Cerebral Hemodynamics in High-Risk Neonates Probed by Diffuse Optical Spectroscopies

Advances in medical and surgical care of the critically ill neonates have decreasedmortality, yet a significant number of these neonates suffer from neurodevelopmentaldelays and failure in school. Thus, clinicians are now focusing on prevention ofneurologic injury and improvement of neurocognitive outcome in these high-risk infants. Assessment of cerebral oxygenation, cerebral blood volume, and the regulation of cerebral blood flow (CBF) during the neonatal period is vital for evaluating brain health. Traditional CBF imaging methods fail, however, for both ethical and logistical reasons. In this dissertation, I demonstrate the use of non-invasive optical modalities, i.e., diffuse optical spectroscopy and diffuse correlation spectroscopy, to study cerebral oxygenation and cerebral blood flow in the critically ill neonatal population. The optical techniques utilize near-infrared (NIR) light to probe the static and dynamic physiological properties of deep tissues. Diffuse correlation spectroscopy (DCS) employs the transport of temporal correlation functions of diffusing light to extract relative changes in blood flow in biological tissues. Diffuse optical spectroscopy (DOS) employs the wavelength-dependent attenuation of NIR light to assess the concentrations of the primary chromophores in the tissue, namely oxy- and deoxy-hemoglobin. This dissertation presents both validation and clinical applications of novel diffuse optical spectroscopies in two specific critically ill neonatal populations: very-low birth weight preterm infants,and infants born with complex congenital heart defects. For validation of DCS in neonates, the blood flow index quantified by DCS is shown to correlate well with velocity measurements in the middle cerebral artery acquired by transcranial Doppler ultrasound. In patients with congenital heart defects DCS-measured relative changes in CBF due to hypercapnia agree strongly with relative changes in blood flow in the jugular veins as measured by phase-encoded velocity mapping magnetic resonance. For applications in the clinic, CO2 reactivity in patients with congenital heart defects prior to various stages of reconstructive surgery was quantified; our initial results suggest that CO2 reactivity is not systematically related to brain injury in this population. Additionally, the cerebral effects of various interventions, such as blood transfusion and sodium bicarbonate infusion, were investigated. In preterm infants, monitoring with DCS reveals a resilience of these patients to maintain constant CBF during a small postural manipulation

Multi-Contrast Photoacoustic Computed Tomography

Imaging of small animals has played an indispensable role in preclinical research by providing high dimensional physiological, pathological, and phenotypic insights with clinical relevance. Yet pure optical imaging suffers from either shallow penetration (up to ~1–2 mm) or a poor depth-to-resolution ratio (~3), and non-optical techniques for whole-body imaging of small animals lack either spatiotemporal resolution or functional contrast. A stand-alone single-impulse photoacoustic computed tomography (PACT) system has been built, which successfully mitigates these limitations by integrating high spatiotemporal resolution, deep penetration, and full-view fidelity, as well as anatomical, dynamical, and functional contrasts. Based on hemoglobin absorption contrast, the whole-body dynamics and large scale brain functions of rodents have been imaged in real time. The absorption contrast between cytochrome and lipid has enabled PACT to resolve MRI-like whole brain structures. Taking advantage of the distinct absorption signature of melanin, unlabeled circulating melanoma cells have been tracked in real time in vivo. Assisted by near-infrared dyes, the perfusion processes have been visualized in rodents. By localizing single-dyed droplets, the spatial resolution of PACT has been improved by six-fold in vivo. The migration of metallic-based microrobots toward the targeted regions in the intestines has been monitored in real time. Genetically encoded photochromic proteins benefit PACT in detection sensitivity and specificity. The unique photoswitching characteristics of different photochromic proteins allow quantitative multi-contrast imaging at depths. A split version of the photochromic protein has permitted PA detection of protein-protein interactions in deep-seated tumors. The photochromic behaviors have also been utilized to guide photons to form an optical focus inside live tissue. As a rapidly evolving imaging technique, PACT promises pre-clinical applications and clinical translation.</p

Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model

It recently has been demonstrated that magnetic resonance imaging can be used to map changes in brain hemodynamics produced by human mental operations. One method under development relies on blood oxygenation level-dependent (BOLD) contrast: a change in the signal strength of brain water protons produced by the paramagnetic effects of venous blood deoxyhemoglobin. Here we discuss the basic quantitative features of the observed BOLD-based signal changes, including the signal amplitude and its magnetic field dependence and dynamic effects such as a pronounced oscillatory pattern that is induced in the signal from primary visual cortex during photic stimulation experiments. The observed features are compared with the results of Monte Carlo simulations of water proton intravoxel phase dispersion produced by local field gradients generated by paramagnetic deoxyhemoglobin in nearby venous blood vessels. The simulations suggest that the effect of water molecule diffusion is strong for the case of blood capillaries, but, for larger venous blood vessels, water diffusion is not an important determinant of deoxyhemoglobin-induced signal dephasing. We provide an expression for the apparent in-plane relaxation rate constant (R2*) in terms of the main magnetic field strength, the degree of the oxygenation of the venous blood, the venous blood volume fraction in the tissue, and the size of the blood vessel

