A compact setup for behavioral studies measuring limb acceleration.

Behavioral studies contribute largely to a broader understanding of human brain mechanisms and the process of learning and memory. An established method to quantify motor learning is the analysis of thumb activity. In combination with brain stimulation, the effect of various treatments on neural plasticity and motor learning can be assessed. So far, the setups for thumb abduction measurements employed consist of bulky amplifiers and digital-to-analog devices to record the data. We developed a compact hardware setup to measure acceleration data which can be integrated into a wearable, including a sensor board and a microcontroller board which can be connected to a PC via USB. Additionally, we provide two software packages including graphical user interfaces, one to communicate with the hardware and one to evaluate and process the data. This work demonstrates the construction and application of our setup at the example of thumb acceleration measurement with a custom made glove and its use for research. Using integrated circuits, the size of the measurement devices is reduced to this wearable. It is simple to construct and can be operated easily by non-technical staff.

Low energy magnetic stimulation of the phrenic nerve - a simulation study.

Peripheral magnetic stimulation is a promising assistive technique for rehabilitation. Today's magnetic stimulation devices, designed for transcranial stimulation, operate at currents of 6 kA and higher. This makes them expensive and bulky. Many motor neurons in peripheral nerves are more accessible, have large diameters, and require significantly lower field strengths for stimulation. In this work, we present a simulation environment to determine the threshold current required to trigger an action potential in phrenic nerve motor neurons for different coil geometries. An anatomical model was used for coil placement and realistic field calculations. The field distribution was calculated using the finite integration technique and then applied to a neuronal model to simulate the axon membrane dynamics. For general applicability, the coil-nerve distance and the axon diameter were varied. We show that the required current was approximately 1.3 kA for a nerve-coil distance of 35 mm, which corresponds to 20% of the available power of a commercial TMS device. By including the nearby vagus nerve in the simulations, we showed that accidental stimulation of this nerve is highly unlikely. Our results pave the way for the development of smaller, less complex, and more affordable stimulators and promise to increase the use of peripheral magnetic stimulators in clinical settings.

Multi-Scale Investigation of Human Renal Tissue in Three Dimensions.

Histopathology as a diagnostic mainstay for tissue evaluation is strictly a 2D technology. Combining and supplementing this technology with 3D imaging has been proposed as one future avenue towards refining comprehensive tissue analysis. To this end, we have developed a laboratory-based X-ray method allowing for the investigation of tissue samples in three dimensions with isotropic volume information. To assess the potential of our method for micro-morphology evaluation, we selected several kidney regions from three patients with cystic kidney disease, obstructive nephropathy and diabetic glomerulopathy. Tissue specimens were processed using our in-house-developed X-ray eosin stain and investigated with a commercial microCT and our in-house-built NanoCT. The microCT system provided overview scans with voxel sizes of [Formula: see text] and the NanoCT was employed for higher resolutions including voxel sizes from [Formula: see text] to 210 nm. We present a methodology allowing for a precise micro-morphologic investigation in three dimensions which is compatible with conventional histology. Advantages of our methodology are its versatility with respect to multi-scale investigations, being laboratory-based, allowing for non-destructive imaging and providing isotropic volume information. We believe, that after future developmental work this method might contribute to advanced multi-modal tissue diagnostics.

Optimal pulse configuration for peripheral inductive nerve stimulation.

Peripheral magnetic stimulation is a promising technique for several applications like rehabilitation or diagnose of neuronal pathways. However, most available magnetic stimulation devices are designed for transcranial stimulation and require high-power, expensive hardware. Modern technology such as rectangular pulses allows to adapt parameters like pulse shape and duration in order to reduce the required energy. Nevertheless, the effect of different temporal electromagnetic field shapes on neuronal structures is not yet fully understood. We created a simulation environment to find out how peripheral nerves are affected by induced magnetic fields and what pulse shapes have the lowest energy requirements. Using the electric field distribution of afigure-of-8coil together with an axon model in saline solution, we calculated the potential along the axon and determined the required threshold current to elicit an action potential. Further, for the purpose of selective stimulation, we investigated different axon diameters. Our results show that rectangular pulses have the lowest thresholds at a pulse duration of 20µs. For sinusoidal coil currents, the optimal pulse duration was found to be 40µs. Most importantly, with an asymmetric rectangular pulse, the coil current could be reduced from 2.3 kA (cosine shaped pulse) to 600 A. In summary, our results indicate that for magnetic nerve stimulation the use of rectangular pulse shapes holds the potential to reduce the required coil current by a factor of 4, which would be a massive improvement.

