On-scalp MEG using high-Tc SQUIDs: Measuring brain activity with superconducting magnetometers

This thesis describes work done towards realizing on-scalp magnetoencephalography (MEG) based on high critical temperature (high-Tc) superconducting quantum interference device (SQUID) sensors. MEG is a non-invasive neuroimaging modality that records the magnetic fields produced by neural currents with good spatial and high temporal resolution. However, state-of-the-art MEG is limited by the use of liquid helium-cooled sensors (T ~ 4 K). The amount of thermal insulation between the sensors and the subject\u27s head that is required to achieve the extreme temperature difference (~300 K), typically realized in the form of superinsulation foil and ~2 centimeters of vacuum, limits measurable signals. Replacing the sensors with high-Tc SQUIDs can mitigate this problem. High-Tc SQUIDs operate at much higher temperatures (90 K) allowing significant reduction of the stand-off distance (to ~1 mm). They can furthermore be cooled with liquid nitrogen (77 K), a cheaper, more sustainable alternative to the liquid helium used for cooling in conventional MEG systems.The work described in this thesis can be divided into three main areas: (I) simulation work for practical implementations of on-scalp systems, (II) development of a 7-channel high-Tc SQUID-based on-scalp MEG system, and (III) on-scalp MEG recordings.In the first part, spatial information density (SID), a metric to evaluate the performance of simulated MEG sensor arrays, is introduced and - along with total information capacity - used to compare the performance of various simulated full-head on-scalp MEG sensor arrays.\ua0Simulations demonstrate the potential of on-scalp MEG, with all on-scalp systems exhibiting higher information capacity than the state-of-the-art. SID further reveals more homogeneous sampling of the brain with flexible systems. A method for localizing magnetometers in on-scalp MEG systems is introduced and tested in simulations. The method uses small, magnetic dipole-like coils to determine the location and orientation of individual sensors, enabling straightforward co-registration in flexible on-scalp MEG systems. The effects of different uncertainties and errors on the accuracy of the method were quantified.In the second part, design, construction, and performance of a 7-channel on-scalp MEG system is described. The system houses seven densely-packed (2 mm edge-to-edge), head-aligned high-Tc SQUID magnetometers (9.2 mm x 8.6 mm) inside a single, liquid nitrogen-cooled cryostat. With a single filling, the system can be utilized for MEG recordings for >16 h with low noise levels (~0-130 fT). Using synchronized clocks and a direct injection feedback scheme, the system achieves low sensor crosstalk (<0.6%).\ua0In the third part, on-scalp MEG recordings with the 7-channel system as well as its predecessor, a single-channel system, are presented. The recordings are divided into proof-of-principle and benchmarking experiments. The former consist of well-studied, simple paradigms such as auditory evoked activity and visual alpha. Expected signal components were clearly seen in the on-scalp recordings. The benchmarking studies were done to compare and contrast on-scalp with state-of-the-art MEG. To this end, a number of experimental stimulus paradigms were recorded on human subjects with the high-Tc SQUID-based on-scalp systems as well as a state-of-the-art, commercial full-head MEG system. Results include the expected signal gains that are associated with recording on-scalp as well as new details of the neurophysiological signals. Using the previously described on-scalp MEG co-registration method enabled source localization with high agreement to the full-head recording (the distance between dipoles localized with the two systems was 4.2 mm)

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. Coregistration 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. (C) 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V

Critical comments on EEG sensor space dynamical connectivity analysis

Many different analysis techniques have been developed and applied to EEG recordings that allow one to investigate how different brain areas interact. One particular class of methods, based on the linear parametric representation of multiple interacting time series, is widely used to study causal connectivity in the brain. However, the results obtained by these methods should be interpreted with great care. The goal of this paper is to show, both theoretically and using simulations, that results obtained by applying causal connectivity measures on the sensor (scalp) time series do not allow interpretation in terms of interacting brain sources. This is because 1) the channel locations cannot be seen as an approximation of a source's anatomical location and 2) spurious connectivity can occur between sensors. Although many measures of causal connectivity derived from EEG sensor time series are affected by the latter, here we will focus on the well-known time domain index of Granger causality (GC) and on the frequency domain directed transfer function (DTF). Using the state-space framework and designing two simulation studies we show that mixing effects caused by volume conduction can lead to spurious connections, detected either by time domain GC or by DTF. Therefore, GC/DTF causal connectivity measures should be computed at the source level, or derived within analysis frameworks that model the effects of volume conduction. Since mixing effects can also occur in the source space, it is advised to combine source space analysis with connectivity measures that are robust to mixing

