A built-in coil system attached to the inside walls of a magnetically shielded room for generating an ultra-high magnetic field homogeneity.

The homogeneity of the magnetic field generated by a coil inside a magnetic shield is essential for many applications, such as ultra-low field nuclear magnetic resonance or spin precession experiments. In the course of upgrading the Berlin Magnetically Shielded Room (BMSR-2) with a new inserted Permalloy layer of side length 2.87 m, we designed a built-in coil consisting of four identical square windings attached to its inside walls. The spacings of the four windings were optimized using a recently developed semi-analytic model and finite element analysis. The result reveals a strong dependence of the field homogeneity on the asymmetric placement of the inner two windings and on the chosen material permeability value µs. However, our model calculations also show that these experimental variations can be counterbalanced by an adjustment of the inner winding positions in the millimeter range. Superconducting quantum interference device-based measurements yield for our implementation after fine adjustments of a single winding position a maximum field change of less than 10 pT for a total field of B0 = 2.3 µT within a 10 cm region along the coil axis, which is already better than the residual field of the upgraded BMSR-2.1 after degaussing. Measurements of free spin precession decay signals of polarized Xe129 nuclei show that the transverse relaxation time for the used cell is not limited by the inhomogeneity of the new built-in coil system.

Noninvasive monitoring of blood flow using a single magnetic microsphere.

Noninvasive medical imaging of blood flow relies on mapping the transit of a contrast medium bolus injected intravenously. This has the draw-back that the front of the bolus widens until the tissue of interest is reached and quantitative flow parameters are not easy to obtain. Here, we introduce high resolution (millimeter/millisecond) 3D magnetic tracking of a single microsphere locally probing the flow while passing through a vessel. With this, we successfully localize and evaluate diameter constrictions in an arteria phantom after a single passage of a microsphere. We further demonstrate the potential for clinical application by tracking a microsphere smaller than a red blood cell.

Improved sensitivity and limit-of-detection using a receive-only coil in magnetic particle imaging.

Magnetic particle imaging (MPI) is an imaging modality capable of quantitatively determining the 3D distribution of a magnetic nanoparticle (MNP) ensemble. In this work, we present a method for reducing the MNP limit of detection by employing a new receive-only coil (Rx-coil) for signal acquisition. The new signal detector is designed to improve the sensitivity and thus quality of reconstructed images. We present characterization measurements conducted with the prototype Rx-coil installed in a preclinical MPI scanner. The gradiometric design of the Rx-coil attenuates the unwanted signal contributions arising from the excitation field, leading to a 17 dB lower background level compared to the conventional dual-purpose coil (TxRx-coil), which is crucial for detecting low amounts of MNP. Network analyzer measurements of the frequency-dependent coil sensitivity, as well as spectral analysis of recorded MPI data demonstrate an overall increase of the coil sensitivity of about +12 dB for the Rx-coil. Comparisons of the sensitivity distributions revealed no significant degradations in terms of homogeneity for the Rx-coil compared to the TxRx-coil in an imaging volume of 6 × 3 × 3 cm3. Finally, the limit of detection was determined experimentally for each coil type using a serial dilution of MNPs, resulting in values of 133 ng of iron for the conventional TxRx-coil and 20 ng for the new Rx-coil, using an acquisition time of 2 s. A linear relationship between the reconstructed signal intensities and the iron mass in the samples was observed with coefficients of determination (R2) of above 99% in the range of the limit of detection to 3 103ng(Fe). These results open the way for improved image quality and faster acquisition time in pre-clinical MPI scanners.

Novel magnetic multicore nanoparticles designed for MPI and other biomedical applications: From synthesis to first in vivo studies.

Synthesis of novel magnetic multicore particles (MCP) in the nano range, involves alkaline precipitation of iron(II) chloride in the presence of atmospheric oxygen. This step yields green rust, which is oxidized to obtain magnetic nanoparticles, which probably consist of a magnetite/maghemite mixed-phase. Final growth and annealing at 90°C in the presence of a large excess of carboxymethyl dextran gives MCP very promising magnetic properties for magnetic particle imaging (MPI), an emerging medical imaging modality, and magnetic resonance imaging (MRI). The magnetic nanoparticles are biocompatible and thus potential candidates for future biomedical applications such as cardiovascular imaging, sentinel lymph node mapping in cancer patients, and stem cell tracking. The new MCP that we introduce here have three times higher magnetic particle spectroscopy performance at lower and middle harmonics and five times higher MPS signal strength at higher harmonics compared with Resovist®. In addition, the new MCP have also an improved in vivo MPI performance compared to Resovist®, and we here report the first in vivo MPI investigation of this new generation of magnetic nanoparticles.

