On-scalp MEG SQUIDs are sensitive to early somatosensory activity unseen by conventional MEG.

Magnetoencephalography (MEG) has a unique capacity to resolve the spatio-temporal development of brain activity from non-invasive measurements. Conventional MEG, however, relies on sensors that sample from a distance (20-40 â€‹mm) to the head due to thermal insulation requirements (the MEG sensors function at 4 â€‹K in a helmet). A gain in signal strength and spatial resolution may be achieved if sensors are moved closer to the head. Here, we report a study comparing measurements from a seven-channel on-scalp SQUID MEG system to those from a conventional (in-helmet) SQUID MEG system. We compared the spatio-temporal resolution between on-scalp and conventional MEG by comparing the discrimination accuracy for neural activity patterns resulting from stimulating five different phalanges of the right hand. Because of proximity and sensor density differences between on-scalp and conventional MEG, we hypothesized that on-scalp MEG would allow for a more high-resolved assessment of these activity patterns, and therefore also a better classification performance in discriminating between neural activations from the different phalanges. We observed that on-scalp MEG provided better classification performance during an early post-stimulus period (10-20 â€‹ms). This corresponded to the electroencephalographic (EEG) component P16/N16 and was an unexpected observation as this component is usually not observed in conventional MEG. This finding shows that on-scalp MEG enables a richer registration of the cortical signal, indicating a sensitivity to what are potentially sources in the thalamo-cortical radiation. We had originally expected that on-scalp MEG would provide better classification accuracy based on activity in proximity to the P60m component compared to conventional MEG. This component indeed allowed for the best classification performance for both MEG systems (60-75%, chance 50%). However, we did not find that on-scalp MEG allowed for better classification than conventional MEG at this latency. We suggest that this absence of differences is due to the limited sensor coverage in the recording, in combination with our strategy for positioning the on-scalp MEG sensors. We show how the current sensor coverage may have limited our chances to register the necessary between-phalange source field dissimilarities for fair hypothesis testing, an approach we otherwise believe to be useful for future benchmarking measurements.

On-scalp MEG sensor localization using magnetic dipole-like coils: A method for highly accurate co-registration.

Source modelling in magnetoencephalography (MEG) requires precise co-registration of the sensor array and the anatomical structure of the measured individual's head. In conventional MEG, the positions and orientations of the sensors relative to each other are fixed and known beforehand, requiring only localization of the head relative to the sensor array. Since the sensors in on-scalp MEG are positioned on the scalp, locations of the individual sensors depend on the subject's head shape and size. The positions and orientations of on-scalp sensors must therefore be measured at every recording. This can be achieved by inverting conventional head localization, localizing the sensors relative to the head - rather than the other way around. In this study we present a practical method for localizing sensors using magnetic dipole-like coils attached to the subject's head. We implement and evaluate the method in a set of on-scalp MEG recordings using a 7-channel on-scalp MEG system based on high critical temperature superconducting quantum interference devices (high-Tc SQUIDs). The method allows individually localizing the sensor positions, orientations, and responsivities with high accuracy using only a short averaging time (≤ 2 â€‹mm, < 3° and < 3%, respectively, with 1-s averaging), enabling continuous sensor localization. Calibrating and jointly localizing the sensor array can further improve the accuracy of position and orientation (< 1 â€‹mm and < 1°, respectively, with 1-s coil recordings). We demonstrate source localization of on-scalp recorded somatosensory evoked activity based on co-registration with our method. Equivalent current dipole fits of the evoked responses corresponded well (within 4.2 â€‹mm) with those based on a commercial, whole-head MEG system.

Grooved Dayem Nanobridges as Building Blocks of High-Performance YBa2Cu3O7-δ SQUID Magnetometers.

