Recording human cortical population spikes non-invasively--An EEG tutorial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Non-invasive single-trial EEG detection of evoked human neocortical population spikes.

QUESTION: Human high-frequency (>400 Hz) 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. METHODS: Spatio-temporal features were extracted from band-pass filtered (400-900 Hz) 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. RESULTS: 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. CONCLUSIONS: 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. SIGNIFICANCE: While low-frequency EEG reflects summed postsynaptic potentials, and thereby neuronal input, we suggest that high-frequency EEG (>400 Hz) 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.

An advanced phantom study assessing the feasibility of neuronal current imaging by ultra-low-field NMR.

In ultra-low-field (ULF) NMR/MRI, a common scheme is to magnetize the sample by a polarizing field of up to hundreds of mT, after which the NMR signal, precessing in a field on the order of several µT, is detected with superconducting quantum interference devices (SQUIDs). In our ULF-NMR system, we polarize with up to 50mT and deploy a single-stage DC-SQUID current sensor with an integrated input coil which is connected to a wire-wound Nb gradiometer. We developed this system (white noise 0.50fT/√Hz) for assessing the feasibility of imaging neuronal currents by detecting their effect on the ULF-NMR signal. Magnetoencephalography investigations of evoked brain activity showed neuronal dipole moments below 50nAm. With our instrumentation, we have studied two different approaches for neuronal current imaging. In the so-called DC effect, long-lived neuronal activity shifts the Larmor frequency of the surrounding protons. An alternative strategy is to exploit fast neuronal activity as a tipping pulse. This so-called AC effect requires the proton Larmor frequency to match the frequency of the neuronal activity, which ranges from near-DC to ∼kHz. We emulated neuronal activity by means of a single dipolar source in a physical phantom, consisting of a hollow sphere filled with an aqueous solution of CuSO4 and NaCl. In these phantom studies, with physiologically relevant dipole depths, we determined resolution limits for our set-up for the AC and the DC effect of ∼10µAm and ∼50nAm, respectively. Hence, the DC effect appears to be detectable in vivo by current ULF-NMR technology.

Magnetic resonance imaging at frequencies below 1 kHz.

Within the magnetic resonance imaging (MRI) community the trend is going to higher and higher magnetic fields, ranging from 1.5 T to 7 T, corresponding to Larmor frequencies of 63.8-298 MHz. Since for high-field MRI the magnetization increases with the applied magnetic field, the signal-to-noise-ratio increases as well, thus enabling higher image resolutions. On the other hand, MRI is possible also at ultra-low magnetic fields, as was shown by different groups. The goal of our development was to reach a Larmor frequency range of the low-field MRI system corresponding to the frequency range of human brain activities ranging from near zero-frequency (near-DC) to over 1 kHz. Here, first 2D MRI images of phantoms taken at Larmor frequencies of 100 Hz and 731 Hz will be shown and discussed. These frequencies are examples of brain activity triggered by electrostimulation of the median nerve. The method will allow the magnetic fields of the brain currents to influence the magnetic resonance image, and thus lead to a direct functional imaging modality of neuronal currents.

Are high-frequency (600 Hz) oscillations in human somatosensory evoked potentials due to phase-resetting phenomena?

OBJECTIVE: Median nerve somatosensory evoked potentials (SEP) contain a brief oscillatory wavelet burst at about 600 Hz (σ-burst) superimposed on the initial cortical component (N20). While invasive single-cell recordings suggested that this burst is generated by increased neuronal spiking activity in area 3b, recent non-invasive scalp recordings could not reveal concomitant single-trial added-activity, suggesting that the SEP burst might instead be generated by phase-reset of ongoing high-frequency EEG. Here, a statistical model and exemplary data are presented reconciling these seemingly contradictory results. METHODS: A statistical model defined the conditions required to detect added-activity in a set of single-trial SEP. Its predictions were tested by analyzing human single-trial scalp SEP recorded with custom-made low-noise amplifiers. RESULTS: The noise level in previous studies did not allow to detect single-trial added-activity in the period concomitant with the trial-averaged σ-burst. In contrast, optimized low-noise recordings do reveal added-activity in a set of single-trials. CONCLUSIONS: The experimental noise level is the decisive factor determining the detectability of added-activity in single-trials. A low-noise experiment provided direct evidence that the SEP σ-burst is at least partly generated by added-activity matching earlier invasive single-cell recordings. SIGNIFICANCE: Quantitative criteria are provided for the feasibility of single-trial detectability of band-limited added-activity.

