Globally, the demand for improved health care delivery while managing escalating costs is a major challenge. Measuring the biomagnetic fields that emanate from the human brain already impacts the ...treatment of epilepsy, brain tumours and other brain disorders. This roadmap explores how superconducting technologies are poised to impact health care. Biomagnetism is the study of magnetic fields of biological origin. Biomagnetic fields are typically very weak, often in the femtotesla range, making their measurement challenging. The earliest in vivo human measurements were made with room-temperature coils. In 1963, Baule and McFee (1963 Am. Heart J. 55 95−6) reported the magnetic field produced by electric currents in the heart ('magnetocardiography'), and in 1968, Cohen (1968 Science 161 784−6) described the magnetic field generated by alpha-rhythm currents in the brain ('magnetoencephalography'). Subsequently, in 1970, Cohen et al (1970 Appl. Phys. Lett. 16 278-80) reported the recording of a magnetocardiogram using a Superconducting QUantum Interference Device (SQUID). Just two years later, in 1972, Cohen (1972 Science 175 664-6) described the use of a SQUID in magnetoencephalography. These last two papers set the scene for applications of SQUIDs in biomagnetism, the subject of this roadmap. The SQUID is a combination of two fundamental properties of superconductors. The first is flux quantization-the fact that the magnetic flux Φ in a closed superconducting loop is quantized in units of the magnetic flux quantum, Φ0 h/2e, 2.07 × 10−15 Tm2 (Deaver and Fairbank 1961 Phys. Rev. Lett. 7 43-6, Doll R and Näbauer M 1961 Phys. Rev. Lett. 7 51-2). Here, h is the Planck constant and e the elementary charge. The second property is the Josephson effect, predicted in 1962 by Josephson (1962 Phys. Lett. 1 251-3) and observed by Anderson and Rowell (1963 Phys. Rev. Lett. 10 230-2) in 1963. The Josephson junction consists of two weakly coupled superconductors separated by a tunnel barrier or other weak link. A tiny electric current is able to flow between the superconductors as a supercurrent, without developing a voltage across them. At currents above the 'critical current' (maximum supercurrent), however, a voltage is developed. In 1964, Jaklevic et al (1964 Phys. Rev. Lett. 12 159-60) observed quantum interference between two Josephson junctions connected in series on a superconducting loop, giving birth to the dc SQUID. The essential property of the SQUID is that a steady increase in the magnetic flux threading the loop causes the critical current to oscillate with a period of one flux quantum. In today's SQUIDs, using conventional semiconductor readout electronics, one can typically detect a change in Φ corresponding to 10−6 Φ0 in one second. Although early practical SQUIDs were usually made from bulk superconductors, for example, niobium or Pb-Sn solder blobs, today's devices are invariably made from thin superconducting films patterned with photolithography or even electron lithography. An extensive description of SQUIDs and their applications can be found in the SQUID Handbooks (Clarke and Braginski 2004 Fundamentals and Technology of SQUIDs and SQUID Systems vol I (Weinheim, Germany: Wiley-VCH), Clarke and Braginski 2006 Applications of SQUIDs and SQUID Systems vol II (Weinheim, Germany: Wiley-VCH)). The roadmap begins (chapter 1) with a brief review of the state-of-the-art of SQUID-based magnetometers and gradiometers for biomagnetic measurements. The magnetic field noise referred to the pick-up loop is typically a few fT Hz−1/2, often limited by noise in the metallized thermal insulation of the dewar rather than by intrinsic SQUID noise. The authors describe a pathway to achieve an intrinsic magnetic field noise as low as 0.1 fT Hz−1/2, approximately the Nyquist noise of the human body. They also descibe a technology to defeat dewar noise. Chapter 2 reviews the neuroscientific and clinical use of magnetoencephalography (MEG), by far the most widespread application of biomagnetism with systems containing typically 300 sensors cooled to liquid-helium temperature, 4.2 K. Two important clinical applications are presurgical mapping of focal epilepsy and of eloquent cortex in brain-tumor patients. Reducing the sensor-to-brain separation and the system noise level would both improve spatial resolution. The very recent commercial innovation that replaces the need for frequent manual transfer of liquid helium with an automated system that collects and liquefies the gas and transfers the liquid to the dewar will make MEG systems more accessible. A highly promising means of placing the sensors substantially closer to the scalp for MEG is to use high-transition-temperature (high-Tc) SQUID sensors and flux transformers (chapter 3). Operation of these devices at liquid-nitrogen temperature, 77 K, enables one to minimize or even omit metallic thermal insulation between the