Myelin bilayer mapping in the human brain in vivo.

PURPOSE: To quantitatively map the myelin lipid-protein bilayer in the live human brain. METHODS: This goal was pursued by integrating a multi-TE acquisition approach targeting ultrashort T2 signals with voxel-wise fitting to a three-component signal model. Imaging was performed at 3 T in two healthy volunteers using high-performance RF and gradient hardware and the HYFI sequence. The design of a suitable imaging protocol faced substantial constraints concerning SNR, imaging volume, scan time, and RF power deposition. Model fitting to data acquired using the proposed protocol was made feasible through simulation-based optimization, and filtering was used to condition noise presentation and overall depiction fidelity. RESULTS: A multi-TE protocol (11 TEs of 20-780 µs) for in vivo brain imaging was developed in adherence with applicable safety regulations and practical scan time limits. Data acquired using this protocol produced accurate model fitting results, validating the suitability of the protocol for this purpose. Structured, grainy texture of myelin bilayer maps was observed and determined to be a manifestation of correlated image noise resulting from the employed acquisition strategy. Map quality was significantly improved by filtering to uniformize the k-space noise distribution and simultaneously extending the k-space support. The final myelin bilayer maps provided selective depiction of myelin, reconciling competitive resolution (1.4 mm) with adequate SNR and benign noise texture. CONCLUSION: Using the proposed technique, quantitative maps of the myelin bilayer can be obtained in vivo. These maps offer unique information content with potential applications in basic research, diagnosis, disease monitoring, and drug development.

Quantitative magnetic resonance mapping of the myelin bilayer reflects pathology in multiple sclerosis brain tissue.

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by loss of myelin (demyelination) and, to a certain extent, subsequent myelin repair (remyelination). To better understand the pathomechanisms underlying de- and remyelination and to monitor the efficacy of treatments aimed at regenerating myelin, techniques offering noninvasive visualizations of myelin are warranted. Magnetic resonance (MR) imaging has long been at the forefront of efforts to visualize myelin, but it has only recently become feasible to access the rapidly decaying resonance signals stemming from the myelin lipid-protein bilayer itself. Here, we show that direct MR mapping of the bilayer yields highly specific myelin maps in brain tissue from patients with MS. Furthermore, examination of the bilayer signal behavior is found to reveal pathological alterations in normal-appearing white and gray matter. These results indicate promise for in vivo implementations of the myelin bilayer mapping technique, with prospective applications in basic research, diagnostics, disease monitoring, and drug development.

Mapping the myelin bilayer with short-T2 MRI: Methods validation and reference data for healthy human brain.

PURPOSE: To explore the properties of short-T2 signals in human brain, investigate the impact of various experimental procedures on these properties and evaluate the performance of three-component analysis. METHODS: Eight samples of non-pathological human brain tissue were subjected to different combinations of experimental procedures including D2 O exchange and frozen storage. Short-T2 imaging techniques were employed to acquire multi-TE (33-2067 µs) data, to which a three-component complex model was fitted in two steps to recover the properties of the underlying signal components and produce amplitude maps of each component. For validation of the component amplitude maps, the samples underwent immunohistochemical myelin staining. RESULTS: The signal component representing the myelin bilayer exhibited super-exponential decay with T2,min of 5.48 µs and a chemical shift of 1.07 ppm, and its amplitude could be successfully mapped in both white and gray matter in all samples. These myelin maps corresponded well to myelin-stained tissue sections. Gray matter signals exhibited somewhat different components than white matter signals, but both tissue types were well represented by the signal model. Frozen tissue storage did not alter the signal components but influenced component amplitudes. D2 O exchange was necessary to characterize the non-aqueous signal components, but component amplitude mapping could be reliably performed also in the presence of H2 O signals. CONCLUSIONS: The myelin mapping approach explored here produced reasonable and stable results for all samples. The extensive tissue and methodological investigations performed in this work form a basis for signal interpretation in future studies both ex vivo and in vivo.

Pulse encoding for ZTE imaging: RF excitation without dead-time penalty.