Selection of potential iron oxide nanoparticles for breast cancer treatment based on in vitro cytotoxicity and cellular uptake.

Superparamagnetic iron oxide nanoparticles (SPIONs) are promising tools for the treatment of different diseases. Their magnetic properties enable therapies involving magnetic drug targeting (MDT), hyperthermia or imaging. Depending on the intended treatment, specific characteristics of SPIONs are required. While particles used for imaging should circulate for extended periods of time in the vascular system, SPIONs intended for MDT or hyperthermia should be accumulated in the target area to come into close proximity of, or to be incorporated into, specific tumor cells. In this study, we determined the impact of several accurately characterized SPION types varying in size, zeta potential and surface coating on various human breast cancer cell lines and endothelial cells to identify the most suitable particle for future breast cancer therapy. We analyzed cellular SPION uptake, magnetic properties, cell proliferation and toxicity using atomic emission spectroscopy, magnetic susceptometry, flow cytometry and microscopy. The results demonstrated that treatment with dextran-coated SPIONs (SPIONDex) and lauric acid-coated SPIONs (SPIONLA) with an additional protein corona formed by human serum albumin (SPIONLA-HSA) resulted in very moderate particle uptake and low cytotoxicity, whereas SPIONLA had in part much stronger effects on cellular uptake and cellular toxicity. In summary, our data show significant dose-dependent and particle type-related response differences between various breast cancer and endothelial cells, indicating the utility of these particle types for distinct medical applications.

Magnetic field imaging with microfabricated optically-pumped magnetometers.

A multichannel imaging system is presented, consisting of 25 microfabricated optically-pumped magnetometers. The sensor probes have a footprint of less than 1 cm2 and a sensitive volume of 1.5 mm × 1.5 mm × 1.5 mm and connect to a control unit through optical fibers of length 5 m. Operating at very low ambient magnetic fields, the sensor array has an average magnetic sensitivity of 24 fT/Hz1/2, with a standard deviation of 5 fT/Hz1/2 when the noise of each sensor is averaged between 10 and 50 Hz. Operating in Earth's magnetic field, the magnetometers have a field sensitivity around 5 pT/Hz1/2. The vacuum-packaged sensor heads are optically heated and consume on average 76 ± 7 mW of power each. The heating power is provided by an array of eight diode lasers. Magnetic field imaging of small probe coils was obtained with the sensor array and fits to the expected field pattern agree well with the measured data.

Magnetic Particle Spectroscopy Reveals Dynamic Changes in the Magnetic Behavior of Very Small Superparamagnetic Iron Oxide Nanoparticles During Cellular Uptake and Enables Determination of Cell-Labeling Efficacy.

In vivo tracking of nanoparticle-labeled cells by magnetic resonance imaging (MRI) crucially depends on accurate determination of cell-labeling efficacy prior to transplantation. Here, we analyzed the feasibility and accuracy of magnetic particle spectroscopy (MPS) for estimation of cell-labeling efficacy in living THP-1 cells incubated with very small superparamagnetic iron oxide nanoparticles (VSOP). Cell viability and proliferation capacity were not affected by the MPS measurement procedure. In VSOP samples without cell contact, MPS enabled highly accurate quantification. In contrast, MPS constantly overestimated the amount of cell associated and internalized VSOP. Analyses of the MPS spectrum shape expressed as harmonic ratio A5/A3 revealed distinct changes in the magnetic behavior of VSOP in response to cellular uptake. These changes were proportional to the deviation between MPS and actual iron amount, therefore allowing for adjusted iron quantification. Transmission electron microscopy provided visual evidence that changes in the magnetic properties correlated with cell surface interaction of VSOP as well as with alterations of particle structure and arrangement during the phagocytic process. Altogether, A5/A3-adjusted MPS enables highly accurate, cell-preserving VSOP quantification and furthermore provides information on the magnetic characteristics of internalized VSOP.