Are brain currents detectable by means of low-field NMR? A phantom study.

A number of different methods have been developed in order to detect the spreading of neuronal currents by means of noninvasive imaging techniques. However, all of these are subjected to limitations in the temporal or spatial resolution. A new approach of neuronal current detection is based on the use of low-field nuclear magnetic resonance (LF-NMR) that records brain activity directly. In the following, we describe a phantom study in order to assess the feasibility of neuronal current detection using LF-NMR. In addition to that, necessary preliminary subject studies examining somatosensory evoked neuronal currents are presented. During the phantom study, the influences of two different neuronal time signals on (1)H-NMR signals were observed. The measurements were carried out by using a head phantom with an integrated current dipole to simulate neuronal activity. Two LF-NMR methods based on a DC and an AC (resonant) mechanism were utilized to study the feasibility of detecting both types of magnetic brain signals. Measurements were made inside an extremely magnetically shielded room by using a superconducting quantum interference device magnetometer system. The measurement principles were validated applying currents of higher intensity than those typical of the neuronal currents. Through stepwise reduction of the amplitude of the current dipole strength, the resolution limits of the two measuring procedures were found. The results indicate that it is necessary to improve the signal-to-noise ratio of the measurement system by at least a factor of 38 in order to detect typical human neuronal activity directly by means of LF-NMR. In addition to that, ways of achieving this factor are discussed.

Nuclear magnetic relaxation in water revisited.

In this study, we revisited nuclear magnetic relaxation of (1)H in water at very low Larmor frequencies that has been studied intensively in earlier years. We make use of the recently developed superconducting quantum interference device based ultra-low field NMR technique, which enables much easier access to the longitudinal spin-lattice relaxation time T(1) and the transversal spin-spin relaxation time T(2) below several kHz than traditional field cycling methods. Our data reproduce and complement the earlier results, in that they corroborate the finding of an exchange process with a correlation time of about 0.34 ms at room temperature which can be attributed to the migration of hydronium and hydroxyl ions in neutral water via hydrogen bridges. The corresponding relaxation process is driven by the interaction of the protons with (17)O and contributes to the T(1) and the T(2) relaxation rate by about 0.12 s(-1). In addition, we found evidence of a very slow exchange process at about 100 Hz that has hitherto not been reported.

Simultaneous measurements of somatosensory evoked AC and near-DC MEG signals.

Magnetoencephalography measurements of somatosensory evoked brain activity taken inside an extremely magnetically shielded room are reported. The massive low frequency shielding in combination with a high sampling rate enabled the simultaneous observation of AC and near-DC effects. Neuronal activation was achieved by repetitive electrostimulation of the right median nerve above motor threshold using repetition rates from 3 Hz to 12 Hz. Stimulation sequences lasted for 10 s and were interspersed with periods of rest of equal length. The recorded magnetic fields, inferred for the N20m and a sustained near-DC component, revealed mainly dipolar patterns with mutually rotated orientations with angles of rotation of 30° and 75°. At the start of the stimulation we observed a fast rise within 100 ms in the evoked magnetic near-DC fields for which a maximum equivalent current dipole strength of 65 nAm was obtained. The sustained fields decayed by a factor of ∼4 to a lower DC-level B(γ) with a time constant τ of order of seconds. For 12 Hz repetition rate B(γ) was decreased. We suggest that the sustained neuronal activity evoked by repetitive electrostimulation could provide a suitable scheme to realize the direct detection of DC effects of neuronal currents via low field magnetic resonance.

NMR at very low fields.

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.

Polarization encoding as a novel approach to MRI.

In magnetic resonance imaging (MRI), there have been three basic techniques to encode the spatial origin of the signals, i.e. Fourier and radio frequency encoding and the use of sensitivity information of sensor arrays. In this paper, we introduce a new encoding method, which we call polarization encoding. The method utilizes sets of polarizing fields with various spatial profiles; it is tailored for MRI at ultra-low fields (ULF MRI). In ULF MRI, signals from a prepolarized sample are typically detected using an array of SQUID (superconducting quantum interference device) sensors at microtesla fields. The prepolarization is achieved with a field of the order of 10-100mT preceding the signal acquisition. In polarization encoding, the prepolarizing field is varied in a way to gain additional information about the sample. The method may also prove useful for modalities that in the absence of any precession aim to image the DC magnetization profile of a sample.