PURPOSE: To overcome limitations in the duration of RF excitation in zero-TE (ZTE) MRI by exploiting intrinsic encoding properties of RF pulses to retrieve data missed during the dead time caused by the pulse. METHODS: An enhanced ZTE signal model was developed using multiple RF pulses, which enables accessing information hidden in the pulse-induced dead time via encoding intrinsically applied by the RF pulses. Such ZTE with pulse encoding was implemented by acquisition of two ZTE data sets using excitation with similar frequency-swept pulses differing only by a small off-resonance in their center frequency. In this way, the minimum scan time is doubled but each acquisition contributes equally to the SNR, as with ordinary averaging. The method was demonstrated on long-T2 and short-T2 phantoms as well as in in vivo experiments. RESULTS: ZTE with pulse encoding provided good image quality at unprecedented dead-time gaps, demonstrated here up to 6 Nyquist dwells. In head imaging, the ability to use longer excitation pulses led to approximately 2-fold improvements in SNR efficiency as compared with conventional ZTE and allowed the creation of T1 contrast. CONCLUSION: Exploiting intrinsic encoding properties of RF pulses in a new signal model enables algebraic reconstruction of ZTE data sets with large dead-time gaps. This permits larger flip angles, which can be used to achieve enhanced T1 contrast and significant improvements in SNR efficiency in case the Ernst angle can be better approached, thus broadening the range of application of ZTE MRI.

HYFI: Hybrid filling of the dead-time gap for faster zero echo time imaging.

The aim of this work was to improve the SNR efficiency of zero echo time (ZTE) MRI pulse sequences for faster imaging of short-T2 components at large dead-time gaps. ZTE MRI with hybrid filling (HYFI) is a strategy for retrieving inner k-space data missed during the dead-time gaps arising from radio-frequency excitation and switching in ZTE imaging. It performs hybrid filling of the inner k-space with a small single-point-imaging core surrounded by a stack of shells acquired on radial readouts in an onion-like fashion. The exposition of this concept is followed by translation into guidelines for parameter choice and implementation details. The imaging properties and performance of HYFI are studied in simulations as well as phantom, in vitro and in vivo imaging, with an emphasis on comparison with the pointwise encoding time reduction with radial acquisition (PETRA) technique. Simulations predict higher SNR efficiency for HYFI compared with PETRA at preserved image quality, with the advantage increasing with the size of the k-space gap. These results are confirmed by imaging experiments with gap sizes of 25 to 50 Nyquist dwells, in which scan times for similar image quality could be reduced by 25% to 60%. The HYFI technique provides both high SNR efficiency and image quality, thus outperforming previously known ZTE-based pulse sequences, in particular for large k-space gaps. Promising applications include direct imaging of ultrashort-T2 components, such as the myelin bilayer or collagen, T2 mapping of ultrafast relaxing signals, and ZTE imaging with reduced chemical shift artifacts.

High-resolution MRI of mummified tissues using advanced short-T2 methodology and hardware.

PURPOSE: Evolutionary medicine aims to study disease development from a long-term perspective, and through the analysis of mummified tissue, timescales of several thousand years are unlocked. Due to the status of mummies as ancient relics, noninvasive techniques are preferable, and, currently, CT imaging is the most widespread method. However, CT images lack soft-tissue contrast, making complementary MRI data desirable. Unfortunately, the dehydrated nature and short T2 times of mummified tissues render them practically invisible to standard MRI techniques. Specialized short-T2 approaches have therefore been used, but currently suffer severe resolution limitations. The purpose of the present study is to improve resolution in MRI of mummified tissues. METHODS: The zero-TE-based hybrid filling technique, together with a high-performance magnetic field gradient, was used to image three ancient Egyptian mummified human body parts: a hand, a foot, and a head. A similar pairing has already been shown to increase resolution and image quality in MRI of short-T2 tissues. RESULTS: MRI images of yet unparalleled image quality were obtained for all samples, reaching isotropic resolutions of 0.6 mm and SNR values above 100. The same general features as present in CT images were depicted but with different contrast, particularly for regions containing embalming substances. CONCLUSION: Mummy MRI is a potentially valuable tool for (paleo)pathological studies, as well as for investigations into ancient mummification processes. The results presented here show sufficient improvement in the depiction of mummified tissues to clear new paths for the exploration of this field.

Advances in MRI of the myelin bilayer.

