Shaped Magnetogel Microparticles for Multispectral Magnetic Resonance Contrast and Sensing.

Multispectral magnetic resonance imaging (MRI) contrast agents are microfabricated three-dimensional magnetic structures that encode nearby water protons with discrete frequencies. The agents have a unique radiofrequency (RF) resonance that can be tuned by engineering the geometric parameters of these microstructures. Multispectral contrast agents can be used as sensors by incorporating a stimulus-driven shape-changing response into their structure. These geometrically encoded magnetic sensors (GEMS) enable MRI-based sensing via environmentally induced changes to their geometry and their corresponding RF resonance. Previously, GEMS have been made using thin-film lithography techniques in a cleanroom environment. While these approaches offer precise control of the microstructure, they can be a limitation for researchers who do not have cleanroom access or microfabrication expertise. Here, an alternative approach for GEMS fabrication based on soft lithography is introduced. The fabrication scheme uses cheap, accessible materials and simple chemistry to produce shaped magnetic hydrogel microparticles with multispectral MRI contrast properties. The microparticles can be used as sensors by fabricating them out of shape-reconfigurable, "smart" hydrogels. The change in shape causes a corresponding shift in the resonance of the GEMS, producing an MRI-addressable readout of the microenvironment. Proof-of-principle experiments showing a multispectral response to pH change with cylindrical shell-shaped magnetogel GEMS are presented.

Multifield and inverse-contrast switching of magnetocaloric high contrast ratio MRI labels.

PURPOSE: Demonstrating multifield and inverse contrast switching of magnetocaloric high contrast ratio MRI labels that either have increasing or decreasing moment versus temperature slopes depending on the material at physiological temperatures and different MRI magnetic field strengths. METHODS: Two iron-rhodium samples of different purity (99% and 99.9%) and a lanthanum-iron-silicon sample were obtained from commercial vendors. Temperature and magnetic field-dependent magnetic moment measurements of the samples were performed on a vibrating sample magnetometer. Temperature-dependent MRI of different iron-rhodium and lanthanum-iron-silicon samples were performed on 3 different MRI scanners at 1 Tesla (T), 4.7T, and 7T. RESULTS: Sharp, first-order magnetic phase transition of each iron-rhodium sample at a physiologically relevant temperature (~37°C) but at different MRI magnetic fields (1T, 4.7T, and 7T, depending on the sample) showed clear image contrast changes in temperature-dependent MRI. Iron-rhodium and lanthanum-iron-silicon samples with sharp, first-order magnetic phase transitions at the same MRI field of 1T and physiological temperature of 37°C, but with positive and negative slope of magnetization versus temperature, respectively, showed clear inverse contrast image changes. Temperature-dependent MRI on individual microparticle samples of lanthanum-iron-silicon also showed sharp image contrast changes. CONCLUSION: Magnetocaloric materials of different purity and composition were demonstrated to act as diverse high contrast ratio switchable MRI contrast agents. Thus, we show that a range of magnetocaloric materials can be optimized for unique image contrast response under MRI-appropriate conditions at physiological temperatures and be controllably switched in situ.

Magnetocaloric materials as switchable high contrast ratio MRI labels.

PURPOSE: To develop switchable and tunable labels with high contrast ratio for MRI using magnetocaloric materials that have sharp first-order magnetic phase transitions at physiological temperatures and typical MRI magnetic field strengths. METHODS: A prototypical magnetocaloric material iron-rhodium (FeRh) was prepared by melt mixing, high-temperature annealing, and ice-water quenching. Temperature- and magnetic field-dependent magnetization measurements of wire-cut FeRh samples were performed on a vibrating sample magnetometer. Temperature-dependent MRI of FeRh samples was performed on a 4.7T MRI. RESULTS: Temperature-dependent MRI clearly demonstrated image contrast changes due to the sharp magnetic state transition of the FeRh samples in the MRI magnetic field (4.7T) and at a physiologically relevant temperature (~37°C). CONCLUSION: A magnetocaloric material, FeRh, was demonstrated to act as a high contrast ratio switchable MRI contrast agent due to its sharp first-order magnetic phase transition in the DC magnetic field of MRI and at physiologically relevant temperatures. A wide range of magnetocaloric materials are available that can be tuned by materials science techniques to optimize their response under MRI-appropriate conditions and be controllably switched in situ with temperature, magnetic field, or a combination of both.

