New Limit on the Permanent Electric Dipole Moment of

We report results of a new technique to measure the electric dipole moment of ^{129}Xe with ^{3}He comagnetometry. Both species are polarized using spin-exchange optical pumping, transferred to a measurement cell, and transported into a magnetically shielded room, where SQUID magnetometers detect free precession in applied electric and magnetic fields. The result from a one week measurement campaign in 2017 and a 2.5 week campaign in 2018, combined with detailed study of systematic effects, is d_{A}(^{129}Xe)=(1.4±6.6_{stat}±2.0_{syst})×10^{-28} e cm. This corresponds to an upper limit of |d_{A}(^{129}Xe)|<1.4×10^{-27} e cm (95% C.L.), a factor of 5 more sensitive than the limit set in 2001.

Constraints on spin-dependent short-range interaction between nucleons.

We search for a spin-dependent P- and T-violating nucleon-nucleon interaction mediated by light pseudoscalar bosons such as axions or axionlike particles. We employ an ultrasensitive low-field magnetometer based on the detection of free precession of colocated 3He and 129Xe nuclear spins using SQUIDs as low-noise magnetic flux detectors. The precession frequency shift in the presence of an unpolarized mass was measured to determine the coupling of pseudoscalar particles to the spin of the bound neutron. For boson masses between 2 and 500 µeV (force ranges between 3×1(-4) m and 10(-1) m) we improved the laboratory upper bounds by up to 4 orders of magnitude.

Magnetorelaxometric quantification of magnetic nanoparticles in an artery model after ex vivo magnetic drug targeting.

In magnetic drug targeting a chemotherapeutic agent is bound to coated magnetic nanoparticles, which are administered to the blood vessel system and subsequently focused by an external applied magnetic field. The optimization of intra-arterial magnetic drug targeting (MDT) requires detailed knowledge about the biodistribution of particles in the artery and the respective surrounding after the application. Here, we demonstrate the potential of magnetorelaxometry for quantifying the distribution of magnetic nanoparticles in the artery. To this end, we present a magnetorelaxometry investigation of a MDT study in an artery model. In particular, the absolute magnetic nanoparticle accumulation along the artery as well as the uptake profile along the region around the MDT-magnet position was quantified.

Characterization of the behavior of alginate-based microcapsules in vitro and in vivo.

OBJECTIVES: Functional formulations providing protection of nutritional products against gastric juice or a capable of delivering them to distinct areas of the gastrointestinal tract are increasingly utilized by the food industry. However, the application of functional excipients that are established in pharmaceutical applications is limited in case of food products, as they are typically not classified as Generally Recognized As Safe (GRAS). MATERIALS: Accordingly, we investigated whether two alginate-based microcapsule preparations (capsule diameter 1 - 2 mm) either based on alginate and maize starch (MS-type) or alginate and casein (OCF27-type) and both created from ingredients classified as food supplements provide functional properties with respect to regional gastrointestinal targeting. METHODS: For this purpose the in vitro disintegration and swelling of the microcapsules was tested in various media. Furthermore, individual microcapsules, magnetically labelled with 100 - 200 microg black iron oxide, were ingested by healthy volunteers under fasting and fed conditions. Gastrointestinal transit as well as the gastrointestinal disintegration behavior were determined by using Magnetic Marker Monitoring. RESULTS: The results of in vitro and in vivo investigations show that both types of microcapsules are resistant to gastric juice for approximately 10 hrs under fasting and fed conditions. However, the disintegration characteristics of the two types of microcapsules within the intestines are different. CONCLUSION: Whilst the MS-type of capsules disintegrated predominantly within the small intestine shortly after gastric emptying, the OCF27-type of capsules underwent a rather slow disintegration predominantly in the colon.

Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying.

The rate and extent of amoxicillin and clavulanic acid absorption from pharmacokinetically enhanced extended release (ER) tablets is strongly influenced by the intake conditions. In order to investigate the cause of the food effects, a pharmacokinetic study with simultaneous imaging of the in vivo behaviour of the ER tablets by magnetic marker monitoring (MMM) was performed. Under fasting conditions the amoxicillin AUC (1854+/-280microg min ml(-1)) was significantly lower than after intake at the beginning of the breakfast (2452+/-354microg min ml(-1)) or after the breakfast (2605+/-446microg min ml(-1)). In contrast, clavulanic acid AUC was well comparable after tablet intake under fasting conditions and intake at the beginning of a breakfast (191+/-46 and 189+/-44microg min ml(-1), respectively) but significantly lower following a breakfast (126+/-71microg min ml(-1)). The localization data showed that the reduced bioavailability of amoxicillin under fasting conditions is due to early gastric emptying in combination with poor absorption from deeper parts of the small intestine. Prolonged gastric residence of clavulanic acid caused by intragastric tablet deposition in the proximal stomach was identified as the reason for the decreased bioavailability of clavulanic acid after tablet intake following the meal.

