Delineating between-subject heterogeneity in alpha networks with Spatio-Spectral Eigenmodes.

Between subject variability in the spatial and spectral structure of oscillatory networks can be highly informative but poses a considerable analytic challenge. Here, we describe a data-driven modal decomposition of a multivariate autoregressive model that simultaneously identifies oscillations by their peak frequency, damping time and network structure. We use this decomposition to define a set of Spatio-Spectral Eigenmodes (SSEs) providing a parsimonious description of oscillatory networks. We show that the multivariate system transfer function can be rewritten in these modal coordinates, and that the full transfer function is a linear superposition of all modes in the decomposition. The modal transfer function is a linear summation and therefore allows for single oscillatory signals to be isolated and analysed in terms of their spectral content, spatial distribution and network structure. We validate the method on simulated data and explore the structure of whole brain oscillatory networks in eyes-open resting state MEG data from the Human Connectome Project. We are able to show a wide between participant variability in peak frequency and network structure of alpha oscillations and show a distinction between occipital 'high-frequency alpha' and parietal 'low-frequency alpha'. The frequency difference between occipital and parietal alpha components is present within individual participants but is partially masked by larger between subject variability; a 10Hz oscillation may represent the high-frequency occipital component in one participant and the low-frequency parietal component in another. This rich characterisation of individual neural phenotypes has the potential to enhance analyses into the relationship between neural dynamics and a person's behavioural, cognitive or clinical state.

Delivering strong 1H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange.

Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this area's most compelling outcomes. Methods to optimize the low-cost parahydrogen-based approach signal amplification by reversible exchange with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H labeling in both the agent and catalyst and achieve polarization lifetimes of ca 2 min with 50% polarization in the case of methyl-4,6-d2 -nicotinate. Because a 1.5-T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this technique's generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine, and isonicotinamide analogs that feature as building blocks in biochemistry and many disease-treating drugs.

Achieving High Levels of NMR-Hyperpolarization in Aqueous Media With Minimal Catalyst Contamination Using SABRE.

Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1 H NMR signals in a range of substrates in aqueous media. To achieve this outcome, phase-transfer catalysis is exploited, which leads to less than 1.5×10-6  mol dm-3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline-based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called catalyst separated hyperpolarization through signal amplification by reversible exchange or CASH-SABRE. We illustrate this method for the substrates pyrazine, 5-methylpyrimidine, 4,6-d2 -methyl nicotinate, 4,6-d2 -nicotinamide and pyridazine achieving 1 H signal gains of approximately 790-, 340-, 3000-, 260- and 380-fold per proton at 9.4 T at the time point at which phase separation is complete.

Achieving High 1 H Nuclear Hyperpolarization Levels with Long Lifetimes in a Range of Tuberculosis Drug Scaffolds.

Despite the successful use of isoniazid, rifampicin, pyrazinamide and ethambutol in the treatment of tuberculosis (TB), it is a disease of growing global concern. We illustrate here a series of methods that will dramatically improve the magnetic resonance imaging (MRI) detectability of nineteen TB-relevant agents. We note that the future probing of their uptake and distribution in vivo would be expected to significantly enhance their efficacy in disease treatment. This improvement in detectability is achieved by use of the parahydrogen based SABRE protocol in conjunction with the 2 H-labelling of key sites within their molecular structures and the 2 H-labelling of the magnetization transfer catalyst. The T1 relaxation times and polarization levels of these agents are quantified under test conditions to produce a protocol to identify structurally optimized motifs for future detection. For example, deuteration of the 6-position of a pyrazinamide analogue leads to a structural form that exhibits T1 values of 144.5 s for 5-H with up to 20 % polarization. This represents a >7-fold extension in relaxation time and almost 10-fold improvement in polarization level when compared to its unoptimized structure.

A Simple Route to Strong Carbon-13 NMR Signals Detectable for Several Minutes.