頭部構造と各層内血流変化が光マッピング画像に及ぼす影響

Optical mapping has been applied to image brain activation two-dimensionally along the head surface by detecting the intensity changes of light that passes through the brain. In optical mapping for imaging brain activity, it is assumed that the head tissue is spatially homogeneous and temporally invariable except the activated region in the brain. However, in the superficial layers above the brain, the tissues are inhomogeneous and vary hemodynamically. Furthermore, light propagation and the optical pathlength inside the head are highly dependent on the anatomy and physiology in the head. In particular, the spatial variations in the thickness of skull and cerebrospinal fluid (CSF) layers, the existence of the blood vessels and the hemodynamic changes in the superficial layers such as the CSF and skin layers would have significant influences on light propagation and would result in the difference in the mapping images. However, itis difficult to know these influences by in vivo experiments. The aim of this study is to investigate these influences by numerical and experimental methods. Three-dimensional head models are used to simulate light propagation in the head by solving the photon diffusion equation using the finite element method (FEM), and the optical mapping images are constructed from the simulated measurement data. Tissue-mimicking phantoms with spatially varying thickness and changeable optical properties of head layers were also developed and multi-channel near-infrared spectroscopy (NIRS) experiments were performed on the dynamic phantoms. In the numerical simulations and phantom experiments, the changes in the optical densities (ΔOD) due to activated regions are obtained to construct the mapping images, and the light path probability distributions between one pair of source and detector are calculated to show the sensitivity of the tissue regions to the mapping images. As theresults, the influences of (1) the spatial variations of the skull and CSF layers and (2) the blood volume changes in the skin and CSF layers on the mapping images of brain activities are investigated quantitatively. The optical mapping for the single or multiple activated regions and the effects of the position of the activated regions relative to theprobe arrays on mapping images are also discussed. The quantitative results about the influences of the superficial layers in this study provide information for compensating the optical mapping images among different individuals or different head regions in an individual. In vivo experiments considering the influences of structural and hemodynamic differences in the superficial layers onoptical mapping remain as a future subject.電気通信大学201

Label-free photoacoustic tomography of whole mouse brain structures ex vivo

Capitalizing on endogenous hemoglobin contrast, photoacoustic-computed tomography (PACT), a deep-tissue high-resolution imaging modality, has drawn increasing interest in neuroimaging. However, most existing studies are limited to functional imaging on the cortical surface and the deep brain structural imaging capability of PACT has never been demonstrated. Here, we explicitly studied the limiting factors of deep brain PACT imaging. We found that the skull distorted the acoustic signal and blood suppressed the structural contrast from other chromophores. When the two effects are mitigated, PACT can potentially provide high-resolution label-free imaging of structures in the entire mouse brain. With 100-μm in-plane resolution, we can clearly identify major structures of the brain, which complements magnetic resonance microscopy for imaging small-animal brain structures. Spectral PACT studies indicate that structural contrasts mainly originate from cytochrome distribution and that the presence of lipid sharpens the image contrast; brain histology results provide further validation. The feasibility of imaging the structure of the brain in vivo is also discussed. Our results demonstrate that PACT is a promising modality for both structural and functional brain imaging

Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities

New Advances in Susceptibility Weighted MRI to Determine Physiological Parameters