sensors and the dewar. Noise levels of a few fT Hz−1/2 have already been achieved, and lower values are likely. The dewars can be made relatively flexible, and thus able to be placed close to the skull irrespective of the size of the head, potentially providing higher spatial resolution than liquid-helium based systems. The successful realization of a commercial high-Tc MEG system would have a major commercial impact. Chapter 4 introduces the concept of SQUID-based ultra-low-field magnetic resonance imaging (ULF MRI) operating at typically several kHz, some four orders of magnitude lower than conventional, clinical MRI machines. Potential advantages of ULF MRI include higher image contrast than for conventional MRI, enabling methodologies not currently available. Examples include screening for cancer without a contrast agent, imaging traumatic brain injury (TBI) and degenerative diseases such as Alzheimer's, and determining the elapsed time since a stroke. The major current problem with ULF MRI is that its signal-to-noise ratio (SNR) is low compared with high-field MRI. Realistic solutions to this problem are proposed, including implementing sensors with a noise level of 0.1 fT Hz−1/2. A logical and exciting prospect (chapter 5) is to combine MEG and ULF MRI into a single system in which both signal sources are detected with the same array of SQUIDs. A prototype system is described. The combination of MEG and ULF MRI allows one to obtain structural images of the head concurrently with the recording of brain activity. Since all MEG images require an MRI to determine source locations underlying the MEG signal, the combined modality would give a precise registration of the two images; the combination of MEG with high-field MRI can produce registration errors as large as 5 mm. The use of multiple sensors for ULF MRI increases both the SNR and the field of view. Chapter 6 describes another potentially far-reaching application of ULF MRI, namely neuronal current imaging (NCI) of the brain. Currently available neuronal imaging techniques include MEG, which is fast but has relatively poor spatial resolution, perhaps 10 mm, and functional MRI (fMRI) which has a millimeter resolution but is slow, on the order of seconds, and furthermore does not directly measure neuronal signals. NCI combines the ability of direct measurement of MEG with the spatial precision of MRI. In essence, the magnetic fields generated by neural currents shift the frequency of the magnetic resonance signal at a location that is imaged by the three-dimensional magnetic field gradients that form the basis of MRI. The currently achieved sensitivity of NCI is not quite sufficient to realize its goal, but it is close. The realization of NCI would represent a revolution in functional brain imaging. Improved techniques for immunoassay are always being sought, and chapter 7 introduces an entirely new topic, magnetic nanoparticles for immunoassay. These particles are bio-funtionalized, for example with a specific antibody which binds to its corresponding antigen, if it is present. Any resulting changes in the properties of the nanoparticles are detected with a SQUID. For liquid-phase detection, there are three basic methods: AC susceptibility, magnetic relaxation and remanence measurement. These methods, which have been successfully implemented for both in vivo and ex vivo applications, are highly sensitive and, although further development is required, it appears highly likely that at least some of them will be commercialized. Chapter 8 concludes the roadmap with an assessment of the commercial market for MEG systems. Despite the huge advances that have been realized since MEG was first introduced, the number of commercial systems deployed around the world remains small, around 250 units employing about 50 000 SQUIDs. The slow adoption of this technology is undoubtedly in part due to the high cost, not least because of the need to surround the entire system in an expensive magnetically shielded room. Nonetheless, the recent introduction of automatically refilling liquid-helium systems, the ongoing reduction in sensor noise, the potential availability of high-Tc SQUID systems, the availability of new and better software and the combination of MEG with ULF MRI all have the potential to increase the market size in the not-so-distant future. In particular, there is a great and growing need for better noninvasive technologies to measure brain function. There are hundreds of millions of people in the world who suffer from brain disorders such as epilepsy, stroke, dementia or depression. The enormous cost to society of these diseases can be reduced by earlier and more accurate detection and diagnosis. Once the challenges outlined in this roadmap have been met and the outstanding problems have been solved, the potential demand for SQUID-based health technology can be expected to increase by ten- if not hundred-fold.
