Neural magnetic field dependent fMRI toward direct functional connectivity measurements: A phantom study

Recently, the main issue in neuroscience has been the imaging of the functional connectivity in the brain. No modality that can measure functional connectivity directly, however, has been developed yet. Here, we show the novel MRI sequence, called the partial spinlock sequence toward direct measurements of functional connectivity. This study investigates a probable measurement of phase differences directly associated with functional connectivity. By employing partial spinlock imaging, the neural magnetic field might influence the magnetic resonance signals. Using simulation and phantom studies to model the neural magnetic fields, we showed that magnetic resonance signals vary depending on the phase of an externally applied oscillating magnetic field with non-right flip angles. These results suggest that the partial spinlock sequence is a promising modality for functional connectivity measurements

Methods for functional brain imaging

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011.Cataloged from PDF version of thesis.Includes bibliographical references.Magnetic resonance imaging (MRI) has demonstrated the potential for non-invasive mapping of structure and function (fMRI) in the human brain. In this thesis, we propose a series of methodological developments towards improved fMRI of auditory processes. First, the inefficiency of standard fMRI that acquires brain volumes one slice at a time is addressed. The proposed single-shot method is capable, for the first time, of imaging the entire brain in a single-acquisition while still maintaining adequate spatial resolution for fMRI. This method dramatically increases the temporal resolution of fMRI (20 fold) and improves sampling efficiency as well as the ability to discriminate against detrimental physiological noise. To accomplish this it exploits highly accelerated parallel imaging techniques and MRI signal detection with a large number of coil elements. We then address a major problem in the application of fMVIRI to auditory studies. In standard fMRI, loud acoustic noise is generated by the rapid switching of the gradient magnetic fields required for image encoding, which interferes with auditory stimuli and enforces inefficient and slow sampling strategies. We demonstrate a fMRI method that uses parallel imaging and redesigned gradient waveforms to both minimize and slow down the gradient switching to substantially reduce acoustic noise while still enabling rapid acquisitions for fMRI. Conventional fMRI is based on a hemodynamic response that is secondary to the underlying neuronal activation. In the final contribution of this thesis, a novel image contrast is introduced that is aimed at the direct observation of neuronal magnetic fields associated with functional activation. Early feasibility studies indicate that the imaging is sensitive to oscillating magnetic fields at amplitudes similar to those observed by magnetoencephalography.by Thomas Witzel.Ph.D

Novel MRI Technologies for Structural and Functional Imaging of Tissues with Ultra-short T₂ Values

Conventional MRI has several limitations such as long scan durations, motion artifacts, very loud acoustic noise, signal loss due to short relaxation times, and RF induced heating of electrically conducting objects. The goals of this work are to evaluate and improve the state-of-the-art methods for MRI of tissue with short T₂, to prove the feasibility of in vivo Concurrent Excitation and Acquisition, and to introduce simultaneous electroglottography measurement during functional lung MRI