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) suffer from low sensitivity and limited nuclear spin memory lifetimes. Although hyperpolarization techniques increase sensitivity, there is also a desire to increase relaxation times to expand the range of applications addressable by these methods. Here, we demonstrate a route to create hyperpolarized magnetization in 13 C nuclear spin pairs that last much longer than normal lifetimes by storage in a singlet state. By combining molecular design and low-field storage with para-hydrogen derived hyperpolarization, we achieve more than three orders of signal amplification relative to equilibrium Zeeman polarization and an order of magnitude extension in state lifetime. These studies use a range of specifically synthesized pyridazine derivatives and dimethyl p-tolyl phenyl pyridazine is the most successful, achieving a lifetime of about 190 s in low-field, which leads to a 13 C-signal that is visible for 10 minutes.

Harnessing polarisation transfer to indazole and imidazole through signal amplification by reversible exchange to improve their NMR detectability.

The signal amplification by reversible exchange (SABRE) approach has been used to hyperpolarise the substrates indazole and imidazole in the presence of the co-ligand acetonitrile through the action of the precataysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)]. 2 H-labelled forms of these catalysts were also examined. Our comparison of the two precatalysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)], coupled with 2 H labelling of the N-heterocyclic carbene and associated relaxation and polarisation field variation studies, demonstrates the critical and collective role these parameters play in controlling the efficiency of signal amplification by reversible exchange. Ultimately, with imidazole, a 700-fold1 H signal gain per proton is produced at 400 MHz, whilst for indazole, a 90-fold increase per proton is achieved. The co-ligand acetonitrile proved to optimally exhibit a 190-fold signal gain per proton in these measurements, with the associated studies revealing the importance the substrate plays in controlling this value. Copyright © 2017 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.

MEG Adaptation Resolves the Spatiotemporal Characteristics of Face-Sensitive Brain Responses.

An unresolved goal in face perception is to identify brain areas involved in face processing and simultaneously understand the timing of their involvement. Currently, high spatial resolution imaging techniques identify the fusiform gyrus as subserving processing of invariant face features relating to identity. High temporal resolution imaging techniques localize an early latency evoked component-the N/M170-as having a major generator in the fusiform region; however, this evoked component is not believed to be associated with the processing of identity. To resolve this, we used novel magnetoencephalographic beamformer analyses to localize cortical regions in humans spatially with trial-by-trial activity that differentiated faces and objects and to interrogate their functional sensitivity by analyzing the effects of stimulus repetition. This demonstrated a temporal sequence of processing that provides category-level and then item-level invariance. The right fusiform gyrus showed adaptation to faces (not objects) at ∼150 ms after stimulus onset regardless of face identity; however, at the later latency of ∼200-300 ms, this area showed greater adaptation to repeated identity faces than to novel identities. This is consistent with an involvement of the fusiform region in both early and midlatency face-processing operations, with only the latter showing sensitivity to invariant face features relating to identity. SIGNIFICANCE STATEMENT: Neuroimaging techniques with high spatial-resolution have identified brain structures that are reliably activated when viewing faces and techniques with high temporal resolution have identified the time-varying temporal signature of the brain's response to faces. However, until now, colocalizing face-specific mechanisms in both time and space has proven notoriously difficult. Here, we used novel magnetoencephalographic analysis techniques to spatially localize cortical regions with trial-by-trial temporal activity that differentiates between faces and objects and to interrogate their functional sensitivity by analyzing effects of stimulus repetition on the time-locked signal. These analyses confirm a role for the right fusiform region in early to midlatency responses consistent with face identity processing and convincingly deliver upon magnetoencephalography's promise to resolve brain signals in time and space simultaneously.

Iridium Cyclooctene Complex That Forms a Hyperpolarization Transfer Catalyst before Converting to a Binuclear C-H Bond Activation Product Responsible for Hydrogen Isotope Exchange.