Magnetorelaxometry procedures for quantitative imaging and characterization of magnetic nanoparticles in biomedical applications.

BACKGROUND: Quantitative knowledge about the spatial distribution and local environment of magnetic nanoparticles (MNPs) inside an organism is essential for guidance and improvement of biomedical applications such as magnetic hyperthermia and magnetic drug targeting. Magnetorelaxometry (MRX) provides such quantitative information by detecting the magnetic response of MNPs following a fast change in the applied magnetic field. METHODS: In this article, we review our MRX based procedures that enable both the characterization and the quantitative imaging of MNPs in a biomedical environment. RESULTS: MRX characterization supported the selection of an MNP system with colloidal stability and suitable cellular MNP uptake. Spatially resolved MRX, a procedure employing multi-channel MRX measurements allowed for in-vivo monitoring of the MNP distribution in a pre-clinical carcinoma animal model. Extending spatially resolved MRX by consecutive magnetization of distinct parts of the sample led to a demonstration of MRX tomography. With this tomography, we reconstructed the three dimensional MNP distribution inside animal sized phantoms with a sensitivity of milligrams of MNPs per cm3. In addition, the targeting efficiency of MNPs in whole blood was assessed using a flow phantom and MRX quantification. CONCLUSION: These MRX based measurement and analysis procedures have substantially supported the development of MNP based biomedical applications.

The 170ms Response to Faces as Measured by MEG (M170) Is Consistently Altered in Congenital Prosopagnosia.

Modularity of face processing is still a controversial issue. Congenital prosopagnosia (cPA), a selective and lifelong impairment in familiar face recognition without evidence of an acquired cerebral lesion, offers a unique opportunity to support this fundamental hypothesis. However, in spite of the pronounced behavioural impairment, identification of a functionally relevant neural alteration in congenital prosopagnosia by electrophysiogical methods has not been achieved so far. Here we show that persons with congenital prosopagnosia can be distinguished as a group from unimpaired persons using magnetoencephalography. Early face-selective MEG-responses in the range of 140 to 200ms (the M170) showed prolonged latency and decreased amplitude whereas responses to another category (houses) were indistinguishable between subjects with congenital prosopagnosia and unimpaired controls. Latency and amplitude of face-selective EEG responses (the N170) which were simultaneously recorded were statistically indistinguishable between subjects with cPA and healthy controls which resolves heterogeneous and partly conflicting results from existing studies. The complementary analysis of categorical differences (evoked activity to faces minus evoked activity to houses) revealed that the early part of the 170ms response to faces is altered in subjects with cPA. This finding can be adequately explained in a common framework of holistic and part-based face processing. Whereas a significant brain-behaviour correlation of face recognition performance and the size of the M170 amplitude is found in controls a corresponding correlation is not seen in subjects with cPA. This indicates functional relevance of the alteration found for the 170ms response to faces in cPA and pinpoints the impairment of face processing to early perceptual stages.

Flow cytometry for intracellular SPION quantification: specificity and sensitivity in comparison with spectroscopic methods.

Due to their special physicochemical properties, iron nanoparticles offer new promising possibilities for biomedical applications. For bench to bedside translation of super-paramagnetic iron oxide nanoparticles (SPIONs), safety issues have to be comprehensively clarified. To understand concentration-dependent nanoparticle-mediated toxicity, the exact quantification of intracellular SPIONs by reliable methods is of great importance. In the present study, we compared three different SPION quantification methods (ultraviolet spectrophotometry, magnetic particle spectroscopy, atomic adsorption spectroscopy) and discussed the shortcomings and advantages of each method. Moreover, we used those results to evaluate the possibility to use flow cytometric technique to determine the cellular SPION content. For this purpose, we correlated the side scatter data received from flow cytometry with the actual cellular SPION amount. We showed that flow cytometry provides a rapid and reliable method to assess the cellular SPION content. Our data also demonstrate that internalization of iron oxide nanoparticles in human umbilical vein endothelial cells is strongly dependent to the SPION type and results in a dose-dependent increase of toxicity. Thus, treatment with lauric acid-coated SPIONs (SEON(LA)) resulted in a significant increase in the intensity of side scatter and toxicity, whereas SEON(LA) with an additional protein corona formed by bovine serum albumin (SEON(LA-BSA)) and commercially available Rienso(®) particles showed only a minimal increase in both side scatter intensity and cellular toxicity. The increase in side scatter was in accordance with the measurements for SPION content by the atomic adsorption spectroscopy reference method. In summary, our data show that flow cytometry analysis can be used for estimation of uptake of SPIONs by mammalian cells and provides a fast tool for scientists to evaluate the safety of nanoparticle products.