Human-sized magnetic particle imaging for brain applications.

Determining the brain perfusion is an important task for diagnosis of vascular diseases such as occlusions and intracerebral haemorrhage. Even after successful diagnosis, there is a high risk of restenosis or rebleeding such that patients need intense attention in the days after treatment. Within this work, we present a diagnostic tomographic imager that allows access to brain perfusion quantitatively in short intervals. The device is based on the magnetic particle imaging technology and is designed for human scale. It is highly sensitive and allows the detection of an iron concentration of 263 pmolFe ml-1, which is one of the lowest iron concentrations imaged by MPI so far. The imager is self-shielded and can be used in unshielded environments such as intensive care units. In combination with the low technical requirements this opens up a variety of medical applications and would allow monitoring of stroke on intensive care units.

Dynamic In Vivo Chest X-ray Dark-Field Imaging in Mice.

X-ray grating interferometry is a powerful emerging tool in biomedical imaging, providing access to three complementary image modalities. In addition to the conventional attenuation modality, interferometry provides a phase modality, which visualizes soft tissue structures, and a dark-field modality, which relates to the number and size of sub-resolution scattering objects. A particularly strong dark-field signal originates from the alveoli or air sacs in the lung. Dark-field lung radiographs in animal models have already shown increased sensitivity in diagnosing lung diseases, such as lung cancer or emphysema, compared to conventional X-ray chest radiography. However, to date, X-ray dark-field lung imaging has either averaged information over several breaths or has been captured during a breath hold. In this paper, we demonstrate the first time-resolved dark-field imaging of a breath cycle in a mechanically ventilated mouse, in vivo, which was obtained using a grating interferometer. We achieved a time resolution of 0.1 s, visualizing the changes in the dark-field, phase, and attenuation images during inhalation and exhalation. These measurements show that the dark-field signal depends on the air volume and, hence, the alveolar dimensions of the lung. Conducting this type of scan with animal disease models would help to locate the optimum breath point for single-image diagnostic dark-field imaging and could indicate if the changes in the dark-field signal during breath provide a diagnostically useful complementary measure.

Analysis of 2D NMR relaxation data using Chisholm approximations.

To analyze 2D NMR relaxation data based on a discrete delta-like relaxation map we extended the Padé-Laplace method to two dimensions. We approximate the forward Laplace image of the time domain signal by a Chisholm approximation, i.e. a rational polynomial in two dimensions. The poles and residues of this approximation correspond to the relaxation rates and weighting factors of the underlying relaxation map. In this work we explain the principle ideas of our algorithm and demonstrate its applicability. Therefore we compare the inversion results of the Chisholm approximation and Tikhonov regularization method as a function of SNR when the investigated signal is based on a given discrete relaxation map. Our algorithm proved to be reliable for SNRs larger than 50 and is able to compete with the Tikhonov regularization method. Furthermore we show that our method is also able to detect the simulated relaxation compartments of narrow Gaussian distributions with widths less or equal than 0.05s-1. Finally we investigate the resolution limit with experimental data. For a SNR of 750 the Chisholm approximation method was able to resolve two relaxation compartments in 8 of 10 cases when both compartments differ by a factor of 1.7.

First experimental evidence of the feasibility of multi-color magnetic particle imaging.