[IrCl(COE)2]2 (1) reacts with pyridine (py) and H2 to form crystallographically characterized IrCl(H)2(COE)(py)2 (2). 2 undergoes py loss to form 16-electron IrCl(H)2(COE)(py) (3), with equivalent hydride ligands. When this reaction is studied with parahydrogen, 1 efficiently achieves hyperpolarization of free py (and nicotinamide, nicotine, 5-aminopyrimidine, and 3,5-lutudine) via signal amplification by reversible exchange (SABRE) and hence reflects a simple and readily available precatayst for this process. 2 reacts further over 48 h at 298 K to form crystallographically characterized (Cl)(H)(py)(µ-Cl)(µ-H)(κ-µ-NC5H4)Ir(H)(py)2 (4). This dimer is active in the hydrogen isotope exchange process that is used in radiopharmaceutical preparations. Furthermore, while [Ir(H)2(COE)(py)3]PF6 (6) forms upon the addition of AgPF6 to 2, its stability precludes its efficient involvement in SABRE.

Long-lived states to sustain SABRE hyperpolarised magnetisation.

The applicability of the magnetic resonance (MR) technique in the liquid phase is limited by poor sensitivity and short nuclear spin coherence times which are insufficient for many potential applications. Here we illustrate how it is possible to address both of these issues simultaneously by harnessing long-lived hyperpolarised spin states that are formed by adapting the Signal Amplification by Reversible Exchange (SABRE) technique. We achieve more than 4% net 1H-polarisation in a long-lived form that remains detectable for over ninety seconds by reference to proton pairs in the biologically important molecule nicotinamide and a pyrazine derivative whose in vivo imaging will offer a new route to probe disease in the future.

A Hyperpolarizable 1 H Magnetic Resonance Probe for Signal Detection 15†Minutes after Spin Polarization Storage.

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are two extremely important techniques with applications ranging from molecular structure determination to human imaging. However, in many cases the applicability of NMR and MRI are limited by inherently poor sensitivity and insufficient nuclear spin lifetime. Here we demonstrate a cost-efficient and fast technique that tackles both issues simultaneously. We use the signal amplification by reversible exchange (SABRE) technique to hyperpolarize the target 1 H nuclei and store this polarization in long-lived singlet (LLS) form after suitable radiofrequency (rf) pulses. Compared to the normal scenario, we achieve three orders of signal enhancement and one order of lifetime extension, leading to 1 H NMR signal detection 15 minutes after the creation of the detected states. The creation of such hyperpolarized long-lived polarization reflects an important step forward in the pipeline to see such agents used as clinical probes of disease.

Toward biocompatible nuclear hyperpolarization using signal amplification by reversible exchange: quantitative in situ spectroscopy and high-field imaging.

Signal amplification by reversible exchange (SABRE) of a substrate and parahydrogen at a catalytic center promises to overcome the inherent insensitivity of magnetic resonance. In order to apply the new approach to biomedical applications, there is a need to develop experimental equipment, in situ quantification methods, and a biocompatible solvent. We present results detailing a low-field SABRE polarizer which provides well-controlled experimental conditions, defined spins manipulations, and which allows in situ detection of thermally polarized and hyperpolarized samples. We introduce a method for absolute quantification of hyperpolarization yield in situ by means of a thermally polarized reference. A maximum signal-to-noise ratio of ∼10(3) for 148 µmol of substance, a signal enhancement of 10(6) with respect to polarization transfer field of SABRE, or an absolute (1)H-polarization level of ≈10(-2) is achieved. In an important step toward biomedical application, we demonstrate (1)H in situ NMR as well as (1)H and (13)C high-field MRI using hyperpolarized pyridine (d3) and (13)C nicotinamide in pure and 11% ethanol in aqueous solution. Further increase of hyperpolarization yield, implications of in situ detection, and in vivo application are discussed.

Probing signal amplification by reversible exchange using an NMR flow system.