Fetal magnetocardiography measurements with an array of microfabricated optically pumped magnetometers.

Following the rapid progress in the development of optically pumped magnetometer (OPM) technology for the measurement of magnetic fields in the femtotesla range, a successful assembly of individual sensors into an array of nearly identical sensors is within reach. Here, 25 microfabricated OPMs with footprints of 1 cm(3) were assembled into a conformal array. The individual sensors were inserted into three flexible belt-shaped holders and connected to their respective light sources and electronics, which reside outside a magnetically shielded room, through long optical and electrical cables. With this setup the fetal magnetocardiogram of a pregnant woman was measured by placing two sensor belts over her abdomen and one belt over her chest. The fetal magnetocardiogram recorded over the abdomen is usually dominated by contributions from the maternal magnetocardiogram, since the maternal heart generates a much stronger signal than the fetal heart. Therefore, signal processing methods have to be applied to obtain the pure fetal magnetocardiogram: orthogonal projection and independent component analysis. The resulting spatial distributions of fetal cardiac activity are in good agreement with each other. In a further exemplary step, the fetal heart rate was extracted from the fetal magnetocardiogram. Its variability suggests fetal activity. We conclude that microfabricated optically pumped magnetometers operating at room temperature are capable of complementing or in the future even replacing superconducting sensors for fetal magnetocardiography measurements.

Magnetoencephalographic accuracy profiles for the detection of auditory pathway sources.

The detection limits for cortical and brain stem sources associated with the auditory pathway are examined in order to analyse brain responses at the limits of the audible frequency range. The results obtained from this study are also relevant to other issues of auditory brain research. A complementary approach consisting of recordings of magnetoencephalographic (MEG) data and simulations of magnetic field distributions is presented in this work. A biomagnetic phantom consisting of a spherical volume filled with a saline solution and four current dipoles is built. The magnetic fields outside of the phantom generated by the current dipoles are then measured for a range of applied electric dipole moments with a planar multichannel SQUID magnetometer device and a helmet MEG gradiometer device. The inclusion of a magnetometer system is expected to be more sensitive to brain stem sources compared with a gradiometer system. The same electrical and geometrical configuration is simulated in a forward calculation. From both the measured and the simulated data, the dipole positions are estimated using an inverse calculation. Results are obtained for the reconstruction accuracy as a function of applied electric dipole moment and depth of the current dipole. We found that both systems can localize cortical and subcortical sources at physiological dipole strength even for brain stem sources. Further, we found that a planar magnetometer system is more suitable if the position of the brain source can be restricted in a limited region of the brain. If this is not the case, a helmet-shaped sensor system offers more accurate source estimation.

Characterization of magnetic nanoparticle systems with respect to their magnetic particle imaging performance.

The optimization of magnetic nanoparticles (MNPs) as markers for magnetic particle imaging (MPI) requires an understanding of the relationship between the harmonics spectrum and the structural and magnetic properties of the MNPs. Although magnetic particle spectroscopy (MPS) - carried out at the same excitation frequency as the given MPI system - represents a straightforward technique to study MNPs for their suitability for MPI, a complete understanding of the mechanisms and differences between different tracer materials requires additional measurements of the static and dynamic magnetic behavior covering additional field and time ranges. Furthermore, theoretical models are needed, which correctly account for the static and dynamic magnetic properties of the markers. In this paper, we give an overview of currently used theoretical models for the explanation of amplitude and phase of the harmonics spectra as well as of the various static and dynamic magnetic techniques, which are applied for the comprehensive characterization of MNPs for MPI. We demonstrate on two multicore MNP model systems, Resovist(®) and FeraSpin™ Series, how a detailed picture of the MPI performance can be obtained by combining various static and dynamic magnetic measurements.

Efficient drug-delivery using magnetic nanoparticles--biodistribution and therapeutic effects in tumour bearing rabbits.

To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR: This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

Validity of subthalamic-cortical coherency observed in patients with Parkinson's disease.

