Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE

Machine learning approaches for early prediction of hypertension.

Hypertension afflicts one in every three adults and is a leading cause of mortality in 516, 955 patients in USA. The chronic elevation of cerebral perfusion pressure (CPP) changes the cerebrovasculature of the brain and disrupts its vasoregulation mechanisms. Reported correlations between changes in smaller cerebrovascular vessels and hypertension may be used to diagnose hypertension in its early stages, 10-15 years before the appearance of symptoms such as cognitive impairment and memory loss. Specifically, recent studies hypothesized that changes in the cerebrovasculature and CPP precede the systemic elevation of blood pressure. Currently, sphygmomanometers are used to measure repeated brachial artery pressure to diagnose hypertension after its onset. However, this method cannot detect cerebrovascular alterations that lead to adverse events which may occur prior to the onset of hypertension. The early detection and quantification of these cerebral vascular structural changes could help in predicting patients who are at a high risk of developing hypertension as well as other cerebral adverse events. This may enable early medical intervention prior to the onset of hypertension, potentially mitigating vascular-initiated end-organ damage. The goal of this dissertation is to develop a novel efficient noninvasive computer-aided diagnosis (CAD) system for the early prediction of hypertension. The developed CAD system analyzes magnetic resonance angiography (MRA) data of human brains gathered over years to detect and track cerebral vascular alterations correlated with hypertension development. This CAD system can make decisions based on available data to help physicians on predicting potential hypertensive patients before the onset of the disease

Doctor of Philosophy

dissertationHigh arterial tortuosity, or twistedness, is a sign of many vascular diseases. Some ocular diseases are clinically diagnosed in part by assessment of increased tortuosity of ocular blood vessels. Increased arterial tortuosity is seen in other vascular diseases but is not commonly used for clinical diagnosis. This study develops the use of existing magnetic resonance angiography (MRA) image data to study arterial tortuosity in a range of arteries of hypertensive and intracranial aneurysm patients. The accuracy of several centerline extraction algorithms based on Dijkstra's algorithm was measured in numeric phantoms. The stability of the algorithms was measured in brain arteries. A centerline extraction algorithm was selected based on its accuracy. A centerline tortuosity metric was developed using a curve of tortuosity scores. This tortuosity metric was tested on phantoms and compared to observer-based tortuosity rankings on a test data set. The tortuosity metric was then used to measure and compare with negative controls the tortuosity of brain arteries from intracranial aneurysm and hypertension patients. A Dijkstra based centerline extraction algorithm employing a distance-from-edge weighted center of mass (DFE-COM) cost function of the segmented arteries was selected based on generating 15/16 anatomically correct centerlines in a looping artery iv compared to 15/16 for the center of mass (COM) cost function and 7/16 for the inverse modified distance from edge cost function. The DFE-COM cost function had a lower root mean square error in a lopsided phantom (0.413) than the COM cost function (0.879). The tortuosity metric successfully ordered electronic phantoms of arteries by tortuosity. The tortuosity metric detected an increase in arterial tortuosity in hypertensive patients in 13/13 (10/13 significant at α = 0.05). The metric detected increased tortuosity in a subset of the aneurysm patients with Loeys-Dietz syndrome (LDS) in 7/7 (three significant at α = 0.001). The tortuosity measurement combination of the centerline algorithm and the distance factor metric tortuosity curve was able to detect increases in arterial tortuosity in hypertensives and LDS patients. Therefore the methods validated here can be used to study arterial tortuosity in other hypertensive population samples and in genetic subsets related to LDS

Multiscale imaging of the mouse cortex using two-photon microscopy and wide-field illumination