Optically controlled on-coil amplifier with RF monitoring feedback.

PURPOSE: To develop a new optically controlled on-coil amplifier that facilitates safe use of multi-channel radiofrequency (RF) transmission in MRI by real-time monitoring of signal phase and amplitude. METHODS: Monitoring was carried out with a 4-channel prototype system by sensing, down sampling, digitizing, and optically transmitting the RF transmit signal to a remote PC to control the amplifiers. Performance was evaluated with benchtop and 7 T MRI experiments. RESULTS: Monitored amplitude and phase were stable across repetitions and had standard deviations of 0.061 µT and 0.0073 rad, respectively. The feedback system allowed inter-channel phase and B1 amplitude to be adjusted within two iterations. MRI experiments demonstrated the feasibility of this approach to perform safe and accurate multi-channel RF transmission and monitoring at high field. CONCLUSION: We demonstrated a 4-channel transceiver system based on optically controlled on-coil amplifiers with RF signal monitoring and feedback control. The approach allows the safe and precise control of RF transmission fields, required to achieve uniform excitation at high field. Magn Reson Med 79:2833-2841, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Sensory and optogenetically driven single-vessel fMRI.

Magnetic resonance imaging (MRI) sensitivity approaches vessel specificity. We developed a single-vessel functional MRI (fMRI) method to image the contribution of vascular components to blood oxygenation level-dependent (BOLD) and cerebral blood volume (CBV) fMRI signal. We mapped individual vessels penetrating the rat somatosensory cortex with 100-ms temporal resolution by MRI with sensory or optogenetic stimulation. The BOLD signal originated primarily from venules, and the CBV signal from arterioles. The single-vessel fMRI method and its combination with optogenetics provide a platform for mapping the hemodynamic signal through the neurovascular network with specificity at the level of individual arterioles and venules.

Optically controlled switch-mode current-source amplifiers for on-coil implementation in high-field parallel transmission.

PURPOSE: We tested the feasibility of implementing parallel transmission (pTX) for high-field MRI using a radiofrequency (RF) amplifier design to be located on or in the immediate vicinity of an RF transmit coil. METHOD: We designed a current-source switch-mode amplifier based on miniaturized, nonmagnetic electronics. Optical RF carrier and envelope signals to control the amplifier were derived, through a custom-built interface, from the RF source accessible in the scanner control. Amplifier performance was tested by benchtop measurements as well as with imaging at 7T (300 MHz) and 11.7 T (500 MHz). The ability to perform pTX was evaluated by measuring interchannel coupling and phase adjustment in a two-channel setup. RESULTS: The amplifier delivered in excess of 44 W RF power and caused minimal interference with MRI. The interface derived accurate optical control signals with carrier frequencies ranging from 64 to 750 MHz. Decoupling better than 14 dB was obtained between two coil loops separated by only 1 cm. Application to MRI was demonstrated by acquiring artifact-free images at 7 T and 11.7 T. CONCLUSION: We propose an optically controlled miniaturized RF amplifier for on-coil implementation at high fields that should facilitate implementation of high-density pTX arrays. Magn Reson Med 76:340-349, 2016. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Deciphering laminar-specific neural inputs with line-scanning fMRI.

Using a line-scanning method during functional magnetic resonance imaging (fMRI), we obtained high temporal (50-ms) and spatial (50-µm) resolution information along the cortical thickness and showed that the laminar position of fMRI onset coincides with distinct neural inputs in rat somatosensory and motor cortices. This laminar-specific fMRI onset allowed us to identify the neural inputs underlying ipsilateral fMRI activation in the barrel cortex due to peripheral denervation-induced plasticity.

Measuring collective cell movement and extracellular matrix interactions using magnetic resonance imaging.

Collective cell behaviors in migration and force generation were studied at the mesoscopic-level using cells grown in a 3D extracellular matrix (ECM) simulating tissues. Magnetic resonance imaging (MRI) was applied to investigate dynamic cell mechanics at this level. MDCK, NBT2, and MEF cells were embedded in 3D ECM, forming clusters that then migrated and generated forces affecting the ECM. The cells demonstrated MRI contrast due to iron accumulation in the clusters. Timelapse-MRI enabled the measurement of dynamic stress fields generated by the cells, as well as simultaneous monitoring of the cell distribution and ECM deformation/remodeling. We found cell clusters embedded in the 3D ECM can exert translational forces to pull and push, as well as torque, their surroundings. We also observed that the sum of forces generated by multiple cell clusters may result in macroscopic deformation. In summary, MRI can be used to image cell-ECM interactions mesoscopically.

