely developing of a simple test for assessing motion sickness susceptibility, and a novel approach for motion sickness desensitization.