We present noise measurements performed on a YBa2Cu3O7-δ nanoscale weak-link-based magnetometer consisting of a superconducting quantum interference device (SQUID) galvanically coupled to a 3.5 × 3.5 mm2 pick-up loop, reaching white flux noise levels and magnetic noise levels as low as [Formula: see text] and 100 fT/[Formula: see text] at T = 77 K, respectively. The low noise is achieved by introducing grooved Dayem bridges (GDBs), a new concept of a weak link. A fabrication technique has been developed for the realization of nanoscale grooved bridges, which substitutes standard Dayem bridge weak links. The introduction of these novel key blocks reduces the parasitic inductance of the weak links and increases the differential resistance of the SQUIDs. This greatly improves the device performance, thus resulting in a reduction of the white noise.

Nanopatterning of Weak Links in Superconducting Oxide Interfaces.

The interface between two wide band-gap insulators, LaAlO3 and SrTiO3 (LAO/STO), hosts a quasi-two-dimensional electron gas (q2DEG), two-dimensional superconductivity, ferromagnetism, and giant Rashba spin-orbit coupling. The co-existence of two-dimensional superconductivity with gate-tunable spin-orbit coupling and multiband occupation is of particular interest for the realization of unconventional superconducting pairing. To investigate the symmetry of the superconducting order parameter, phase sensitive measurements of the Josephson effect are required. We describe an approach for the fabrication of artificial superconducting weak links at the LAO/STO interface using direct high-resolution electron beam lithography and low-energy argon ion beam irradiation. The method does not require lift-off steps or sacrificial layers. Therefore, resolution is only limited by the electron beam lithography and pattern transfer. We have realized superconducting weak links with a barrier thickness of 30-100 nm. The barrier transparency of the weak links can be controlled by the irradiation dose and further tuned by a gate voltage. Our results open up new possibilities for the realization of quantum devices in oxide interfaces.

Detection of interictal epileptiform discharges: A comparison of on-scalp MEG and conventional MEG measurements.

OBJECTIVE: Conventional MEG provides an unsurpassed ability to, non-invasively, detect epileptic activity. However, highly resolved information on small neuronal populations required in epilepsy diagnostics is lost and can be detected only intracranially. Next-generation on-scalp magnetencephalography (MEG) sensors aim to retrieve information unavailable to conventional non-invasive brain imaging techniques. To evaluate the benefits of on-scalp MEG in epilepsy, we performed the first-ever such measurement on an epilepsy patient. METHODS: Conducted as a benchmarking study focusing on interictal epileptiform discharge (IED) detectability, an on-scalp high-temperature superconducting quantum interference device magnetometer (high-Tc SQUID) system was compared to a conventional, low-temperature SQUID system. Co-registration of electroencephalopraphy (EEG) was performed. A novel machine learning-based IED-detection algorithm was developed to aid identification of on-scalp MEG unique IEDs. RESULTS: Conventional MEG contained 24 IEDs. On-scalp MEG revealed 47 IEDs (16 co-registered by EEG, 31 unique to the on-scalp MEG recording). CONCLUSION: Our results indicate that on-scalp MEG might capture IEDs not seen by other non-invasive modalities. SIGNIFICANCE: On-scalp MEG has the potential of improving non-invasive epilepsy evaluation.

A 7-Channel High-[Formula: see text] SQUID-Based On-Scalp MEG System.

OBJECTIVE: To present the technical design and demonstrate the feasibility of a multi-channel on-scalp magnetoencephalography (MEG) system based on high critical temperature (high-[Formula: see text]) superconducting quantum interference devices (SQUIDs). METHODS: We built a liquid nitrogen-cooled cryostat that houses seven YBCO SQUID magnetometers arranged in a dense, head-aligned array with minimal distance to the room-temperature environment for all sensors. We characterize the performance of this 7-channel system in terms of on-scalp MEG utilization and present recordings of spontaneous and evoked brain activity. RESULTS: The center-to-center spacing between adjacent SQUIDs is 12.0 and 13.4 mm and all SQUIDs are in the range of 1-3 mm of the head surface. The cryostat reaches a base temperature of  âˆ¼ 70 K and stays cold for 16 h with a single 0.9 L filling. The white noise levels of the magnetometers is 50-130 fT/Hz1/2 at 10 Hz and they show low sensor-to-sensor feedback flux crosstalk ( 0.6%). We demonstrate evoked fields from auditory stimuli and single-shot sensitivity to alpha modulation from the visual cortex. CONCLUSION: All seven channels in the system sensitively sample neuromagnetic fields with mm-scale scalp standoff distances. The hold time of the cryostat furthermore is sufficient for a day of recordings. As such, our multi-channel high-[Formula: see text] SQUID-based system meets the demands of on-scalp MEG. SIGNIFICANCE: The system presented here marks the first high-[Formula: see text] SQUID-based on-scalp MEG system with more than two channels. It enables us to further explore the benefits of on-scalp MEG in future recordings.