The detection of the free precession of co‐located 3He/129Xe nuclear spins (clock comparison) is used as ultra‐sensitive probe for non‐magnetic spin interactions, since the magnetic dipole ...interaction (Zeeman‐term) drops out in the weighted frequency difference, i.e., Δω = ωHe‐ γHe/γXe·ωXe of the respective Larmor frequencies. Recent results are reported on searches for (i) short‐range P‐ and T‐violating interactions between nucleons, and (ii) Lorentz violating signatures by monitoring the Larmor frequencies as the laboratory reference frame rotates with respect to distant stars (sidereal modulation). Finally, a new experimental initiative to search for an electric dipole moment of 129Xe (CP‐violation) is discussed, which strongly benefits from the long spin‐coherence times obtained, reaching T2,He*> 100 h and T2,Xe*> 8 h in case of 3He and 129Xe, respectively.
The detection of the free precession of co‐located 3He/129Xe nuclear spins (clock comparison) is used as ultra‐sensitive probe for non‐magnetic spin interactions, since the magnetic dipole interaction (Zeeman‐term) drops out in the weighted frequency difference, i.e., Δω = ωHe‐ γHe/γXe·ωXe of the respective Larmor frequencies. Recent results are reported on searches for (i) short‐range P‐ and T‐violating interactions between nucleons, and (ii) Lorentz violating signatures by monitoring the Larmor frequencies as the laboratory reference frame rotates with respect to distant stars (sidereal modulation). Finally, a new experimental initiative to search for an electric dipole moment of 129Xe (CP‐violation) is discussed, which strongly benefits from the long spin‐coherence times obtained, reaching T*2,He> 100 h and T*2,Xe> 8 h in case of 3He and 129Xe, respectively.
Functional magnetic resonance imaging (fMRI) visualizes activated brain areas with a high spatial resolution. The activation signal is determined by the local change of cerebral blood oxygenation, ...blood volume and blood flow which serve as surrogate marker for the neuronal signal itself. Here, the complex coupling between these parameters and the electrophysiologic activity is characterized non-invasively in humans during a simple motor task using simultaneously DC-magnetoencephalography (DC-MEG), for the detection of neuronal signals, and time-resolved near-infrared spectroscopy (trNIRS), for cortical metabolic/vascular responses: over the left primary motor cortex hand area of healthy subjects DC-fields and trNIRS parameters followed closely the 30 s motor task cycles, i.e., finger movements of the right hand alternating with rest. In subjects showing a sufficient signal-to-noise ratio the analysis of variance of photon time of flight proved that the task-related trNIRS changes originated from the cortex. While onset and relaxation started simultaneously, trNIRS signals reached 50% of the maximum level 1–4 s later than the DC-MEG-signals. The non-invasive ‘dual’ setup helps to characterize simultaneously the two complementary aspects of the ‘hemodynamic inverse problem’, i.e., the coupling of neuronal and vascular/metabolic signals, in healthy subjects and provides a new analysis perspective for pathophysiological coupling concepts in diverse diseases, e.g., in stroke, hypertension and Alzheimer’s disease.
NMR at very low fields Trahms, Lutz; Burghoff, Martin
Magnetic resonance imaging,
10/2010, Letnik:
28, Številka:
8
Journal Article
Recenzirano
Abstract Although nuclear magnetic resonance in low fields around or below the Earth's magnetic field is almost as old as nuclear magnetic resonance itself, the recent years have experienced a ...revival of this technique that is opposed to the common trend towards higher and higher fields. The background of this development is the expectation that the low-field domain may open a new window for the study of molecular structure and dynamics. Here, we will give an overview on the specific features in the low-field domain, both from the technical and from the physical point of view. In addition, we present a short passage on the option of magnetic resonance imaging in fields of the micro-Tesla range.
Non-invasively recorded somatosensory high-frequency oscillations (sHFOs) evoked by electric nerve stimulation are markers of human cortical population spikes. Previously, their analysis was based on ...massive averaging of EEG responses. Advanced neurotechnology and optimized off-line analysis can enhance the signal-to-noise ratio of sHFOs, eventually enabling single-trial analysis.