Magnetic particle imaging is a new approach to visualizing magnetic nanoparticles. It is capable of 3D real-time in vivo imaging of particles injected into the blood stream and is a candidate for medical imaging applications. To date, only one particle type has been imaged at a time, however, the ability to separate signals acquired simultaneously from different particle types or from particles in different environments would substantially increase the scope of the method. Different colors could be assigned to different signal sources to allow for visualization in a single image. Successful signal separation has been reported in spectroscopic experiments, but it was unclear how well separation would work in conjunction with spatial encoding in an imaging experiment. This work presents experimental evidence of the separability of signals from different particle types and aggregation states (fluid versus powder) using a 'multi-color' reconstruction approach. Several mechanisms are discussed that may form the basis for successful signal separation.

Quantitative "Hot Spot" Imaging of Transplanted Stem Cells using Superparamagnetic Tracers and Magnetic Particle Imaging (MPI).

Magnetic labeling of stem cells enables their non-invasive detection by magnetic resonance imaging (MRI). Practically, most MRI studies have been limited to visualization of local engraftment as other sources of endogenous hypointense contrast complicate the interpretation of systemic (whole body) cell distribution. In addition, MRI cell tracking is inherently non-quantitative in nature. We report here on the potential of magnetic particle imaging (MPI) as a novel tomographic technique for non-invasive hot spot imaging and quantification of stem cells using superparamagnetic iron oxide (SPIO) tracers. Neural and mesenchymal stem cells, representing small and larger cell bodies, were labeled with three different SPIO tracer formulations, including two preparations that have previously been used in clinical MRI cell tracking studies (Feridex® and Resovist®). Magnetic particle spectroscopy (MPS) measurements demonstrated a linear correlation between MPI signal and iron content, for both homogeneous solutions of free particles in solution and for internalized and aggregated particles in labeled cells over a wide range of concentrations. The overall MP signal ranged from 1×10-3 - 3×10-4 Am2/g Fe, which was equivalent to 2×10-14 - 1×10-15 Am2 per cell, indicating that cell numbers can be quantified with MPI analogous to the use of radiotracers in nuclear medicine or fluorine tracers in 19F MRI. When SPIO-labeled cells were transplanted in mouse brain, they could be readily detected by MPI at a detection threshold of about 5×104 cells, with MPI/MRI overlays showing an excellent agreement between the hypointense MRI areas and MPI hot spots. The calculated tissue MPI signal ratio for 100,000 vs. 50,000 implanted cells was 2.08. Hence, MPI has potential to be further developed for quantitative and easy-to-interpret, tracer-based non-invasive imaging of cells, preferably with MRI as an adjunct anatomical imaging modality.

Nanoparticle encapsulation in red blood cells enables blood-pool magnetic particle imaging hours after injection.

Magnetic particle imaging (MPI) is a new medical imaging approach that is based on the nonlinear magnetization response of super-paramagnetic iron oxide nanoparticles (SPIOs) injected into the blood stream. To date, real-time MPI of the bolus passage of an approved MRI SPIO contrast agent injected into the tail vein of living mice has been demonstrated. However, nanoparticles are rapidly removed from the blood stream by the mononuclear phagocyte system. Therefore, imaging applications for long-term monitoring require the repeated administration of bolus injections, which complicates quantitative comparisons due to the temporal variations in concentration. Encapsulation of SPIOs into red blood cells (RBCs) has been suggested to increase the blood circulation time of nanoparticles. This work presents first evidence that SPIO-loaded RBCs can be imaged in the blood pool of mice several hours after injection using MPI. This finding is supported by magnetic particle spectroscopy performed to quantify the iron concentration in blood samples extracted from the mice 3 and 24 h after injection of SPIO-loaded RBCs. Based on these results, new MPI applications can be envisioned, such as permanent 3D real-time visualization of the vessel tree during interventional procedures, bleeding monitoring after stroke, or long-term monitoring and treatment control of cardiovascular diseases.

Fast reconstruction in magnetic particle imaging.

Magnetic particle imaging (MPI) is a new tomographic imaging method which is able to capture the fast dynamic behavior of magnetic tracer material. From measured induced signals, the unknown magnetic particle concentration is reconstructed using a previously determined system function, which describes the relation between particle position and signal response. After discretization, the system function is represented by a matrix, whose size can prohibit the use of direct solvers for matrix inversion to reconstruct the image. In this paper, we present a new reconstruction approach, which combines efficient compression techniques and iterative reconstruction solvers. The data compression is based on orthogonal transforms, which extract the most relevant information from the system function matrix by thresholding, such that any iterative solver is strongly accelerated. The effect of the compression with respect to memory requirements, computational complexity and image quality is investigated. With the proposed method, it is possible to achieve real-time reconstruction with almost no loss in image quality using measured 4D MPI data.