Characterization of Binding of Magnetic Nanoparticles to Rolling Circle Amplification Products by Turn-On Magnetic Assay.

The specific binding of oligonucleotide-tagged 100 nm magnetic nanoparticles (MNPs) to rolling circle products (RCPs) is investigated using our newly developed differential homogenous magnetic assay (DHMA). The DHMA measures ac magnetic susceptibility from a test and a control samples simultaneously and eliminates magnetic background signal. Therefore, the DHMA can reveal details of binding kinetics of magnetic nanoparticles at very low concentrations of RCPs. From the analysis of the imaginary part of the DHMA signal, we find that smaller MNPs in the particle ensemble bind first to the RCPs. When the RCP concentration increases, we observe the formation of agglomerates, which leads to lower number of MNPs per RCP at higher concentrations of RCPs. The results thus indicate that a full frequency range of ac susceptibility observation is necessary to detect low concentrations of target RCPs and a long amplification time is not required as it does not significantly increase the number of MNPs per RCP. The findings are critical for understanding the underlying microscopic binding process for improving the assay performance. They furthermore suggest DHMA is a powerful technique for dynamically characterizing the binding interactions between MNPs and biomolecules in fluid volumes.

Homogeneous Differential Magnetic Assay.

Assays are widely used for detection of various targets, including pathogens, drugs, and toxins. Homogeneous assays are promising for the realization of point-of-care diagnostics as they do not require separation, immobilization, or washing steps. For low concentrations of target molecules, the speed and sensitivity of homogeneous assays have hitherto been limited by slow binding kinetics, time-consuming amplification steps, and the presence of a high background signal. Here, we present a homogeneous differential magnetic assay that utilizes a differential magnetic readout that eliminates previous limitations of homogeneous assays. The assay uses a gradiometer sensor configuration combined with precise microfluidic sample handling. This enables simultaneous differential measurement of a positive test sample containing a synthesized Vibrio cholerae target and a negative control sample, which reduces the background signal and increases the readout speed. Very low concentrations of targets down to femtomolar levels are thus detectable without any additional amplification of the number of targets. Our homogeneous differential magnetic assay method opens new possibilities for rapid and highly sensitive diagnostics at the point of care.

Development of a Sensitive Induction-Based Magnetic Nanoparticle Biodetection Method.

We developed a novel biodetection method for influenza virus based on AC magnetic susceptibility measurement techniques (the DynoMag induction technique) together with functionalized multi-core magnetic nanoparticles. The sample consisting of an incubated mixture of magnetic nanoparticles and rolling circle amplified DNA coils is injected into a tube by a peristaltic pump. The sample is moved as a plug to the two well-balanced detection coils and the dynamic magnetic moment in each position is read over a range of excitation frequencies. The time for making a complete frequency sweep over the relaxation peak is about 5 minutes (10 Hz⁻10 kHz with 20 data points). The obtained standard deviation of the magnetic signal at the relaxation frequency (around 100 Hz) is equal to about 10-5 (volume susceptibility SI units), which is in the same range obtained with the DynoMag system. The limit of detection with this method is found to be in the range of 1 pM.

Volume-amplified magnetic bioassay integrated with microfluidic sample handling and high-Tc SQUID magnetic readout.