Myelin plays a key role in the function of the central nervous system and is involved in many neurodegenerative diseases. Hence, depiction of myelin is desired for both research and diagnosis. However, MRI of the lipid bilayer constituting the myelin membrane is hampered by extremely rapid signal decay and cannot be accomplished with conventional sequences. Dedicated short-T2 techniques have therefore been employed, yet with extended sequence timings not well matched to the rapid transverse relaxation in the bilayer, which leads to signal loss and blurring. In the present work, capture and encoding of the ultra-short-T2 signals in the myelin bilayer is considerably improved by employing advanced short-T2 methodology and hardware, in particular a high-performance human-sized gradient insert. The approach is applied to tissue samples excised from porcine brain and in vivo in a human volunteer. It is found that the rapidly decaying non-aqueous components in the brain can indeed be depicted with MRI at useful resolution. As a considerable fraction of these signals is related to the myelin bilayer, the presented approach has strong potential to contribute to myelin research and diagnosis.

High-resolution short-T2 MRI using a high-performance gradient.

PURPOSE: To achieve high resolution in imaging of short-T2 materials and tissues by using a high-performance human-sized gradient insert with strength up to 200 mT/m and 100% duty cycle. METHODS: Dedicated short-T2 methodology and hardware are used, such as the pointwise encoding time reduction with radial acquisition (PETRA) technique with modulated excitation pulses, optimized radio-frequency hardware, and a high-performance gradient insert. A theoretical analysis of actual spatial resolution and SNR is provided to support the choice of scan parameters and interpretation of the results. Imaging is performed in resolution phantoms, animal specimen, and human volunteers at both conventional and maximum available gradient strengths and compared using image subtraction. RESULTS: Calculations suggest that increasing gradient strength beyond conventional values considerably improves both actual resolution and SNR efficiency in short-T2 imaging. Resolution improvements are confirmed in all investigated samples, in particular 2 mm slots were resolved in a hard-plastic plate with T2 ≈ 10 µs and in vivo musculoskeletal images were acquired at isotropic 200 µm resolution. Expected improvements in signal yield are realized in fine structures benefitting from high resolution but to less extent in regions of low contrast where decay-related blurring leads to signal overlap between neighboring locations. CONCLUSION: Strong gradients with high duty cycle enable short-T2 imaging at unprecedentedly high resolution, holding the potential for improving MRI of, eg, bone, tendon, lung, or teeth. Moreover, it allows direct access of tissues with T2 of tens of microseconds such as myelin or collagen.

Long-T2 -suppressed zero echo time imaging with weighted echo subtraction and gradient error correction.

PURPOSE: To perform direct, selective MRI of short-T2 tissues using zero echo time (ZTE) imaging with weighted echo subtraction (WSUB). METHODS: Radial imaging was performed at 7T, acquiring both ZTE and gradient echo (GRE) signals created by bipolar gradients. Long-T2 suppression was achieved by weighted subtraction of ZTE and GRE images. Special attention was given to imperfections of gradient dynamics, to which radial GRE imaging is particularly susceptible. To compensate for gradient errors, matching of gradient history was combined with data correction based on trajectory measurement. The proposed approach was first validated in phantom experiments and then demonstrated in musculoskeletal (MSK) imaging. RESULTS: Trajectory analysis and phantom imaging demonstrated that gradient imperfections were successfully addressed. Gradient history matching enabled consistency between antiparallel projections as required for deriving zeroth-order eddy current dynamics. Trajectory measurement provided individual echo times per projection that showed considerable variation between gradient directions. In in vivo imaging of knee, ankle, and tibia, the proposed approach enabled high-resolution 3D depiction of bone, tendons, and ligaments. Distinct contrast of these structures indicates excellent selectivity of long-T2 suppression. Clarity of depiction also confirmed sufficient SNR of short-T2 tissues, achieved by high baseline sensitivity at 7T combined with high SNR efficiency of ZTE acquisition. CONCLUSION: Weighted subtraction of ZTE and GRE data reconciles robust long-T2 suppression with fastest k-space coverage and high SNR efficiency. This approach enables high-resolution imaging with excellent selectivity to short-T2 tissues, which are of major interest in MSK and neuroimaging applications.

Filling the dead-time gap in zero echo time MRI: Principles compared.