Latency analysis of single auditory evoked M100 responses by spatio-temporal filtering.

Appropriate spatial filtering followed by temporal filtering is well suited for the single-trial analysis of multi-channel magnetoencephalogram or electroencephalogram recordings. This is demonstrated by the results of a single-trial latency analysis obtained for auditory evoked M100 responses from nine subjects using two different stimulation frequencies. Spatial filters were derived automatically from the data via noise-adjusted principle component analysis, and single-trial latencies were estimated from the signal phase after complex bandpass filtering. For each of the two stimulation frequencies, estimated single-trial latencies were consistent with results obtained from a standard approach using averaged evoked responses. The quality of the estimated single-trial latencies was additionally assessed by their ability to separate between the two different stimulation frequencies. As a result, more than 80% of the single trials can be classified correctly by their estimated latencies.

Cross-correlation analysis of the correspondence between magnetoencephalographic and near-infrared cortical signals.

OBJECTIVES: The study of neurovascular coupling greatly benefits from combined measurements of neuronal and vascular signals. Two-step signal processing is developed to extract parameters describing the coupling. METHODS: Using a magnetometer in an extremely well shielded room a broadband magnetoencephalogram was simultaneously measured with time-resolved near-infrared spectroscopy during a motor activity paradigm. The raw MEG and NIRS data were denoised separately using independent component analysis. RESULTS: After averaging the resulting signals showed motor activity-related changes. The temporal correspondence between MEG and NIRS was assessed plotting a combined trajectory and calculating a cross-correlation. Compared to the MEG signal, at movement onset the NIRS signal showed an onset delay in the range of seconds. CONCLUSIONS: Multi-variate signal pre-processing followed by temporal delay estimates demonstrated the extraction of neurovascular coupling parameters.

DC-magnetoencephalography and time-resolved near-infrared spectroscopy combined to study neuronal and vascular brain responses.

The temporal relation between vascular and neuronal responses of the brain to external stimuli is not precisely known. For a better understanding of the neuro-vascular coupling changes in cerebral blood volume and oxygenation have to be measured simultaneously with neuronal currents. With this motivation modulation dc-magnetoencephalography was combined with multi-channel time-resolved near-infrared spectroscopy to simultaneously monitor neuronal and vascular parameters on a scale of seconds. Here, the technique is described, how magnetic and optical signals can be measured simultaneously. In a simple motor activation paradigm (alternating 30 s of finger movement with 30 s of rest for 40 min) both signals were recorded non-invasively over the motor cortex of eight subjects. The off-line averaged signals from both modalities showed distinct stimulation related changes. By plotting changes in oxy- or deoxyhaemoglobin as a function of magnetic field a characteristic trajectory was created, which was similar to a hysteresis loop. A parametric analysis allowed quantitative results regarding the timing of coupling: the vascular signal increased significantly slower than the neuronal signal.

Quantification of magnetic nanoparticles by magnetorelaxometry and comparison to histology after magnetic drug targeting.

Magnetic nanoparticles can be used in medicine in vivo as contrast agents and as a drug carrier system for chemotherapeutics. Thus local cancer therapy is performed with Magnetic Drug Targeting (MDT) and allows a specific delivery of therapeutic agents to desired targets, i.e., tumors, by using a chemotherapeutic substance bound to magnetic nanoparticles and focused with an external magnetic field to the tumor after intraarterial application. Important for this therapeutic principle is the distribution of the particles in the whole organism and especially in the tumor. Therefore we used magnetorelaxometry to quantify ferrofluids delivered after MDT. Tissue samples of some mm3 volume of a VX2 squamous cell carcinoma were measured by magnetic relaxation and the amount of iron was determined using the original ferrofluid suspension as a reference. From this the distribution of the magnetic particles within the slice of tumor was reconstructed. Histological cross-sections of the respective tumor offer the opportunity to map quantitatively the particle distribution and the vascularisation in the targeted tumor on a microscopic scale. Our data show that the integral method magnetorelaxometry and microscopic histological methods can complete each other efficiently.

Magnetic particle spectroscopy allows precise quantification of nanoparticles after passage through human brain microvascular endothelial cells.

Crossing the blood-brain barrier is an urgent requirement for the treatment of brain disorders. Superparamagnetic iron oxide nanoparticles (SPIONs) are a promising tool as carriers for therapeutics because of their physical properties, biocompatibility, and their biodegradability. In order to investigate the interaction of nanoparticles with endothelial cell layers in detail, in vitro systems are of great importance. Human brain microvascular endothelial cells are a well-suited blood-brain barrier model. Apart from generating optimal conditions for the barrier-forming cell units, the accurate detection and quantification of SPIONs is a major challenge. For that purpose we use magnetic particle spectroscopy to sensitively and directly quantify the SPION-specific iron content. We could show that SPION concentration depends on incubation time, nanoparticle concentration and location. This model system allows for further investigations on particle uptake and transport at cellular barriers with regard to parameters including particles' shape, material, size, and coating.