The mouse brain can be studied over vast spatial scales ranging from microscopic imaging of single neurons to macroscopic measurements of hemodynamics acquired over the majority of the mouse cortex. However, most neuroimaging modalities are limited by a fundamental trade-off between the spatial resolution and the field-of-view (FOV) over which the brain can be imaged, making it difficult to fully understand the functional and structural architecture of the healthy mouse brain and its disruption in disease. My dissertation has focused on developing multiscale optical systems capable of imaging the mouse brain at both microscopic and mesoscopic spatial scales, specifically addressing the difference in spatial scales imaged with two-photon microscopy (TPM) and optical intrinsic signal imaging (OISI). Central to this work has been the formulation of a principled design strategy for extending the FOV of the two-photon microscope. Using this design approach, we constructed a TPM system with subcellular resolution and a FOV area 100 times greater than a conventional two-photon microscope. To image the ellipsoidal shape of the mouse cortex, we also developed the microscope to image arbitrary surfaces within a single frame using an electrically tunable lens. Finally, to address the speed limitations of the TPM systems developed during my dissertation, I also conducted research in large-scale neural phenomena occurring in the mouse brain imaged with high-speed OISI. The work conducted during my dissertation addresses some of the fundamental principles in designing and applying optical systems for multiscale imaging of the mouse brain

Using Computed Tomography Perfusion to Evaluate the Blood-Brain-Barrier and Blood-Tumor-Barrier Response following Focused Ultrasound Sonication with Microbubble Administration

The blood-brain-barrier (BBB) is the single most limiting factor in the delivery of neurotherapeutics into the brain. Focused ultrasound sonication combined with intravenous microbubble administration (FUSwMB) is a novel technique that can transiently disrupt the BBB, with minimal vascular or tissue damage, allowing for localized drug delivery over the targeted region. The goals of this thesis are to: 1) use computed tomography (CT) perfusion to measure the permeability surface area product (PS) following USwMB in normal rabbits with an intact BBB, and 2) to evaluate the blood-tumor-barrier (BTB) PS response following FUSwMB in a C6 rat glioma model

Magneettikuvauksella ohjattu korkean intensiteetin kohdennettu ultraääniteknologia syöpätautien liitännäishoidoissa ja syöpälääkkeiden annostelussa