Differential infraslow (<0.1 Hz) cortical activations in the affected and unaffected hemispheres from patients with subacute stroke demonstrated by noninvasive DC-magnetoencephalography.

BACKGROUND AND PURPOSE: Sustained mass depolarization of neurons, termed cortical spreading depolarization, is one electrophysiological correlate of the ischemic injury of neurons. Cortical spreading depolarizations spread in the gray matter at a rate of approximately 3 mm/min and are associated with large infraslow extracellular potential changes (<0.05 Hz). Moreover, smaller infraslow potential changes accompany functional activation and might help to assess neuronal repair after stroke. The objective of the present pilot study was to investigate whether it is feasible to apply noninvasive near-DC-magnetoencephalography to detect and monitor infraslow field changes in patients with acute stroke. METHODS: A simple motor condition was used to induce physiological cortical infraslow field changes. Five patients in a subacute state after ischemic stroke performed self-paced simple finger movements (30-second periods of finger movements, always separated by 30-second periods of rest, for a total of 15 minutes). Near-DC-magnetoencephalography signals were recorded over the contralateral primary motor cortex for the affected and unaffected hemisphere, respectively. RESULTS: In all patients, the time courses of the contralateral cortical field amplitudes in the infraslow frequency range followed closely the motor task cycles revealing statistically significant differences between finger movement and rest periods. In 4 of 5 patients, infraslow field amplitudes were significantly stronger over the unaffected hemisphere compared with the affected hemisphere. CONCLUSIONS: This study demonstrates that cortical infraslow activity can be recorded noninvasively in patients in the subacute state after ischemic stroke. It is suggested that near-DC-magnetoencephalography is a promising tool to also detect cortical spreading depolarization noninvasively.

Neuronal current detection with low-field magnetic resonance: simulations and methods.

The noninvasive detection of neuronal currents in active brain networks [or direct neuronal imaging (DNI)] by means of nuclear magnetic resonance (NMR) remains a scientific challenge. Many different attempts using NMR scanners with magnetic fields >1 T (high-field NMR) have been made in the past years to detect phase shifts or magnitude changes in the NMR signals. However, the many physiological (i.e., the contemporarily BOLD effect, the weakness of the neuronal-induced magnetic field, etc.) and technical limitations (e.g., the spatial resolution) in observing the weak signals have led to some contradicting results. In contrast, only a few attempts have been made using low-field NMR techniques. As such, this paper was aimed at reviewing two recent developments in this front. The detection schemes discussed in this manuscript, the resonant mechanism (RM) and the DC method, are specific to NMR instrumentations with main fields below the earth magnetic field (50 microT), while some even below a few microteslas (ULF-NMR). However, the experimental validation for both techniques, with differentiating sensitivity to the various neuronal activities at specific temporal and spatial resolutions, is still in progress and requires carefully designed magnetic field sensor technology. Additional care should be taken to ensure a stringent magnetic shield from the ambient magnetic field fluctuations. In this review, we discuss the characteristics and prospect of these two methods in detecting neuronal currents, along with the technical requirements on the instrumentation.

Dynamics of cortical neurovascular coupling analyzed by simultaneous DC-magnetoencephalography and time-resolved near-infrared spectroscopy.

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.

Combined MEG and EEG methodology for non-invasive recording of infraslow activity in the human cortex.

OBJECTIVE: Periinfarct depolarisation and spreading depression represent key mechanisms of neuronal injury after stroke. Changes in cortical electrical potentials and magnetic fields in the very low frequency range are relevant parameters to characterize these events, which up to now have only been recorded invasively. In this study, we proved whether a non-invasive combined MEG/EEG recording technique is able to quantitatively monitor cortical infraslow activity in humans. METHODS: We used repetitive very slow and slow right finger movements as a physiological motor activation paradigm to induce cortical infraslow activity. Infraslow fields were recorded over the left hemisphere using a modulation-based MEG technique. EEG was performed using 16 standard Ag-Cl electrodes that covered the left motor cortex. RESULTS: We recorded stable focal motor-related infraslow magnetic field changes in seven out of seven subjects. We also found correlating infraslow electrical potential changes in three out of seven subjects. Slow finger movements generated significantly stronger field and potential changes than very slow movements. CONCLUSIONS: This study demonstrates the technical feasibility of combined non-invasive electrical potential and magnetic field measurements to localize and quantitatively monitor physiological, low amplitude, infraslow cortical activity in humans. This specific combination of simultaneous recording techniques allows to benefit from the specific physical advantages of each method. SIGNIFICANCE: This combined non-invasive MEG-EEG methodology is able to provide important information on infraslow neuronal activity originating from tangentially and radially oriented sources. Moreover, this dual approach has the potential to separate neuronal from non-neuronal DC-sources, e.g., radially to the head orientated DC-currents across the skin/scalp/skull/dura occurring during cerebral hypercapnia or hypoxia.