Pulse NMR study of phase transitions in dipalmitoyl phosphatidylcholine multilayer systems.

Pretransition and main transition of aqueous dipalmitoyl phosphatidylcholine (DPPC) dispersions were investigated by pulse NMR. The second moment M2 inter of the proton absorption line shows significant changes at 42 degrees C and about 35 degree C. Over the whole investigated temperature range between 25 and 50 degree C a superposition of at least two distinct second moments assigned to different molecular regions was observed.

A template-free approach for determining the latency of single events of auditory evoked M100.

The phase of the complex output of a narrow band Gaussian filter is taken to define the latency of the auditory evoked response M100 recorded by magnetoencephalography. It is demonstrated that this definition is consistent with the conventional peak latency. Moreover, it provides a tool for reducing the number of averages needed for a reliable estimation of the latency. Single-event latencies obtained by this procedure can be used to improve the signal quality of the conventional average by latency adjusted averaging.

Non-invasive single-trial monitoring of human movement-related brain activation based on DC-magnetoencephalography.

Neuroimaging techniques, such as fMRI, PET and near-infrared spectroscopy, monitor task-related neuronal activations in the brain indirectly through the associated neurovascular/metabolic responses. To assess the primary neuronal activations directly, magnetoencephalography was combined here with a mechanical modulation of the head-to-sensor position and signal separation via independent component analysis. In all of five subjects this approach allowed to monitor the time evolution of DC fields (<0.1 Hz) over the left hemisphere related to complex finger movements of the right hand alternating with rest periods (30 s each). Throughout the recording period of 30 min, stable task-related DC fields were recordable in a single-trial mode, i.e. without any averaging. DC-MEG opens up the possibility of analysing non-invasively cortical DC-activity also in stroke, migraine or epilepsy patients.

Oesophageal transport of solid dosage forms depends on body position, swallowing volume and pharyngeal propulsion velocity.

Knowledge about transit of solid dosage forms (SDF) in the gastrointestinal tract is incomplete. Detection of magnetically marked capsules (MMC) via superconducting quantum interference device (SQUID) allows monitoring of oesophageal transport of SDF with high tempospatial resolution. The aim of the study was to investigate the influence of body position, volume at swallowing, and oesophageal motility on orogastric transport of SDF. In 360 measurements we determined tempospatial characteristics of orogastric transit of SDFs by a SQUID device in six volunteers. They swallowed MMCs with various amounts of water in upright and supine position with and without simultaneous oesophageal manometry. Orogastric transit time, oesophageal transport velocity and rate of oesophageal retention of SDF depend on swallowing volume and body position at all experimental conditions. At 50 mL water bolus and in upright position, the retention rate depends on the pharyngeal propulsion velocity, and the transport velocity of MMCs in the oesophageal body are faster than the propulsive oesophageal contractions. Body position, swallowing volume and pharyngeal propulsion velocity markedly influence the oesophageal transport of SDF. They should be taken in upright body position with at least 50 mL of water to minimize entrapment in the oesophagus.

Magnetoneurography of evoked compound action currents in human cervical nerve roots.

OBJECTIVE: A measurement protocol for magnetoneurography (MNG) is established which allows the non-invasive localization and tracing of evoked compound action currents propagating along cervical nerve roots in man. METHODS: Inside a magnetically shielded room either both median or both ulnar nerves of healthy subjects were conventionally electrostimulated in alternation. Evoked magnetic responses were recorded using a multichannel SQUID-detector with a planar measuring area centered over the neck. Simultaneously, electric surface potentials were recorded using cervical bipolar electrode montages. RESULTS: Upon median (ulnar) nerve stimulation somatosensory evoked magnetic fields up to 20 fT (10 fT) amplitude were detected propagating over the cervical transforaminal root entry zone, with corresponding electrical surface potentials of 1.5 microV (0.5 microV). Furthermore, the signal-to-noise ratio of the spatiotemporal magnetic field mappings in median nerve stimulation experiments allowed dipolar source reconstructions and tracing of the propagation of the compound action currents along nerve root fibers. CONCLUSION: Magnetoneurography allows tracing of the propagation of evoked compound action currents along cervical roots in healthy subjects with millisecond temporal and high spatial resolution. Thus, MNG offers a sensitivity appropriate to serve as a clinical diagnostic tool for localizing focal neuropathies of cervical nerve roots.

Tracing of proximal lumbosacral nerve conduction--a comparison of simultaneous magneto- and electroneurography.