Magnetic stents retain nanoparticle-bound antirestenotic drugs transported by lipid microbubbles.

PURPOSE: Coating coronary stents with antirestenotic drugs revolutionized interventional cardiology. We developed a system for post-hoc drug delivery to uncoated stents. METHODS: We coupled rapamycin or a chemically similar fluorescent dye to superparamagnetic nanoparticles. The antiproliferative activity of rapamycin coupled to nanoparticles was confirmed in vitro in primary porcine vascular cells. The particles were then incorporated into lipid based microbubbles. Commercially available stents were made magnetizable by nickel plating and used to induce strong field gradients in order to capture magnetic microbubbles from flowing liquids when placed in an external magnetic field. RESULTS: Nanoparticle bound Rapamycin dose dependently inhibited cell proliferation in vitro. Magnetic microcbubbles carrying coated nanoparticles were caught by magnets placed external to a flow-through tube. Plating commercial stents with nickel resulted in increased deposition at stent struts and allowed for widely increased distance of external magnets. Deposition depended on circulation time and velocity and distance of magnets. Deposited microbubbles were destroyed by ultrasound and delivered their cargo to targeted sites. CONCLUSIONS: Drugs can be incorporated into nanoparticle loaded microbubbles and thus be delivered to magnetizable stents from circulating fluids by applying external magnetic fields. This technology could allow for post-hoc drug coating of already implanted vascular stents.

[Functional magnetic stimulation as a supposedly 'painless' option for movement induction in plegics]. / Funktionelle Magnetstimulation als "schmerzlose" Variante der künstlichen Bewegungsinduktion bei Lähmungen.

BACKGROUND: It is known in the rehabilitation of central pareses that functional electrical stimulation (FES) of the muscles can induce movement and accomplish training in patients. The main limitations of this method are that patients with preserved sensation experience pain and the reflexes triggered by FES. Therefore the application of the largely "painless" magnetic stimulation (FMS) of the muscles would be a potential alternative in the rehabilitation of patients with partially preserved sensation. As the generation of high force and power levels is considered to be an essential requirement of effective rehabilitation strategies, we have shown in previous work that FMS with large surface magnetic coils fitted to the thigh can generate about 2.5 times higher isometric forces in patients with preserved sensation, than can FES. OBJECTIVES: The goal of the present pilot study was to prove that the mechanical power generated by functional magnetic stimulation is superior to that produced by electrical stimulation too. METHODS: We have measured the mechanical torque, the power, the accomplished work and the kinematics in 4 healthy control subjects, who performed pedalling propelled by FMS and FES until complete muscular exhaustion, using a cycling test-bed under isotonic conditions (constant resistance). RESULTS: We have proved that the generated work, mean power, cadence and smoothness of pedalling essentially depend on peak torque and power. Furthermore, we found evidence that smoother pedalling could be achieved using magnetic, compared to electrical stimulation because of the higher peak torques that were generated by FMS. CONCLUSION: This study supports the concept that peripheral magnetic stimulation is an appropriate rehabilitation method for patients with central pareses and preserved sensory apparatus because FMS is less painful than electrical stimulation.

Comparison of coil designs for peripheral magnetic muscle stimulation.

The recent application of magnetic stimulation in rehabilitation is often said to solve key drawbacks of the established electrical method. Magnetic fields cause less pain, allow principally a better penetration of inhomogeneous biologic tissue and do not require skin contact. However, in most studies the evoked muscle force has been disappointing. In this paper, a comparison of a classical round circular geometry, a commercial muscle-stimulation coil and a novel design is presented, with special emphasis on the physical field properties. These systems show markedly different force responses for the same magnetic energy and highlight the enormous potential of different coil geometries. The new design resulted in a slope of the force recruiting curve being more than two and a half times higher than the other coils. The data were analyzed with respect to the underlying physical causes and field conditions. After a parameter-extraction approach, the results for the three coils span a two-dimensional space with clearly distinguishable degrees of freedom, which can be manipulated nearly separately and reflect the two main features of a field; the peak amplitude and its decay with the distance.