Recording of focal direct current (DC) changes in the human cerebral cortex using refined non-invasive DC-EEG methodology.

A non-invasive DC electroencephalographic (DC-EEG) method was developed to record and analyze focal low-frequency (<0.1 Hz) DC changes in the human cerebral cortex. A simple repetitive finger-movement task was used as a physiological activation paradigm. DC-EEG amplitudes were recorded using a custom-made DC amplifier with automatic offset correction. A total of 16 standard Ag/AgCl electrodes covered the left primary motor cortex. In three of six subjects, reliable focal motor-related DC-EEG shifts over the hand cortex were monitored. This study demonstrates that refined DC-EEG recording and data analysis procedures allow non-invasive recording of low-frequency and low-amplitude focal cortical changes in humans. An important clinical perspective of this technology is the detection of stroke-associated cortical DC activity.

Comparing a template approach and complex bandpass filtering for single-trial analysis of auditory evoked M100.

Two methods for single-trial analysis were compared, an established parametric template approach and a recently proposed non-parametric method based on complex bandpass filtering. The comparison was carried out by means of pseudo-real simulations based on magnetoencephalography measurements of cortical responses to auditory signals. The comparison focused on amplitude and latency estimation of the M100 response. The results show that both methods are well suited for single-trial analysis of the auditory evoked M100. While both methods performed similarly with respect to latency estimation, the non-parametric approach was observed to be more robust for amplitude estimation. The non-parametric approach can thus be recommended as an additional valuable tool for single-trial analysis.

Application of decorrelation-independent component analysis to biomagnetic multi-channel measurements.

Biomagnetic multi-channel recordings are typically a superposition of signals from several biological sources of interest and from biological and technical noise sources. Besides averaging, source localization, and spectral analysis to name only a few methods, independent component analysis is an established tool to resolve the superposition present in raw biomagnetic data on a purely statistical basis. Here the time-delayed decorrelation-independent component analysis algorithm is applied to exemplary magnetocardiographic and magnetoencephalographic data and the successful signal separation is demonstrated.

Pseudo current density maps of electrophysiological heart, nerve or brain function and their physical basis.

BACKGROUND: In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular. METHODS: The physical basis of these intuitive maps is clarified by means of analytically solvable problems. RESULTS: Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method. CONCLUSION: Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.

J-coupling nuclear magnetic resonance spectroscopy of liquids in nT fields.

In ultralow magnetic fields, liquid state nuclear magnetic resonance (NMR) spectra of homonuclear spin systems exhibit line widths dominated by their natural lifetime. Chemical shifts become negligible, and heteronuclear NMR spectra show predominantly the electron-mediated field-independent J-coupling. However, weak polarization and Larmor frequencies down to a few hertz require special detectors, such as Superconducting Quantum Interference Devices (SQUID), that also enable the simultaneous detection of broad band spectra of heteronuclear spin systems. We acquired spectra of 2,2,2-trifluoroethanol and trimethyl phosphate at detection fields varying from 444 nT to 3.34 muT after prepolarizing the sample in a field of 250 muT. Down to a 1H Larmor frequency of 40 Hz, the spectra of trifluoroethanol exhibited four clearly resolvable peaks. The numerical simulation agreed well with the measured spectra. Trimethyl phosphate exhibited two major groups of nonresolved proton lines. At 1H Larmor frequencies below 150 Hz, the separation of the two groups decreased, reflecting the transition from weakly to strongly coupled spin systems. Direct determination of 3J(H,P) from the peak separation is possible only at Larmor frequencies above 150 Hz. The experimental setup allowed an easy adjustment of the detection field over several octaves. This enabled us to adapt the detection field to the best-suited measurement window providing the maximum spectral information. Low-field NMR may open new applications, such as monitoring heteronuclear reactions, low-field imaging, simultaneous NMR/magnetoencephalography measurements, or quantum computing.