Hyperpolarization methods are used in NMR to overcome its inherent sensitivity problem. Herein, the biologically relevant target nicotinamide is polarized by the hyperpolarization technique signal amplification by reversible exchange. We illustrate how the polarization transfer field, and the concentrations of parahydrogen, the polarization-transfer-catalyst and substrate can be used to maximize signal amplification by reversible exchange effectiveness by reference to the first-order spin system of this target. The catalyst is shown to be crucial in this process, first by facilitating the transfer of hyperpolarization from parahydrogen to nicotinamide and then by depleting the resulting polarized states through further interaction. The 15 longitudinal one, two, three and four spin order terms produced are rigorously identified and quantified using an automated flow apparatus in conjunction with NMR pulse sequences based on the only parahydrogen spectroscopy protocol. The rates of build-up of these terms were shown to follow the order four~three > two > single spin; this order parallels their rates of relaxation. The result of these competing effects is that the less-efficiently formed single-spin order terms dominate at the point of measurement with the two-spin terms having amplitudes that are an order of magnitude lower. We also complete further measurements to demonstrate that (13)C NMR spectra can be readily collected where the long-lived quaternary (13)C signals appear with significant intensity. These are improved upon by using INEPT. In summary, we dissect the complexity of this method, highlighting its benefits to the NMR community and its applicability for high-sensitivity magnetic resonance imaging detection in the future.

Representations of the temporal envelope of sounds in human auditory cortex: can the results from invasive intracortical "depth" electrode recordings be replicated using non-invasive MEG "virtual electrodes"?

Magnetoencephalography (MEG) beamformer analyses use spatial filters to estimate neuronal activity underlying the magnetic fields measured by the MEG sensors. MEG "virtual electrodes" are the outputs of beamformer spatial filters. The present study aimed to test the hypothesis that MEG virtual electrodes can replicate the findings from intracortical "depth" electrode studies relevant to the processing of the temporal envelopes of sounds [e.g. Nourski et al. (2009) "Temporal envelope of time-compressed speech represented in the human auditory cortex," J. Neurosci. 29:15564-15574]. Specifically we aimed to determine whether it is possible to use non-invasive MEG virtual electrodes to characterise the representation of temporal envelopes of 6-Hz sinusoidal amplitude modulation (SAM) and speech using both auditory evoked fields (AEFs) and patterns of power changes in high-frequency (>70 Hz) bands. MEG signals were analysed using a location of interest (LOI) approach by seeding virtual electrodes in the left and right posteromedial Heschl's gyri. AEFs showed phase-locking to the temporal envelope of SAM and speech stimuli. Time-frequency analyses revealed no clear differences in high gamma power between the pre-stimulus baseline and the post-stimulus presentation periods. Nevertheless the patterns of changes in high gamma power were significantly correlated with the temporal envelopes of 6-Hz SAM and speech in the majority of participants. The present study reveals difficulties in replicating clear augmentations in high gamma power changes using MEG virtual electrodes cf. intracortical "depth" electrode studies (Nourski et al., 2009).

Utilization of SABRE-derived hyperpolarization to detect low-concentration analytes via 1D and 2D NMR methods.

The characterization of materials by the inherently insensitive method of NMR spectroscopy plays a vital role in chemistry. Increasingly, hyperpolarization is being used to address the sensitivity limitation. Here, by reference to quinoline, we illustrate that the SABRE hyperpolarization technique, which uses para-hydrogen as the source of polarization, enables the rapid completion of a range of NMR measurements. These include the collection of (13)C, (13)C{(1)H}, and NOE data in addition to more complex 2D COSY, ultrafast 2D COSY and 2D HMBC spectra. The observations are made possible by the use of a flow probe and external sample preparation cell to re-hyperpolarize the substrate between transients, allowing repeat measurements to be made within seconds. The potential benefit of the combination of SABRE and 2D NMR methods for rapid characterization of low-concentration analytes is therefore established.

MEG demonstrates a supra-additive response to facial and vocal emotion in the right superior temporal sulcus.

An influential neural model of face perception suggests that the posterior superior temporal sulcus (STS) is sensitive to those aspects of faces that produce transient visual changes, including facial expression. Other researchers note that recognition of expression involves multiple sensory modalities and suggest that the STS also may respond to crossmodal facial signals that change transiently. Indeed, many studies of audiovisual (AV) speech perception show STS involvement in AV speech integration. Here we examine whether these findings extend to AV emotion. We used magnetoencephalography to measure the neural responses of participants as they viewed and heard emotionally congruent fear and minimally congruent neutral face and voice stimuli. We demonstrate significant supra-additive responses (i.e., where AV > [unimodal auditory + unimodal visual]) in the posterior STS within the first 250 ms for emotionally congruent AV stimuli. These findings show a role for the STS in processing crossmodal emotive signals.