Thalamocortical inputs show post-critical-period plasticity.

Experience-dependent plasticity in the adult brain has clinical potential for functional rehabilitation following central and peripheral nerve injuries. Here, plasticity induced by unilateral infraorbital (IO) nerve resection in 4-week-old rats was mapped using MRI and synaptic mechanisms were elucidated by slice electrophysiology. Functional MRI demonstrates a cortical potentiation compared to thalamus 2 weeks after IO nerve resection. Tracing thalamocortical (TC) projections with manganese-enhanced MRI revealed circuit changes in the spared layer 4 (L4) barrel cortex. Brain slice electrophysiology revealed TC input strengthening onto L4 stellate cells due to an increase in postsynaptic strength and the number of functional synapses. This work shows that the TC input is a site for robust plasticity after the end of the previously defined critical period for this input. Thus, TC inputs may represent a major site for adult plasticity in contrast to the consensus that adult plasticity mainly occurs at cortico-cortical connections.

The use of silica coated MnO nanoparticles to control MRI relaxivity in response to specific physiological changes.

MnO nanoparticles have been tested to engineer a delayed increase in MRI T(1) relaxivity caused by cellular uptake via endocytosis into acidic compartments. Various coatings on core-shell structured MnO nanoparticles were tested for those that had the lowest T(1) relaxivity at pH 7.4, a pH where MnO does not dissolve into Mn(2+) ions. The rate of dissolution and release of Mn(2+) of the different coated MnO particles as well as changes in T(1) relaxivity were measured at pH 5, a pH routinely obtained in the endosomal-lysosomal pathway. Of a number of coatings, silica coated MnO (MnO@SiO(2)) had the lowest relaxivity at pH 7.4 (0.29 mm(-1) sec(-1)). About one third of the MnO dissolved within 20 min and the T(1) relaxivity increased to that of free Mn(2+) (6.10 mm(-1) sec(-1)) after three days at pH 5. MRI of MnO@SiO(2) particles injected into the rat brain showed time-dependent signal changes consistent with the in vitro rates. Thalamocortical tract-tracing could be observed due to the released Mn(2+). Intravenous infusion of MnO@SiO(2) particles showed little enhancement in any tissue except gallbladder. The gallbladder enhancement was interpreted to be due to endocytosis by liver cells and excretion of Mn(2+) ions into the gallbladder. The MnO@SiO(2) core-shell nanoparticles show the best potential for delaying the release of MRI contrast until endocytosis into low pH compartments activate MRI contrast. The delayed enhancement may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be recycled by endocytosis.

Mapping cortical representations of the rodent forepaw and hindpaw with BOLD fMRI reveals two spatial boundaries.

Electrical stimulation of the rat forepaw and hindpaw was employed to study the spatial distribution of BOLD fMRI. Averaging of multiple fMRI sessions significantly improved the spatial stability of the BOLD signal and enabled quantitative determination of the boundaries of the BOLD fMRI maps. The averaged BOLD fMRI signal was distributed unevenly over the extent of the map and the data at the boundaries could be modeled with major and minor spatial components. Comparison of three-dimensional echo-planar imaging (EPI) fMRI at isotropic 300 µm resolution demonstrated that the border locations of the major spatial component of BOLD signal did not overlap between the forepaw and hindpaw maps. Interestingly, the border positions of the minor BOLD fMRI spatial components extended significantly into neighboring representations. Similar results were found for cerebral blood volume (CBV) weighted fMRI obtained using iron oxide particles, suggesting that the minor spatial components may not be due to vascular mislocalization typically associated with BOLD fMRI. Comparison of the BOLD fMRI maps of the forepaw and hindpaw to histological determination of these representations using cytochrome oxidase (CO) staining demonstrated that the major spatial component of the BOLD fMRI activation maps accurately localizes the borders. Finally, 2-3 weeks following peripheral nerve denervation, cortical reorganization/plasticity at the boundaries of somatosensory limb representations in adult rat brain was studied. Denervation of the hindpaw caused a growth in the major component of forepaw representation into the adjacent border of hindpaw representation, such that fitting to two components no longer led to a better fit as compared to using one major component. The border of the representation after plasticity was the same as the border of its minor component in the absence of any plasticity. It is possible that the minor components represent either vascular effects that extend from the real neuronal representations or the neuronal communication between neighboring regions. Either way the results will be useful for studying mechanisms of plasticity that cause alterations in the boundaries of neuronal representations.