On mapping epilepsy : magneto- and electroencephalographic characterizations of epileptic activities

Epilepsy is one of the most common neurological disorder, affecting up to 10 individuals per 1000 persons. The disorder have been known for several thousand years, with the first clinical descriptions dating back to ancient times. Nonetheless, characterization of the dynamics underlying epilepsy remains largely unknown. Understanding these patophysiological processes requires unifying both a neurobiological perspective, as well as a technically advanced neuroimaging perspective. The incomplete insight into epilepsy dynamics is reflected by the insufficient treatment options. Approximately 30% of all patients do not respond to anti-epileptic drugs (AEDs) and thus suffers from recurrent seizures despite adequate pharmacological treatments. These pharmacoresistant patients often undergo epilepsy surgery evaluations. Epilepsy surgery aims to resect the part of the brain that generates the epileptic seizure activity (seizure onset zone, SOZ). Nonetheless, up to 50% of all patients relapse after surgery. This can be due to incomplete mapping of both the SOZ and of other structures that might be involved in seizure initiation and propagation. Such cortical and subcortical structures are collectively referred to as the epileptic network. Historically, epilepsy was considered to be either a generalized disorder involving the entire brain, or a highly localized, focal, disorder. The modern technological development of both structural and functional neuroimaging has drastically altered this view. This development has made significant contributions to the now prevailing view that both generalized and focal epilepsies arise from more or less widespread pathological network pathways. Visualization of these pathways play an important role in the presurgical planning. Thus, both improved characterization and understanding of such pathways are pivotal in improvement of epilepsy diagnostics and treatments. It is evident that epilepsy research needs to stand on two legs: Both improved understanding of pathological, neurobiological and neurophysiological process, and improved neuroimaging instrumentation. Epilepsy research do not only span from visualization to understanding of neurophysiological processes, but also from cellular, neuronal, microscopic processes, to dynamical, large-scale network processes. It is well known that neurons involved in epileptic activities exhibit specific, pathological firing patterns. Genetic mutations resulting in neuronal ion channel defects can cause severe, and even lethal, epileptic syndromes in children, clearly illustrating a role for neuron membrane properties in epilepsy. However, cellular processes themselves cannot explain how epileptic seizures can involve, and propagate across, large cortical areas and generate seizure-specific symptomatologies. A strict cellular perspective can neither explain epilepsy-associated pathological interactions between larger distant regions in between seizures. Instead, the dynamical effects of cellular synchronization across both mesoscopic and macroscopic scales also need to be considered. Today, the only means to study such effects in human subjects are by combinations of neuroimaging modalities. However, as all measurement techniques, these exhibit individual limitations that affect the kind of information that can be inferred from these. Thus, once more we reach the conclusion that epilepsy research needs to rest upon both a neurophysiological/neurobiological leg, and a technical/instrumentational leg. In accordance with this necessity of a dual approach to epilepsy, this thesis covers both neurophysiological aspects of epileptic activity development, as well as functional neuroimaging instrumentation development with focus on epileptic activity detection and localization. Part 1 (neurophysiological part) is concerned with the neurophysiological dynamical changes that underlie development of so called interictal epileptiform discharges (IEDs) with special focus on the role of low-frequency oscillations. To this aim, both conventional magnetoencephalography (MEG) and intracranial electroencephalography (iEEG) with neurostimulation is analyzed. Part 2 (instrumentation part) is concerned with development of cutting-edge, novel on-scalp magnetoencephalography (osMEG) within clinical epilepsy evaluations and research with special focus on IEDs. The theses cover both modeling of osMEG characteristics, as well as the first-ever osMEG recording of a temporal lobe epilepsy patient

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\u27s 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\u27s head shape and size. The positions and orientations of on-scalp sensors must therefore be measured a 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\u27s 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-T-c SQUIDs). The method allows individually localizing the sensor positions, orientations, and responsivities with high accuracy using only a short averaging time (<= 2 mm, < 3 degrees 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 mm and < 1 degrees, respectively, with 1-s coil recordings). We demonstrate source localization of on-scalp recorded somatosensory evoked activity based on coregistration with our method. Equivalent current dipole fits of the evoked responses corresponded well (within 4.2 mm) with those based on a commercial, whole-head MEG system