PURPOSE: MRI of tissues with short coherence lifetimes T2 or T2* can be performed efficiently using zero echo time (ZTE) techniques such as algebraic ZTE, pointwise encoding time reduction with radial acquisition (PETRA), and water- and fat-suppressed proton projection MRI (WASPI). They share the principal challenge of recovering data in central k-space missed due to an initial radiofrequency dead time. The purpose of this study was to compare the three techniques directly, with a particular focus on their behavior in the presence of ultra-short-lived spins. METHODS: The most direct comparison was enabled by aligning acquisition and reconstruction strategies of the three techniques. Image quality and short- T2* performance were investigated using point spread functions, 3D simulations, and imaging of phantom and bone samples with short (<1 ms) and ultra-short (<100 µs) T2*. RESULTS: Algebraic ZTE offers favorable properties but is limited to k-space gaps up to approximately three Nyquist dwells. At larger gaps, PETRA enables robust imaging with little compromise in image quality, whereas WASPI may be prone to artifacts from ultra-short T2* species. CONCLUSION: For small k-space gaps (<4 dwells) and T2* much larger than the dead time, all techniques enable artifact-free short- T2* MRI. However, if these requirements are not fulfilled careful consideration is needed and PETRA will generally achieve better image quality. Magn Reson Med 79:2036-2045, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Multi-Rate Acquisition for Dead Time Reduction in Magnetic Resonance Receivers: Application to Imaging With Zero Echo Time.

For magnetic resonance imaging of tissues with very short transverse relaxation times, radio-frequency excitation must be immediately followed by data acquisition with fast spatial encoding. In zero-echo-time (ZTE) imaging, excitation is performed while the readout gradient is already on, causing data loss due to an initial dead time. One major dead time contribution is the settling time of the filters involved in signal down-conversion. In this paper, a multi-rate acquisition scheme is proposed to minimize dead time due to filtering. Short filters and high output bandwidth are used initially to minimize settling time. With increasing time since the signal onset, longer filters with better frequency selectivity enable stronger signal decimation. In this way, significant dead time reduction is accomplished at only a slight increase in the overall amount of output data. Multi-rate acquisition was implemented with a two-stage filter cascade in a digital receiver based on a field-programmable gate array. In ZTE imaging in a phantom and in vivo, dead time reduction by multi-rate acquisition is shown to improve image quality and expand the feasible bandwidth while increasing the amount of data collected by only a few percent.

A high-performance gradient insert for rapid and short-T2 imaging at full duty cycle.

PURPOSE: The goal of this study was to devise a gradient system for MRI in humans that reconciles cutting-edge gradient strength with rapid switching and brings up the duty cycle to 100% at full continuous amplitude. Aiming to advance neuroimaging and short-T2 techniques, the hardware design focused on the head and the extremities as target anatomies. METHODS: A boundary element method with minimization of power dissipation and stored magnetic energy was used to design anatomy-targeted gradient coils with maximally relaxed geometry constraints. The design relies on hollow conductors for high-performance cooling and split coils to enable dual-mode gradient amplifier operation. With this approach, strength and slew rate specifications of either 100 mT/m with 1200 mT/m/ms or 200 mT/m with 600 mT/m/ms were reached at 100% duty cycle, assuming a standard gradient amplifier and cooling unit. RESULTS: After manufacturing, the specified values for maximum gradient strength, maximum switching rate, and field geometry were verified experimentally. In temperature measurements, maximum local values of 63°C were observed, confirming that the device can be operated continuously at full amplitude. Testing for peripheral nerve stimulation showed nearly unrestricted applicability in humans at full gradient performance. In measurements of acoustic noise, a maximum average sound pressure level of 132 dB(A) was determined. In vivo capability was demonstrated by head and knee imaging. Full gradient performance was employed with echo planar and zero echo time readouts. CONCLUSION: Combining extreme gradient strength and switching speed without duty cycle limitations, the described system offers unprecedented options for rapid and short-T2 imaging. Magn Reson Med 79:3256-3266, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

A virtually 1H-free birdcage coil for zero echo time MRI without background signal.