Die Magnetresonanztomographie bietet die Möglichkeit der Bestimmung des Blutoxygenierungsgrades kleiner venöser Gefäße und damit lokaler Hirnareale mit Hilfe einer Multiecho-Gradientenecho-Sequenz. Mit dieser Sequenz kann der Signalzerfall in einem Voxel, welches von einer einzelnen Vene bzw. von Blutkapillaren durchzogen ist, bestimmt werden. Der Signalzerfall ist charakteristisch für die von der Vene oder den Kapillaren erzeugten Feldinhomogenitäten, so dass sich Aussagen über den Blutoxygenierungsgrad und Blutvolumenanteil treffen lassen. Durch Fitten simulierter Signalverläufe an gemessene Phantom- und Probandendaten konnte gezeigt werden, dass es mit der hier vorgestellten Methode möglich ist, den venösen Blutoxygenierungsgrad zu quantifizieren. Weiterhin konnte eine durch gezielte Modulation des zerebralen Blutflusses hervorgerufene Änderung der Blutoxygenierung in vivo nachgewiesen werden. Die Erweiterung des Modells eines einzelnen Gefäßes auf ein Gefäßnetzwerk diente als Grundlage zur theoretischen Beschreibung der Blutkapillaren, die das Hirngewebe durchziehen und mit Sauerstoff versorgen. Dieses Netzwerkmodel konnte in Phantomexperimenten verifiziert werden. Dagegen zeigte sich bei einer Probandenmessung, dass es nicht möglich ist einzig anhand des gemessenen Signalverlaufs valide Werte für die Blutoxygenierung und den Blutvolumenanteil eindeutig zu bestimmen. Die hohe Korrelation zwischen beiden Parametern bewirkt, dass mehrere Paare von Oxygenierungs- und Volumenwerten passende Signalkurven liefern. Eine unabhängige Quantifizierung oder Abschätzung des venösen Blutvolumens kann hier helfen eindeutige Oxygenierungswerte zu erhalten. Im Rahmen der vorliegenden Dissertation konnte das Signalverhalten von suszeptibilitätssensitiven Messungen in der Magnetresonanztomographie genauer untersucht und eine Methode zur nicht-invasiven Bestimmung der venösen Blutoxygenierung an einzelnen Gefäßen entwickelt werden. Erste in vivo Ergebnisse des Gefäßnetzwerkes verdeutlichen, dass für eine genaue Quantifizierung der Blutoxygenierung weitere Parameter, wie das Blutvolumen, unabhängig bestimmt werden müssen. Dennoch ist es möglich, die Methode am einzelnen Blutgefäß zur besseren Charakterisierung von Pathologien sowie physiologischen Änderungen, z.B. bei der funktionellen Magnetresonanztomographie, einzusetzen.Magnetic resonance imaging allows to determine the blood oxygenation level of small venous vessels or the blood capillary network by evaluating the magnetic resonance signal acquired with multi-echo gradient-echo sequences. The signal formation of a voxel traversed by a vein or interspersed with capillaries shows a characteristic decay or modulation as a function of time from which the blood oxygenation and blood volume fraction can be derived. It could be demonstrated in phantom measurements that the signal of a single vessel traversed voxel correctly matched the calculations of numerical signal simulation. By fitting the signal simulation to in vivo measurements of cerebral venous vessels, vessel size and venous blood oxygenation was determined quantitatively. Furthermore, it was possible to detect and to quantify a physiologically induced change in cerebral venous blood oxygenation. To describe the signal of the blood capillary network in normal brain matter, an extension of the single vessel model to a vessel network was applied. This network model was also validated in phantom experiments. As a result of these investigations it was found that the two parameters describing the network, the blood volume fraction and blood oxygenation level, are correlated to each other and can not be separated without additional information by simply fitting the signal simulation to the measurement. This finding was of special importance in the initial in vivo measurements conducted in the present work. Where, independent blood volume determination may help to further validate the quantified blood oxygenation level. In the present work a non-invasive method was developed to quantify cerebral blood oxygenation levels in single veins. This was possible by investigating the signal evolution of susceptibility sensitive magnetic resonance imaging. The initial result of the vessel network signal reveals, that for obtaining a valid blood oxygenation level, the volume fraction has to be further determined by an independent measurement. Nevertheless, is has been demonstrated that the quantification of the blood oxygenation level in single venous vessels is possible and can be applied in clinical diagnosis for better characterization of cerebral pathologies or in physiological investigations, like in functional magnetic resonance imaging

High-Field Functional MRI from the Perspective of Single Vessels in Rats and Humans

Functional MRI (fMRI) has been employed to map brain activity and connectivity based on the neurovascular coupled hemodynamic signal. However, in most cases of fMRI studies, the cerebral vascular hemodynamic signal has been imaged in a spatially smoothed manner due to the limit of spatial resolution. There is a need to improve the spatiotemporal resolution of fMRI to map dynamic signal from individual venule or individual arteriole directly. Here, the thesis aims to provide a vascular-specific view of hemodynamic response during active state or resting state. To better characterize the temporal features of task-related fMRI signal from different vascular compartments, we implemented a line-scanning method to acquire vessel-specific blood-oxygen-level-dependent (BOLD) / cerebral-blood-volume (CBV) fMRI signal at 100-ms temporal resolution with sensory or optogenetic stimulation. Furthermore, we extended the line-scanning method with multi-echo scheme to provide vessel-specific fMRI with the higher contrast-to-noise ratio (CNR), which allowed us to directly map the distinct evoked hemodynamic signal from arterioles and venules at different echo time (TE) from 3 ms to 30 ms. The line-scanning fMRI methods acquire single k-space line per TR under a reshuffled k space acquisition scheme which has the limitation of sampling the fMRI signal in real-time for resting-state fMRI studies. To overcome this, we implemented a balanced Steady-state free precession (SSFP) to map task-related and resting-state fMRI (rsfMRI) with high spatial resolution in anesthetized rats. We reveal venule-dominated functional connectivity for BOLD fMRI and arteriole-dominated functional connectivity for CBV fMRI. The BOLD signal from individual venules and CBV signal from individual arterioles show correlations at an ultra-slow frequency (< 0.1 Hz), which are correlated with the intracellular calcium signal measured in neighboring neurons. In complementary data from awake human subjects, the BOLD signal is spatially correlated among sulcus veins and specified intracortical veins of the visual cortex at similar ultra-slow rhythms. This work provides a high-resolution fMRI approach to resolve brain activation and functional connectivity at the level of single vessels, which opened a new avenue to investigate brian functional connectivity at the scale of vessels