Human erythrocytes as nanoparticle carriers for magnetic particle imaging.

The potential of red blood cells (RBCs) loaded with iron oxide nanoparticles as a tracer material for magnetic particle imaging (MPI) has been investigated. MPI is an emerging, quantitative medical imaging modality which holds promise in terms of sensitivity in combination with spatial and temporal resolution. Steady-state and dynamic magnetization measurements, supported by semi-empirical modeling, were employed to analyze the MPI signal generation using RBCs as novel biomimetic constructs. Since the superparamagnetic iron oxide (SPIO) bulk material that is used in this study contains nanoparticles with different sizes, it is suggested that during the RBC loading procedure, a preferential entrapment of nanoparticles with hydrodynamic diameter ≤60 nm occurs by size-selection through the erythrocyte membrane pores. This affects the MPI signal of an erythrocyte-based tracer, compared to bulk. The reduced signal is counterbalanced by a higher in vivo stability of the SPIO-loaded RBCs constructs for MPI applications.

Weighted iterative reconstruction for magnetic particle imaging.

Magnetic particle imaging (MPI) is a new imaging technique capable of imaging the distribution of superparamagnetic particles at high spatial and temporal resolution. For the reconstruction of the particle distribution, a system of linear equations has to be solved. The mathematical solution to this linear system can be obtained using a least-squares approach. In this paper, it is shown that the quality of the least-squares solution can be improved by incorporating a weighting matrix using the reciprocal of the matrix-row energy as weights. A further benefit of this weighting is that iterative algorithms, such as the conjugate gradient method, converge rapidly yielding the same image quality as obtained by singular value decomposition in only a few iterations. Thus, the weighting strategy in combination with the conjugate gradient method improves the image quality and substantially shortens the reconstruction time. The performance of weighting strategy and reconstruction algorithms is assessed with experimental data of a 2D MPI scanner.

Three-dimensional real-time in vivo magnetic particle imaging.

Magnetic particle imaging (MPI) is a new tomographic imaging method potentially capable of rapid 3D dynamic imaging of magnetic tracer materials. Until now, only dynamic 2D phantom experiments with high tracer concentrations have been demonstrated. In this letter, first in vivo 3D real-time MPI scans are presented revealing details of a beating mouse heart using a clinically approved concentration of a commercially available MRI contrast agent. A temporal resolution of 21.5 ms is achieved at a 3D field of view of 20.4 x 12 x 16.8 mm(3) with a spatial resolution sufficient to resolve all heart chambers. With these abilities, MPI has taken a huge step toward medical application.

Trajectory analysis for magnetic particle imaging.

Recently a new imaging technique called magnetic particle imaging was proposed. The method uses the nonlinear response of magnetic nanoparticles when a time varying magnetic field is applied. Spatial encoding is achieved by moving a field-free point through an object of interest while the field strength in the vicinity of the point is high. A resolution in the submillimeter range is provided even for fast data acquisition sequences. In this paper, a simulation study is performed on different trajectories moving the field-free point through the field of view. The purpose is to provide mandatory information for the design of a magnetic particle imaging scanner. Trajectories are compared with respect to density, speed and image quality when applied in data acquisition. Since simulation of the involved physics is a time demanding task, moreover, an efficient implementation is presented utilizing caching techniques.

Experimental results on fast 2D-encoded magnetic particle imaging.

This paper presents the first experimental results on magnetic particle imaging with full 2D encoding. The encoding speed achieved was 3.88 ms for a field of view of 1x1 cm2. Small phantoms composed of several dots each filled with 200 nl undiluted Resovist (500 mmol(Fe) l(-1)) were scanned. A resolution of better than 1 mm was achieved for a frame rate of 25 frames s(-1).