The rationale for developing dedicated low-noise EEG technology for sHFOs is unfolded. Detailed recording procedures and tailored analysis principles are explained step-by-step. Source codes in Matlab and Python are provided as supplementary material online.
Combining synergistic hardware and analysis improvements, evoked sHFOs at around 600 Hz ('σ-bursts') can be studied in single-trials. Additionally, optimized spatial filters increase the signal-to-noise ratio of components at about 1 kHz ('κ-bursts') enabling their detection in non-invasive surface EEG.
sHFOs offer a unique possibility to record evoked human cortical population spikes non-invasively. The experimental approaches and algorithms presented here enable also non-specialized EEG laboratories to combine measurements of conventional low-frequency EEG with the analysis of concomitant cortical population spike responses.
Human high-frequency (>400Hz) components of somatosensory evoked potentials (hf-SEPs), which can be recorded non-invasively at the scalp, are generated by cortical population spikes, as inferred from ...microelectrode recordings in non-human primates. It is a critical limitation to broader neurophysiological study of hf-SEPs in that hundreds of responses have to be averaged to detect hf-SEPs reliably. Here, we establish a framework for detecting human hf-SEPs non-invasively in single trials.
Spatio-temporal features were extracted from band-pass filtered (400-900Hz) hf-SEPs by bilinear Common Spatio-Temporal Patterns (bCSTP) and then classified by a weighted Extreme Learning Machine (w-ELM). The effect of varying signal-to-noise ratio (SNR), number of trials, and degree of w-ELM re-weighting was characterized using surrogate data. For practical demonstration of the algorithm, median nerve hf-SEPs were recorded inside a shielded room in four subjects, spanning the hf-SEP signal-to-noise ratio characteristic for a larger population, utilizing a custom-built 29-channel low-noise EEG amplifier.
Using surrogate data, the SNR proved to be pivotal to detect hf-SEPs in single trials efficiently, with the trade-off between sensitivity and specificity of the algorithm being obtained by the w-ELM re-weighting parameter. In practice, human hf-SEPs were detected non-invasively in single trials with a sensitivity of up to 99% and a specificity of up to 97% in two subjects, even without any recourse to knowledge of stimulus timing. Matching with the results of the surrogate data analysis, these rates dropped to 62–79% sensitivity and 18–31% specificity in two subjects with lower SNR.
Otherwise buried in background noise, human high-frequency EEG components can be extracted from low-noise recordings. Specifically, refined supervised filter optimization and classification enables the reliable detection of single-trial hf-SEPs, representing non-invasive correlates of cortical population spikes.
While low-frequency EEG reflects summed postsynaptic potentials, and thereby neuronal input, we suggest that high-frequency EEG (>400Hz) can provide non-invasive access to the unaveraged output of neuronal computation, i.e., single-trial population spike activity evoked in the responsive neuronal ensemble.
Based on low-noise superconducting quantum interference devices (SQUIDs) magnetoencephalography allows the non-invasive detection of low-amplitude high-frequency brain responses evoked about 20 ms ...after electric hand nerve stimulation. The main spectral energy of these brief oscillatory bursts (near 600 Hz) is in the range typical for rapidly repeated action potentials. Here, the magnetic fields of median and ulnar nerve evoked 600 Hz bursts are shown to exhibit a somatotopic arrangement at the primary somatosensory hand cortex closely resembling that of the concomitant postsynaptic primary cortical response (`N20m'). Two possible burst generators are discussed: (1) repetitive spike volleys conducted along the terminal segments of somatotopically arranged thalamocortical axons, and (2) early intracortical spike activity in nerve-specific subterritories of the 3b hand area.
Highlights ► Scalp recordings at an unprecedented low noise level show that high-frequency somatosensory evoked potentials (hfSEP) are generated by added-activity and not by a phase-reset of ongoing ...hf-activity as previously suggested. ► These seemingly contradictory results were reconciled by a statistical power analysis identifying the band-limited signal-to-noise ratio as decisive factor for the detectability of single-trial hfSEP added-activity. ► Thus, human scalp hfSEP can be understood as a non-invasively recorded correlate of evoked cortical multi-unit spike responses as inferred from previous invasive recordings.
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