Ablative hyperthermia (more than 55 °C) has been used as a stand-alone treatment for accessible solid tumors not amenable to surgery, whereas mild hyperthermia (40-45 °C) has been shown effective as an adjuvant for both radiotherapy and chemotherapy. An optimal mild hyperthermia treatment is noninvasive and spatially accurate, with precise and homogeneous heating limited to the target region. High-intensity focused ultrasound (HIFU) can noninvasively heat solid tumors deep within the human body. Magnetic resonance imaging (MRI) is ideal for HIFU treatment planning and monitoring in real time due to its superior soft-tissue contrast, high spatial imaging resolution, and the ability to measure temperature changes. The combination of MRI and HIFU therapy is known as magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU). Low temperature-sensitive liposomes (LTSLs) release their drug cargo in response to heat (more than 40 °C) and may improve drug delivery to solid tumors when combined with mild hyperthermia. MR-HIFU provides a way to image and control content release from imageable low-temperature sensitive liposomes (iLTSLs). This ability may enable spatiotemporal control over drug delivery - a concept known as drug dose painting. The objectives of this dissertation work were to develop and implement a clinically relevant volumetric mild hyperthermia heating algorithm, to implement and characterize different sonication approaches (multiple foci vs. single focus), and to evaluate the ability to monitor and control heating in real time using MR-HIFU. In addition, the ability of MR-HIFU to induce the release of a clinical-grade cancer drug encapsulated in LTSLs was investigated, and the potential of MR-HIFU mediated mild hyperthermia for clinical translation as an image-guided drug delivery method was explored. Finally, drug and contrast agent release of iLTSLs as well as the ability of MR-HIFU to induce and monitor the content release were examined, and a computational model that simulates MR-HIFU tissue heating and drug delivery was validated. The combination of a multifoci sonication approach and the mild hyperthermia heating algorithm resulted in precise and homogeneous heating limited to the targeted region both in vitro and in vivo. Heating was more spatially confined compared to the use of single focus sonication method. The improvement in spatial control suggests that multifoci heating is a useful tool in MR-HIFU mediated mild hyperthermia applications for clinical oncology. Using the mild hyperthermia heating algorithm, LTSL + MR-HIFU resulted in significantly higher tumor drug concentrations compared to free drug and LTSL alone. This technique has potential for clinical translation as an image-guided drug delivery method. MR-HIFU also enabled real-time monitoring and control of iLTSL content release. Finally, computational models may allow quantitative in silico comparison of different MR-HIFU heating algorithms as well as facilitate therapy planning for this drug delivery technique.Ablatiivista hypertermiaa (yli 55 °C) on perinteisesti käytetty leikkauksiin soveltumattomien kasvainten hoitoon. Lievän hypertermian (40-45 °C) on sen sijaan todettu olevan tehokas liitännäishoito syöpätautien säde- ja lääkehoidoille. Suotuisa hypertermiahoito on kajoamatonta ja täsmällisesti kohdistettua. Lämmityksen tulisi lisäksi olla tarkkaa, tasalaatuista ja kohdealueeseen rajoittunutta. Korkean intensiteetin kohdennettu ultraääni (HIFU) -hoito mahdollistaa kasvainten kajoamattoman lämmityksen. Magneettikuvauksen (MK) etuina ovat erinomainen pehmytkudoskontrasti, korkea paikkaresoluutio ja kyky mitata lämpötilan muutoksia. Näin ollen MK soveltuu erinomaisesti HIFU -hoitojen suunnitteluun ja seurantaan. MK:n ja HIFU:n yhdistelmää kutsutaan magneettikuvauksella ohjatuksi korkean intensiteetin kohdennetuksi ultraääniteknologiaksi (MR-HIFU). Lämpötilaherkät liposomit ovat suunniteltuja vapauttamaan lääkeainesisältönsä hieman normaalia ruumiinlämpötilaa korkeammissa lämpötiloissa (yli 40 °C). Yhdessä lievän hypertermian kanssa tämänkaltaiset liposomit voivat mahdollistaa kohdistetun lääkeaineen vapauttamisen. Liposomien sisällön vapautumisen tarkkailu voi myös mahdollistaa tarkan lääkemäärän kohdistetun annostelun kasvaimessa. Väitöskirjatyössä kehitettiin kliinisesti merkittävä lämmitysalgoritmi lievän hypertermian aikaansaamiseksi, toteutettiin usean samanaikaisen kohteen sonikaatio (ultraäänialtistus) menetelmä sekä arvioitiin algoritmin ja menetelmän kykyä kontrolloida kudoksen lämpötilaa käyttäen kliinistä MR-HIFU laitetta. Lisäksi tutkittiin HIFU:n kykyä vapauttaa lääkeaine lämpötilaherkistä liposomeista, karakterisoitiin lääke- ja kontrastiaineen vapautuminen kuvannettavissa olevista lämpötilaherkistä liposomeista sekä tarkasteltiin MR-HIFU:lla aikaansaadun lievän hypertermian potentiaalia kohdentaa lääkeaineen vapautuminen kasvaimeen. Tässä työssä myös validoitiin laskennallinen malli, joka simuloi MR-HIFU:lla aikaansaatua lämmitystä ja siitä johtuvaa lääkeaineen vapautumista, sekä todennettiin MR-HIFU:n sopivuus lämpöablaatioon perustuvaan kohdun pehmytkudoskasvainten hoitomenelmään kliinisessä käytössä. Lievän hypertermian lämmitysalgoritmi yhdessä usean kohteen sonikaatiomenetelmän kanssa tuotti täsmällisen, tasalaatuisen sekä paikallisesti rajoitetun lämmityksen kohdealueessa. Usean kohteen sonikaatiomenetelmä voi siis olla hyödyllinen työkalu MR-HIFU:n lievän hypertermian syöpähoidon sovelluksissa. MR-HIFU yhdessä lämpötilaherkkien liposomien kanssa sai aikaan merkittävästi korkeamman kasvaimen lääkeainekonsentraation verrokkiryhmiin nähden, ja saattaa siten soveltua kliiniseen käyttöön kuvantamisavusteisena lääkehoitona. Liposomien sisällön (lääkeaine + MK-kontrastiaine) vapautumisen kuvannettavuus merkitsee, että MR-HIFU saattaa lisäksi mahdollistaa tarkan lääkeannoksen kohdistetun vapauttamisen