MRI-Based Communication with Untethered Intelligent Medical Microrobots

RESUME Les champs magnétiques présent dans un système clinique d’Imagerie par Résonance Magnétique (IRM) peuvent être exploités non seulement, afin d’induire une force de déplacement sur des microrobots magnétiques tout en permettant l’asservissement de leur position - une technique connue sous le nom de Navigation par Résonance Magnétique (NRM), mais aussi pour mettre en œuvre un procédé de communication. Pour des microrobots autonomes équipés de senseurs ayant un certain niveau d'intelligence et opérant à l'intérieur du corps humain, la puissance de transmission nécessaire pour communiquer des informations à un ordinateur externe par des méthodes présentement connues est insuffisante. Dans ce travail, une technique est décrite où une telle perte de puissance d'émission en raison de la mise à l'échelle de ces microrobots peut être compensée par le scanner IRM agissant aussi comme un récepteur très sensible. La technique de communication prend la forme d'une modification de la fréquence du courant électrique circulant le long d'une bobine miniature incorporé dans un microrobot. La fréquence du courant électrique peut être réglée à partir d'une entrée de seuil prédéterminée du senseur mis en place sur le microrobot. La fréquence devient alors corrélée à l’information de l’état du senseur recueilli par le microrobot et elle est déterminée en utilisant l'IRM. La méthode proposée est indépendante de la position et l'orientation du microrobot et peut être étendue à un grand nombre de microrobots pour surveiller et cartographier les conditions physiologiques spécifiques dans une région plus vaste à n’importe quelle profondeur à l'intérieur du corps.----------ABSTRACT The magnetic environment provided by a clinical Magnetic Resonance Imaging (MRI) scanner can be exploited to not only induce a displacement force on magnetic microrobots while allowing MR-tracking for serving control purpose or positional assessment - a technique known as Magnetic Resonance Navigation (MRN), but also for implementing a method of communication with intelligent microrobots. For untethered sensory microrobots having some level of intelligence and operating inside the body, the transmission power necessary to communicate information to an external computer via known methods is insufficient. In this work, a technique is described where such loss of transmission power due to the scaling of these microrobots can be compensated by the same MRI scanner acting as a more sensitive receiver. A communication scheme is implemented in the form of a frequency alteration in the electrical current circulating along a miniature coil embedded in a microrobot. The frequency of the electrical current could be regulated from a predetermined sensory threshold input implemented on the microrobot. Such a frequency provides information on the level of sensory information gathered by the microrobot, and it is determined using MR imaging. The proposed method is independent of the microrobot's position and orientation and can be extended to a larger number of microrobots for monitoring and mapping specific physiological conditions inside a larger region at any depths within the body

Mechanistic Insights for Magnetic Imaging and Control of Cellular Function

The vast biomolecular toolkit for optical imaging and control of cellular function has revolutionized the study of in vitro samples and superficial tissues in living organisms but leaves deep tissue unexplored. To look deeper in tissue and observe system-level biological function in large organisms requires a modality that exploits a more penetrant form of energy than visible light. Magnetic imaging with MRI reveals the previously unseen, with endogenous tissue contrast and practically infinite penetration depth. While these clear advantages have made MRI a cornerstone of modern medical imaging, the sparse library of molecular agents for MRI have severely limited its utility for studies of cellular function in vivo. The development of new molecular agents for MRI has suffered from a lack of tools to study the connection between changes in the microscale cellular environment and the corresponding millimeter-scale MRI contrast. Bridging this gap requires revisiting the mechanistic underpinnings of MRI contrast, casting aside some of the simplifications that smooth over sub-voxel heterogeneity that is rich with information pertinent to the underlying cell state. Here, we will demonstrate theoretical, computational, and experimental connections between subtle changes in microscale cellular environment and resultant MRI contrast. After reviewing some foundational principles of MRI physics in the first chapter, the second chapter of the thesis will explore computational models that have significantly enhanced the development of genetically encoded agents for MRI, including the first genetically encoded contrast agent for diffusion weighted imaging. By improving the efficacy of these genetically encoded agents, we unlock MRI reporter genes for in vivo studies of cellular dynamics much in the same way that the engineering of Green Fluorescent Protein has dramatically improved in vitro studies of cellular function. In the third chapter, we introduce our study that maps microscale magnetic fields in cells and tissues and connects those magnetic fields to MRI contrast. Such a connection has previously been experimentally intractable due to the lack of methods to resolve small magnetic perturbations with microscale resolution. To overcome this challenge, we leverage nitrogen vacancy diamond magnetometry to optically probe magnetic fields in cells with sub-micron resolution and nanotesla sensitivity, together with iterative localization of field sources and Monte Carlo simulation of nuclear spins to predict the corresponding MRI contrast. We demonstrate the utility of this technology in an in vitro model of macrophage iron uptake and histological samples from a mouse model of hepatic iron overload. In addition, we show that this technique can follow dynamic changes in the magnetic field occurring during contrast agent endocytosis by living cells. This approach bridges a fundamental gap between an MRI voxel and its microscopic constituents and provides a new capability for noninvasive imaging of opaque tissues. In the fourth chapter, we focus on the use of magnetic fields to perturb, rather than image, biological function. Recent suggestions of nanoscale heat confinement on the surface of synthetic and biogenic magnetic nanoparticles during heating by radiofrequency alternating magnetic fields have generated intense interest due to the potential utility of this phenomenon in non-invasive control of biomolecular and cellular function. However, such confinement would represent a significant departure from classical heat transfer theory. We present an experimental investigation of nanoscale heat confinement on the surface of several types of iron oxide nanoparticles commonly used in biological research, using an all-optical method devoid of potential artifacts present in previous studies. By simultaneously measuring the fluorescence of distinct thermochromic dyes attached to the particle surface or dissolved in the surrounding fluid during radiofrequency magnetic stimulation, we found no measurable difference between the nanoparticle surface temperature and that of the surrounding fluid for three distinct nanoparticle types. Furthermore, the metalloprotein ferritin produced no temperature increase on the protein surface, nor in the surrounding fluid. Experiments mimicking the designs of previous studies revealed potential sources of artifacts. These findings inform the use of magnetic nanoparticle hyperthermia in engineered cellular and molecular systems and can help direct future resources towards tractable avenues of magnetic control of cellular function.</p