A bioassay based on a high-Tc superconducting quantum interference device (SQUID) reading out functionalized magnetic nanoparticles (fMNPs) in a prototype microfluidic platform is presented. The target molecule recognition is based on volume amplification using padlock-probe-ligation followed by rolling circle amplification (RCA). The MNPs are functionalized with single-stranded oligonucleotides, which give a specific binding of the MNPs to the large RCA coil product, resulting in a large change in the amplitude of the imaginary part of the ac magnetic susceptibility. The RCA products from amplification of synthetic Vibrio cholera target DNA were investigated using our SQUID ac susceptibility system in microfluidic channel with an equivalent sample volume of 3 µl. From extrapolation of the linear dependence of the SQUID signal versus concentration of the RCA coils, it is found that the projected limit of detection for our system is about 1.0 × 105 RCA coils (0.2 × 10-18 mol), which is equivalent to 66 fM in the 3 µl sample volume. This ultra-high magnetic sensitivity and integration with microfluidic sample handling are critical steps towards magnetic bioassays for rapid detection of DNA and RNA targets at the point of care.

Benchmarking for On-Scalp MEG Sensors.

OBJECTIVE: We present a benchmarking protocol for quantitatively comparing emerging on-scalp magnetoencephalography (MEG) sensor technologies to their counterparts in state-of-the-art MEG systems. METHODS: As a means of validation, we compare a high-critical-temperature superconducting quantum interference device (high Tc SQUID) with the low- Tc SQUIDs of an Elekta Neuromag TRIUX system in MEG recordings of auditory and somatosensory evoked fields (SEFs) on one human subject. RESULTS: We measure the expected signal gain for the auditory-evoked fields (deeper sources) and notice some unfamiliar features in the on-scalp sensor-based recordings of SEFs (shallower sources). CONCLUSION: The experimental results serve as a proof of principle for the benchmarking protocol. This approach is straightforward, general to various on-scalp MEG sensors, and convenient to use on human subjects. The unexpected features in the SEFs suggest on-scalp MEG sensors may reveal information about neuromagnetic sources that is otherwise difficult to extract from state-of-the-art MEG recordings. SIGNIFICANCE: As the first systematically established on-scalp MEG benchmarking protocol, magnetic sensor developers can employ this method to prove the utility of their technology in MEG recordings. Further exploration of the SEFs with on-scalp MEG sensors may reveal unique information about their sources.

A new approach for bioassays based on frequency- and time-domain measurements of magnetic nanoparticles.

We demonstrate a one-step wash-free bioassay measurement system capable of tracking biochemical binding events. Our approach combines the high resolution of frequency- and high speed of time-domain measurements in a single device in combination with a fast one-step bioassay. The one-step nature of our magnetic nanoparticle (MNP) based assay reduces the time between sample extraction and quantitative results while mitigating the risks of contamination related to washing steps. Our method also enables tracking of binding events, providing the possibility of, for example, investigation of how chemical/biological environments affect the rate of a binding process or study of the action of certain drugs. We detect specific biological binding events occurring on the surfaces of fluid-suspended MNPs that modify their magnetic relaxation behavior. Herein, we extrapolate a modest sensitivity to analyte of 100 ng/ml with the present setup using our rapid one-step bioassay. More importantly, we determine the size-distributions of the MNP systems with theoretical fits to our data obtained from the two complementary measurement modalities and demonstrate quantitative agreement between them.

Towards an electrowetting-based digital microfluidic platform for magnetic immunoassays.

We demonstrate ElectroWetting-On-Dielectric (EWOD) transport and SQUID gradiometer detection of magnetic nanoparticles (MNPs) suspended in a 2 microl de-ionized water droplet. This proof-of-concept methodology constitutes the first development step towards a highly sensitive magnetic immunoassay platform with SQUID readout and droplet-based sample handling. Magnetic AC-susceptibility measurements were performed on MNPs with a hydrodynamic diameter of 100 nm using a high-Tc dc Superconducting Quantum Interference Device (SQUID) gradiometer as detector. We observed that the signal amplitude per unit volume is 2.5 times higher for a 2 microl sample droplet compared to a 30 microl sample volume.