Using OPMs to measure neural activity in standing, mobile participants

Optically pumped magnetometer-based magnetoencephalography (OP-MEG) can be used to measure neuromagnetic fields while participants move in a magnetically shielded room. Head movements in previous OP-MEG studies have been up to 20 cm translation and ∼30° rotation in a sitting position. While this represents a step-change over stationary MEG systems, naturalistic head movement is likely to exceed these limits, particularly when participants are standing up. In this proof-of-concept study, we sought to push the movement limits of OP-MEG even further. Using a 90 channel (45-sensor) whole-head OP-MEG system and concurrent motion capture, we recorded auditory evoked fields while participants were: (i) sitting still, (ii) standing up and still, and (iii) standing up and making large natural head movements continuously throughout the recording - maximum translation 120 cm, maximum rotation 198°. Following pre-processing, movement artefacts were substantially reduced but not eliminated. However, upon utilisation of a beamformer, the M100 event-related field localised to primary auditory regions. Furthermore, the event-related fields from auditory cortex were remarkably consistent across the three conditions. These results suggest that a wide range of movement is possible with current OP-MEG systems. This in turn underscores the exciting potential of OP-MEG for recording neural activity during naturalistic paradigms that involve movement (e.g. navigation), and for scanning populations who are difficult to study with stationary MEG (e.g. young children)

High-temperature superconducting magnetometers for on-scalp MEG

In the growing field of on-scalp magnetoencephalography (MEG), brain activity is studied by non-invasively mapping the magnetic fields generated by neuronal currents with sensors that are flexibly placed in close proximity to the subject\u27s head. This thesis focuses on high-temperature superconducting magnetometers made from YBa2Cu3Ox-7 (YBCO), which enables a reduction in the sensor-to-room temperature standoff distance from roughly 2 cm (for conventional MEG systems) down to 1 mm. Because of the higher neuromagnetic signal magnitudes available to on-scalp sensors, simulations predict that even a relatively low-sensitivity (higher noise) full-head on-scalp MEG system can extract more information about brain activity than conventional systems.In the first part of this thesis, the development of high critical temperature (high-Tc) superconducting quantum interference device (SQUID) magnetometers for a 7-channel on-scalp MEG system is described. The sensors are single layer magnetometers with a directly coupled pickup loop made on 10 mm 7 10 mm substrates using bicrystal grain boundary Josephson junctions. We found that the kinetic inductance strongly varies with film quality and temperature. Determination of all SQUID parameters by combining measurements and inductance simulations led to excellent agreement between experimental results and theoretical predictions. This allowed us to perform an in-depth magnetometer optimization. The best magnetometers achieve a magnetic field noise level of 44 fT/√Hz at 78 K. Fabricated test SQUIDs provide evidence that noise levels below 30 fT/√Hz are possible for high quality junctions with fairly low critical currents and in combination with the optimized pickup loop design. Different feedback methods for operation in a densely-packed on-scalp MEG system were also investigated. Direct injection of current into the SQUID loop was identified as the best on-chip feedback method with feedback flux crosstalk below 0.5%. By reducing the operation temperature, the noise level can be further reduced, however, the effective area also decreases because of the decreasing kinetic inductance contribution. We present a method that allows for one-time sensor calibration independent of temperature.In the second part, the design, operation, and performance of the constructed 7-channel on-scalp MEG system based on the fabricated magnetometers is presented. With a dense (2 mm edge-to-edge) hexagonal head-aligned array, the system achieves a small sensor-to-head standoff distance of 1-3 mm and dense spatial sampling. The magnetic field noise levels are 50-130 fT/√Hz and the sensor-to-sensor feedback flux crosstalk is below 0.6%. MEG measurements with the system demonstrate the feasibility of the approach and indicate that our on-scalp MEG system allows retrieval of information unavailable to conventional MEG.In the third part, two alternative magnetometer types are studied for the next generation system. The first alternative is magnetometers based on Dayem bridge junctions instead of bicrystal grain boundary junctions. With a magnetometer based on the novel grooved Dayem bridge junctions, a magnetic field noise level of 63 fT/√Hz could be achieved, which shows that Dayem bridge junctions are starting to become a viable option for single layer magnetometers. The second alternative are high-Tc SQUID magnetometers with an inductively coupled flux transformer. The best device with bicrystal grain boundary junctions reaches a magnetic field noise level below 11 fT/√Hz and outperforms the best single layer device for frequencies above 20 Hz.In the last part, the potential of kinetic inductance magnetometers (KIMs) is investigated. We demonstrate the first high-Tc KIMs, which can be operated in fields of 9-28 \ub5T and achieve a noise level of 4 pT/√Hz at 10 kHz