Microfabricated high-moment micrometer-sized MRI contrast agents.

While chemically synthesized superparamagnetic microparticles have enabled much new research based on MRI tracking of magnetically labeled cells, signal-to-noise levels still limit the potential range of applications. Here it is shown how, through top-down microfabrication, contrast agent relaxivity can be increased several-fold, which should extend the sensitivity of such cell-tracking studies. Microfabricated agents can benefit from both higher magnetic moments and higher uniformity than their chemically synthesized counterparts, implying increased label visibility and more quantitative image analyses. To assess the performance of microfabricated micrometer-sized contrast agent particles, analytic models and numerical simulations are developed and tested against new microfabricated agents described in this article, as well as against results of previous imaging studies of traditional chemically synthesized microparticle agents. Experimental data showing signal effects of 500-nm thick, 2-µm diameter, gold-coated iron and gold-coated nickel disks verify the simulations. Additionally, it is suggested that measures of location better than the pixel resolution can be obtained and that these are aided using well-defined contrast agent particles achievable through microfabrication techniques.

The contribution of chemical exchange to MRI frequency shifts in brain tissue.

Recent high-field MRI studies based on resonance frequency contrast have revealed brain structure with unprecedented detail. Although subtle magnetic susceptibility variations caused by iron and myelin seem to be important to this contrast, recent research on protein solutions suggests that chemical exchange between water and macromolecular protons may contribute substantially to the observed gray-white matter frequency contrast. To investigate this, we performed spectroscopic MRI experiments at 14 T on samples of fixed human visual cortex and fresh pig brain. To allow direct observation of any exchange-induced frequency shifts, these samples were soaked in reference chemicals (TSP and dioxane) that are assumed not to be involved in exchange. For both fresh and fixed tissues and with both reference chemicals, substantial negative exchange-induced gray-white matter frequency contrast (-6.3 to -13.5 ppb) was found, whereas intracortical contrast was negligible. The sign of the gray-white matter exchange-induced frequency difference was opposite to the overall gray-white matter frequency difference observed in vivo. This suggests that exchange contributes to, but is not sufficient to explain, the frequency contrast in vivo and tissue susceptibility differences may have a greater contribution than previously thought. The exchange-dependent contribution may report on tissue chemical composition and pH.

Mapping plasticity in the forepaw digit barrel subfield of rat brains using functional MRI.

The topographic organization of the forepaw barrel subfield in layer IV of rat primary somatosensory cortex (S1) is a good model for studying neural function and plasticity. The goal of this study was to test the feasibility of functional MRI (fMRI) to map the forepaw digit representations in the S1 of the rat and its plasticity after digit amputation. Three dimensional echo-planar imaging with 300 micron isotropic resolution at 11.7 T was used to achieve high signal-to-noise ratios and laminar layer resolution. By alternating electrical stimulation of the 2nd (D2) and 4th (D4) digits, functional activation in layer IV of the barrel subfields could be distinguished using a differential analysis. Furthermore, 2 and a half months after the amputation of the 3rd digit in baby rats, the overlapping area between D2 and D4 representations was increased. This indicates that the forepaw barrel subfield previously associated with the ablated digit is now associated with the representation of nearby digits, which is consistent with studies using electrophysiology and cytochrome oxidase staining.

Magnetic susceptibility mapping of brain tissue in vivo using MRI phase data.