Double volumetric navigators for real-time simultaneous shim and motion measurement and correction in Glycogen Chemical Exchange Saturation Transfer (GlycoCEST) MRI

Glycogen is the primary glucose storage mechanism in in living systems and plays a central role in systemic glucose homeostasis. The study of muscle glycogen concentrations in vivo still largely relies on tissue sampling methods via needle biopsy. However, muscle biopsies are invasive and limit the frequency of measurements and the number of sites that can be assessed. Non-invasive methods for quantifying glycogen in vivo are therefore desirable in order to understand the pathophysiology of common diseases with dysregulated glycogen metabolism such as obesity, insulin resistance, and diabetes, as well as glycogen metabolism in sports physiology. Chemical Exchange Saturation Transfer (CEST) MRI has emerged as a non-invasive contrast enhancement technique that enables detection of molecules, like glycogen, whose concentrations are too low to impact the contrast of standard MR imaging. CEST imaging is performed by selectively saturating hydrogen nuclei of the metabolites that are in chemical exchange with those of water molecules and detecting a reduction in MRI signal in the water pool resulting from continuous chemical exchange. However, CEST signal can easily be compromised by artifacts. Since CEST is based on chemical shift, it is very sensitive to field inhomogeneity which may arise from poor initial shimming, subject respiration, heating of shim iron, mechanical vibrations or subject motion. This is a particular problem for molecules that resonate close to water, such as - OH protons in glycogen, where small variations in chemical shift cause misinterpretation of CEST data. The purpose of this thesis was to optimize the CEST MRI sequence for glycogen detection and implement a real-time simultaneous motion and shim correction and measurement method. First, analytical solution of the Bloch-McConnell equations was used to find optimal continuous wave RF pulse parameters for glycogen detection, and results were validated on a phantom with varying glycogen concentrations and in vivo on human calf muscle. Next, the CEST sequence was modified with double volumetric navigators (DvNavs) to measure pose changes and update field of view and zero- and first-order shim parameters. Finally, the impact of B0 field fluctuations on the scan-rescan reproducibility of CEST was evaluated in vivo in 9 volunteers across 10 different scans. Simulation results showed an optimal RF saturation power of 1.5µT and duration of 1s for glycoCEST. These parameters were validated experimentally in vivo and the ability to detect varying glycogen concentrations was demonstrated in a phantom. Phantom data showed that the DvNav-CEST sequence accurately estimates system frequency and linear shim gradient changes due to motion and corrects resulting image distortions. In addition, DvNav-CEST was shown to yield improved CEST quantification in vivo in the presence of motion and motion-induced field inhomogeneity. B0 field fluctuations were found to lower the reproducibility of CEST measures: the mean coefficient of variation (CoV) for repeated scans was 83.70 ± 70.79 % without shim correction. However, the DvNav-CEST sequence was able to measure and correct B0 variations, reducing the CoV to 2.6 ± 1.37 %. The study confirms the possibility of detecting glycogen using CEST MRI at 3 T and shows the potential of the real-time shim and motion navigated CEST sequence for producing repeatable results in vivo by reducing the effect of B0 field fluctuations