PURPOSE: MRI of tissues with rapid transverse relaxation can be performed efficiently using the zero echo time (ZTE) technique. At high bandwidths leading to large relative initial radiofrequency (RF) dead times, the method becomes increasingly sensitive to artifacts related to signal stemming from outside the field of view, particularly from the RF coils. Therefore, in this work, a birdcage coil was designed that is virtually free of 1H signal. METHODS: A transmit-receive birdcage RF coil for MRI of joints at 7T was designed by rigorously avoiding materials containing 1H nuclei, by using purely mechanical connections without glue, and by spoiling of unwanted signal by application of ferromagnetic materials. The coil was tested for residual 1H signal using ZTE phantom and in vivo joint imaging. RESULTS: In standard ZTE imaging, no 1H signal was detected above noise level. Only at extreme averaging, residual signal was observed close to conductors associated with 1H-containing molecules at adjacent glass surfaces. Phantom images with dead times up to 3.8 Nyquist dwells were obtained with only negligible background artifacts. Furthermore, high-quality ZTE images of human joints were acquired. CONCLUSION: A virtually 1H-free birdcage coil is presented, thus enabling in vivo ZTE MRI practically free of background signal, even at high bandwidths. Magn Reson Med 78:399-407, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Symmetrically biased T/R switches for NMR and MRI with microsecond dead time.

For direct NMR detection and imaging of compounds with very short coherence life times the dead time between radio-frequency (RF) pulse and reception of the free induction decay (FID) is a major limiting factor. It is typically dominated by the transient and recovery times of currently available transmit-receive (T/R) switches and amplification chains. A novel PIN diode-based T/R switch topology is introduced allowing for fast switching by high bias transient currents but nevertheless producing a very low video leakage signal and insertion loss (0.5dB). The low transient spike level in conjunction with the high isolation (75dB) prevent saturation of the preamplifier entirely which consequently does not require time for recovery. Switching between transmission and reception is demonstrated within less than 1µs in bench tests as well as in acquisitions of FIDs and zero echo time (ZTE) images with bandwidths up to 500kHz at 7T. Thereby the 2kW switch exhibited a rise-time of 350ns (10-99%) producing however a total video leakage of below 20mV peak-to-peak and less than -89dBm in-band. The achieved switching time renders the RF pulse itself the dominant contribution to the dead time in which a coherence cannot be observed, thus making pulsed NMR experiments almost time-optimal even for compounds with very short signal life times.

Dynamic control of plasmon generation by an individual quantum system.

Controlling light on the nanoscale in a similar way as electric currents has the potential to revolutionize the exchange and processing of information. Although light can be guided on this scale by coupling it to plasmons, that is, collective electron oscillations in metals, their local electronic control remains a challenge. Here, we demonstrate that an individual quantum system is able to dynamically gate the electrical plasmon generation. Using a single molecule in a double tunnel barrier between two electrodes we show that this gating can be exploited to monitor fast changes of the quantum system itself and to realize a single-molecule plasmon-generating field-effect transistor operable in the gigahertz range. This opens new avenues toward atomic scale quantum interfaces bridging nanoelectronics and nanophotonics.

Aptamer-functionalized hydrogel microparticles for fast visual detection of mercury(II) and adenosine.

With a low optical background, high loading capacity, and good biocompatibility, hydrogels are ideal materials for immobilization of biopolymers to develop optical biosensors. We recently immobilized mercury and lead binding DNAs within a monolithic gel and demonstrated ultrasensitive visual detection of these heavy metals. The high sensitivity was attributed to the enrichment of the analytes into the gels. The signaling kinetics was slow, however, taking about 1 h to obtain a stable optical signal because of a long diffusion distance. In this work, we aim to understand the analyte enrichment process and improve the signaling kinetics by preparing hydrogel microparticles. DNA-functionalized gel beads were synthesized using an emulsion polymerization technique and most of the beads were between 10 and 50 µm. Acrydite-modified DNA was incorporated by copolymerization. Visual detection of 10 nM Hg(2+) was still achieved and a stable signal was obtained in just 2 min. The gel beads could be spotted to form a microarray and dried for storage. A new visual sensor for adenosine was designed and immobilized within the gel beads. The adenosine aptamer binds its target about 1000-fold less tightly compared to the mercury binding DNA, allowing a comparison to be made on analyte enrichment by aptamer-functionalized hydrogels.