Phase images in susceptibility-weighted MRI of brain provide excellent contrast. However, the phase is affected by tissue geometry and orientation relative to the main magnetic field (B(0)), and phase changes extend beyond areas of altered susceptibility. Magnetic susceptibility, on the other hand, is an intrinsic tissue property, closely reflecting tissue composition. Therefore, recently developed inverse Fourier-based methods were applied to calculate susceptibility maps from high-resolution phase images acquired at a single orientation at 7 T in the human brain (in vivo and fixed) and at 11.7 T in fixed marmoset brain. In susceptibility images, the contrast of cortical layers was more consistent than in phase images and was independent of the structures' orientation relative to B(0). The contrast of iron-rich deep-brain structures (red nucleus and substantia nigra) in susceptibility images agreed more closely with iron-dominated R(2) (*) images than the phase image contrast, which extended outside the structures. The mean susceptibility in these regions was significantly correlated with their estimated iron content. Susceptibility maps calculated using this method overcome the orientation-dependence and non-locality of phase image contrast and seem to reflect underlying tissue composition. Susceptibility images should be easier to interpret than phase images and could improve our understanding of the sources of susceptibility contrast.

MRI of the basement membrane using charged nanoparticles as contrast agents.

The integrity of the basement membrane is essential for tissue cellular growth and is often altered in disease. In this work a method for noninvasively detecting the structural integrity of the basement membrane, based on the delivery of cationic iron-oxide nanoparticles, was developed. Cationic particles accumulate due to the highly negative charge of proteoglycans in the basement membrane. The kidney was used to test this technique because of its highly fenestrated endothelia and well-established disease models to manipulate the basement membrane charge barrier. After systemic injection of cationic or native ferritin (CF or NF) in rats, ex vivo and in vivo MRI showed selective accumulation of CF, but not NF, causing a 60% reduction in signal intensity in cortex at the location of individual glomeruli. Immunofluorescence and electron microscopy demonstrated that this CF accumulation was localized to the glomerular basement membrane (GBM). In a model of GBM breakdown during focal and segmental glomerulosclerosis, MRI showed reduced single glomerular accumulation of CF, but a diffuse accumulation of CF in the kidney tubules caused by leakage of CF through the glomerulus. Cationic contrast agents can be used to target the basement membrane and detect the breakdown of the basement membrane in disease.

BOLD fMRI and somatosensory evoked potentials are well correlated over a broad range of frequency content of somatosensory stimulation of the rat forepaw.

Electrical stimulation of the rat paw is commonly used to study the hemodynamic, metabolic and neuronal mechanisms of functional MRI (fMRI) responses in somatosensory cortex. Several groups have reported good correlation between the blood oxygenation level-dependent (BOLD) fMRI signal and somatosensory evoked potentials (SEPs) using short, typically 300 micros, square stimulation pulses. The spectral power of these short pulses is evenly distributed over a wide range of frequencies and thus the effects of the frequency content of the stimulation pulse on fMRI responses have not been previously described. Here, the effects that different stimulation pulse waveforms with a range of frequency content have on neuronal activity, as measured by SEPs, and on the amplitude of the BOLD fMRI signal in rat somatosensory cortex are investigated. The peak-to-peak SEP amplitudes increased as the power in the high frequency harmonics of the different pulse waveforms increased, using either triangular or sinusoidal stimuli waveforms from 9 Hz to 180 Hz. Similarly, BOLD fMRI response increased with increased high frequency content of the stimulation pulse. There was a linear correlation between SEPs and BOLD fMRI over the full range of frequency content in the stimulations.

Functional MRI detection of bilateral cortical reorganization in the rodent brain following peripheral nerve deafferentation.

Evidence is emerging for significant inter-hemispheric cortical plasticity in humans, opening important questions about the significance and mechanism for this long range plasticity. In this work, peripheral nerve deafferentation was performed on both the rat forepaw and hindpaw and cortical reorganization was assessed using functional MRI (fMRI). Sensory stimulation of the forepaw or the hindpaw in rats that experienced only partial denervation resulted in activation in only the appropriate, contralateral, primary somatosensory cortex (SI). However, 2-3 weeks following complete denervation of the rats' forepaw or hindpaw, stimulation of the intact paw resulted in fMRI activation of ipsilateral as well as contralateral SI. To address whether inter-cortical communication is required for this cortical reorganization, the healthy hindpaw SI representation was stereotaxically lesioned in rats which had the other hindpaw denervated. No fMRI activation was detected in the ipsilateral SI cortex after lesioning of the contralateral cortex. These results indicate that extensive inter-hemispheric cortical-cortical reorganization can occur in the rodent brain after peripheral nerve deafferentation and that cortical-cortical connections play a role in mediating this inter-hemispheric cortical reorganization.