Quantum control of optically active defects in the solid state

A common thread in the realization of quantum computers, quantum networks, and quantum sensors is the search for promising physical platforms. The dislocations of atoms in the solid state, referred to as defects, have historically been deemed undesirable as they can be deleterious to the operation of electronic and optoelectronic devices. In 1997, it was demonstrated that a single nitrogen-vacancy (NV) center defect in diamond could act as a stable single photon source [1]. In the same study, the electronic spin of the same defect was optically initialized and read out. Remarkably, both of these achievements occurred under ambient conditions. In the decades that have followed, the study of optically active defects in the solid state have garnered significant interest for quantum applications. Motivated by this, in this thesis we demonstrate experimental progress in defects in three materials: silicon carbide, diamond, and sapphire. Silicon carbide is a wide band-gap semiconductor with a mature manufacturing industry. In this material, we show the integration of surface defects (formed at the SiC/SiO2 interface) into microdisk resonators, showing an enhancement in single photon emission. Additionally, we construct a confocal microscopy apparatus and demonstrate room-temperature optically-detected magnetic resonance of silicon-vacancy defects in ~50 nm diameter SiC nanoparticles, further motivating their application for quantum sensing and nanophotonics. While NV-centers have been widely studied, we demonstrate coherent control of the electronic spin states, and coupling to their neighboring nuclear spins, using an apparatus that operates in ambient conditions, outside an otherwise carefully controlled environment of a research laboratory, and which can be constructed for ~USD 20k. This has enabled the development of a teaching lab that has been incorporated into a quantum engineering course for three consecutive years. Lastly, we upgrade a dilution refrigerator for optical access, and using the spin properties of Cr3+ defects in sapphire (ruby), conduct all-optical thermometry, reaching lattice temperatures as low as 143 mK under continuous laser excitation. We measure the spin relaxation time down to these unprecedented temperatures, and demonstrate optically detected magnetic resonance within the rich spin structure of the Cr3+ ions. The sum contribution of these results is the development of the experimental apparatus and techniques in probing the optical and spin characteristics of novel optically active defects, both at room temperature and cryogenic temperatures, which paves the way for the development of advanced spin-photon interfaces. [1] A. Gruber et al. “Scanning Confocal Optical Microscopy and Magnetic Resonance on Single Defect Centers”. In: Science 276.5321 (1997), pp. 2012–2014

Detecting neuroinflammation with molecular MRI

The work in this thesis is focused on the study of neuroinflammation with molecular magnetic resonance imaging (MRI) methods. Neuroinflammation is a response of the central nervous system to pathological insult and it is present in many neurological disorders, such as Alzheimer’s disease. Being able to image neuroinflammation non-invasively with MRI techniques would have an important clinical value for diagnosis and assessment of therapy effectiveness. The aim of this work is to develop and validate an MR biomarker of neuroinflammation using MR Spectroscopy (MRS) and chemical exchange saturation transfer imaging (CEST). First, intravenous administration of lipopolysaccharide (LPS) is used as a mild inflammatory stimulus in wild type mice and in a mouse model of Alzheimer’s disease (AD). Elevated levels of the osmolyte myo-inositol, measured with MRS and microglia activation are found in AD mice after LPS administration. Due to the inherent low spatial resolution of MRS, a CEST MRI method is developed next. A myo-inositol CEST protocol is optimised, using Matlab simulations based on the Bloch-McConnell equations for a three pool model, in order to maximize the contrast and to estimate the amount of signal that can be expected in vivo. In vitro and in vivo tests are presented and a fast CEST sequence is developed, while the experimental difficulties and limitations of the technique are discussed. A CEST protocol is finally applied to evaluate the metabolite response to an LPS inflammatory challenge using MRS and histology as validation. A correlation is described between CEST and MRS myo-inositol levels, as well as between CEST and microglia concentration (Iba1 immunostaining), which highlight the potential of CEST as a non-invasive in vivo neuroinflammatory biomarker

Novel MRI Technologies for Structural and Functional Imaging of Tissues with Ultra-short T2 Values

Conventional MRI has several limitations such as long scan durations, motion artifacts, very high acoustic noise levels, signal loss due to short relaxation times, and RF induced heating of electrically conducting objects. The goals of this thesis are to evaluate state-of-the-art methods for MRI of tissue with short relaxation times, to prove the feasibility of CEA in a clinical MRI system, and to introduce a new electrophysiological measurement unit applied simultaneously with lung MRI