Simultaneous magnetoencephalography (MEG) and local field potential (LFP) recordings in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS) treatment is a promising tool for both clinical application and basic research. Recordings can be accomplished during the time interval between electrode insertion and its connection to the pulse generator while electrodes are being externalized. In nine PD patients, coherence (COH) between LFP and MEG signals was calculated from the data of a 5-min simultaneous MEG-LFP rest recording. For the observed COH patterns, a validation procedure is introduced based on time-shift principal component analysis (TSPCA), which was originally developed to suppress background signals from MEG. Here TSPCA is used as a regression of the MEG signal with filtered versions of the LFP signal to intentionally remove COH. The channel mean of the original COH is compared with the residual channel mean COH after TSPCA application. COH peaks are suppressed in the 15- to 30-Hz range; at lower frequencies, the results are less obvious due to the presence of an artifact caused by a weak remanent magnetization of the externalization wires. The COH suppression is statistically significant for four out of nine subjects, and validation has been achieved, as the COH suppression yields the hypothesized outcome.

Certain types of iron oxide nanoparticles are not suited to passively target inflammatory cells that infiltrate the brain in response to stroke.

Intravenous administration of iron oxide nanoparticles during the acute stage of experimental stroke can produce signal intensity changes in the ischemic region. This has been attributed, albeit controversially, to the infiltration of iron-laden blood-borne macrophages. The properties of nanoparticles that render them most suitable for phagocytosis is a matter of debate, as is the most relevant timepoint for administration. Both of these questions are examined in the present study. Imaging experiments were performed in mice with 30 minutes of middle cerebral artery occlusion (MCAO). Iron oxide nanoparticles with different charges and sizes were used, and mice received 300 µmol Fe/kg intravenously: either superparamagnetic iron oxide nanoparticles (SPIOs), ultrasmall SPIOs, or very small SPIOs. The particles were administered 7 days before MCAO, at the time of reperfusion, or 72 hours after MCAO. Interestingly, there was no observable signal change in the ischemic brains that could be attributed to iron. Furthermore, no Prussian blue-positive cells were found in the brains or blood leukocytes, despite intense staining in the livers and spleens. This implies that the nanoparticles selected for this study are not phagocytosed by blood-borne leukocytes and do not enter the ischemic mouse brain.

Magnetic resonance imaging at frequencies below 1 kHz.

Within the magnetic resonance imaging (MRI) community the trend is going to higher and higher magnetic fields, ranging from 1.5 T to 7 T, corresponding to Larmor frequencies of 63.8-298 MHz. Since for high-field MRI the magnetization increases with the applied magnetic field, the signal-to-noise-ratio increases as well, thus enabling higher image resolutions. On the other hand, MRI is possible also at ultra-low magnetic fields, as was shown by different groups. The goal of our development was to reach a Larmor frequency range of the low-field MRI system corresponding to the frequency range of human brain activities ranging from near zero-frequency (near-DC) to over 1 kHz. Here, first 2D MRI images of phantoms taken at Larmor frequencies of 100 Hz and 731 Hz will be shown and discussed. These frequencies are examples of brain activity triggered by electrostimulation of the median nerve. The method will allow the magnetic fields of the brain currents to influence the magnetic resonance image, and thus lead to a direct functional imaging modality of neuronal currents.

Adapting source grid parameters to improve the condition of the magnetostatic linear inverse problem of estimating nanoparticle distributions.

The problem of estimating magnetic nanoparticle distributions from magnetorelaxometric measurements is addressed here. The objective of this work was to identify source grid parameters that provide a good condition for the related linear inverse problem. The parameters investigated here were the number of sources, the extension of the source grid, and the source direction. A new measure of the condition, the ratio between the largest and mean singular value of the lead field matrix, is proposed. Our results indicated that the source grids should be larger than the sensor area. The sources and, consequently, the magnetic excitation field, should be directed toward the Z-direction. For underdetermined linear inverse problems, such as in our application, the number of sources affects the condition to a relatively small degree. Overdetermined magnetostatic linear inverse problems, however, benefit from a reduction in the number of sources, which considerably improves the condition. The adapted source grids proposed here were used to estimate the magnetostatic dipole from simulated data; the L2-norm, residual, and distances between the estimated and simulated sources were significantly reduced.