OBJECTIVE: The reconstruction of nerve impulse conduction along proximal lumbosacral plexus and nerve roots is compared using simultaneous magneto- and electroneurography. METHODS: In 3 healthy subjects the left tibial nerve was electrostimulated at the ankle. Evoked magnetic fields and electric surface potentials were measured simultaneously over the lumbosacral spine using a multichannel SQUID-detector with a planar measuring area and 25 surface electrodes covering a comparable area centered around L4. Based on either magnetic field or electric potential maps the depolarization front of the evoked compound action currents (CAC) was spatio-temporally reconstructed using a simple equivalent current dipole model in a half-space volume conductor. RESULTS: The mean signal-to-noise ratio in the magnetic (electric) recordings was around 4 (8). Yet, the localization quality for the propagating CAC was lower for electric than magnetic recordings. The local nerve conduction velocity was around 47 m/s (calculated from magnetic data), but fluctuated unphysiologically for electric data. CONCLUSION: In comparison to electroneurography, an anatomically reasonable localization of evoked compound action currents propagating in lumbosacral roots can be obtained by magnetoneurography.

Hyperventilation-induced human cerebral magnetic fields non-invasively monitored by multichannel 'direct current' magnetoencephalography.

Self-paced hyperventilation (HV) induces slow cerebral magnetic field changes which were monitored and mapped continuously over 15 min using 49-channel DC-coupled ('direct current') magnetoencephalography (DC-MEG) based on a modulation technique. In nine/nine healthy subjects HV caused an increase (range: 1.1-6.2 pT) of the mean global DC-MEG field strength which slowly decayed after HV termination (mean time constant: 2 min). The complex HV-related field patterns were distinctly different from mainly dipolar somatosensory evoked field maps (N20m) in four/four subjects. Thus, current sources in the primary somatosensory cortex need not regularly dominate DC-field changes as had been previously considered. Rather, DC-MEG enabled the monitoring of a widely distributed HV-induced enhanced cortical excitability which may serve as model to study epileptic or post-anoxic cerebral hyperexcitability.

Non-invasive magnetoneurography for 3D-monitoring of human compound action current propagation in deep brachial plexus.

Compound action current (CAC) propagation along nerve fibers running deep in the human brachial plexus was 3D-visualized based on non-invasive 49-channel superconducting quantum interference device (SQUID) magnetoneurography. Spatio-temporal mappings over the upper thoracal quadrant of magnetic fields (<100 fT) evoked upon alternating median and ulnar nerve stimulation in seven healthy volunteers showed consistently smoothly propagating dipolar patterns for both the CAC depolarization and repolarization phases. Multipolar current source reconstructions (i) distinguished spatially CAC propagation pathways along either median or ulnar plexus fibers, allowed (ii) to calculate local conduction velocities ( approximately 56 m/s) and (iii) even to estimate the CAC extension along the nerve fibers (depolarization phase: approximately 11 cm). Thus, for deep proximal nerve segments magnetoneurography can provide a detailed tracing of neural activity which is a prerequisite to localize non-invasively focal nerve malfunctions.

Non-invasive long-term recordings of cortical 'direct current' (DC-) activity in humans using magnetoencephalography.

Recently, biomagnetic fields below 0.1 Hz arising from nerve or muscle injury currents have been measured non-invasively using superconducting quantum interference devices (SQUIDs). Here we report first long-term recordings of cortical direct current (DC) fields in humans based on a horizontal modulation (0.4 Hz) of the body and, respectively, head position beneath the sensor array: near-DC fields with amplitudes between 90 and 540 fT were detected in 5/5 subjects over the auditory cortex throughout prolonged stimulation periods (here: 30 s) during which subjects were listening to concert music. These results prove the feasibility to record non-invasively low amplitude near-DC magnetic fields of the human brain and open the perspective for studies on DC-phenomena in stroke, such as anoxic depolarization or periinfarct depolarization, and in migraine patients.

Magnetometry of evoked fields from human peripheral nerve, brachial plexus and primary somatosensory cortex using a liquid nitrogen cooled superconducting quantum interference device.

Superconducting Quantum Interference Devices (SQUIDs) can be used to detect neuromagnetic fields evoked in the peripheral and central nervous system. Up to now, such measurements had to be based on SQUIDs with a low critical temperature (Tc) requiring liquid helium cooling. Recent improvements in high-Tc SQUID technology relying on liquid nitrogen cooling led to a significant reduction in the system's noise level. Hare, first high-Tc recordings of weak neuromagnetic fields are demonstrated. In particular, along the entire somatosensory afferent pathway including peripheral nerves, brachial plexus and primary somatosensory neocortex evoked neuromagnetic activities were detected using conventional recording parameters for bandwidth and number of averages. This opens up a wide perspective for cost-effective high-Tc magnetometry in clinical neuroscience.