Non-parametric statistical thresholding of baseline free MEG beamformer images.

Magnetoencephalography (MEG) provides excellent temporal resolution when examining cortical activity in humans. Inverse methods such as beamforming (a spatial filtering approach) provide the means by which activity at cortical locations can be estimated. To date, the majority of work in this field has been based upon power changes between active and baseline conditions. Recent work, however, has focused upon other properties of the time series data reconstructed by these methods. One such metric, the Source Stability Index (SSI), relates to the consistency of the time series calculated only over an active period without the use of a baseline condition. In this paper we apply non-parametric statistics to SSI volumetric maps of simulation, auditory and somatosensory data in order to provide a robust and principled method of statistical inference in the absence of a baseline condition.

Iridium N-heterocyclic carbene complexes as efficient catalysts for magnetization transfer from para-hydrogen.

While the characterization of materials by NMR is hugely important in the physical and biological sciences, it also plays a vital role in medical imaging. This success is all the more impressive because of the inherently low sensitivity of the method. We establish here that [Ir(H)(2)(IMes)(py)(3)]Cl undergoes both pyridine (py) loss as well as the reductive elimination of H(2). These reversible processes bring para-H(2) and py into contact in a magnetically coupled environment, delivering an 8100-fold increase in (1)H NMR signal strength relative to non-hyperpolarized py at 3 T. An apparatus that facilitates signal averaging has been built to demonstrate that the efficiency of this process is controlled by the strength of the magnetic field experienced by the complex during the magnetization transfer step. Thermodynamic and kinetic data combined with DFT calculations reveal the involvement of [Ir(H)(2)(η(2)-H(2))(IMes)(py)(2)](+), an unlikely yet key intermediate in the reaction. Deuterium labeling yields an additional 60% improvement in signal, an observation that offers insight into strategies for optimizing this approach.

Source stability index: a novel beamforming based localisation metric.

Many experimental studies into human brain function now use magnetoencephalography (MEG) to non-invasively investigate human neuronal activity. A number of different analysis techniques use the observed magnetic fields outside of the head to estimate the location and strength of the underlying neural generators. One such technique, a spatial filtering method known as Beamforming, produces whole-head volumetric images of activation. Typically, a differential power map throughout the head is generated between a time window containing the response to a stimulus of interest and a window containing background brain activity. A statistical test is normally performed to reveal locations which show a significantly different response in the presence of the stimulus. Despite this being a widely used measure, for both phase-locked and non-phase-locked information, it requires a number of assumptions; namely that the baseline activity defined is stable and also that a change in total power is the most effective way of revealing the neuronal sources required for the task. This paper introduces a metric which evaluates the consistency of the response at each location within a cortical volume. Such a method of localisation negates the need for a baseline period of activity to be defined and also moves away from simply considering the energy content of brain activity. The paper presents both simulated and real data. It demonstrates that this new metric of stability is able to more accurately and, crucially, more reliably draw inferences about neuronal sources of interest.

Spatiotemporal reconstruction of the auditory steady-state response to frequency modulation using magnetoencephalography.

The aim of this study was to investigate the mechanisms involved in the perception of perceptually salient frequency modulation (FM) using auditory steady-state responses (ASSRs) measured with magnetoencephalography (MEG). Previous MEG studies using frequency-modulated amplitude modulation as stimuli (Luo et al., 2006, 2007) suggested that a phase modulation encoding mechanism exists for low (<5 Hz) FM modulation frequencies but additional amplitude modulation encoding is required for faster FM modulation frequencies. In this study single-cycle sinusoidal FM stimuli were used to generate the ASSR. The stimulus was either an unmodulated 1-kHz sinusoid or a 1-kHz sinusoid that was frequency-modulated with a repetition rate of 4, 8, or 12 Hz. The fast Fourier transform (FFT) of each MEG channel was calculated to obtain the phase and magnitude of the ASSR in sensor-space and multivariate Hotelling's T(2) statistics were used to determine the statistical significance of ASSRs. MEG beamformer analyses were used to localise the ASSR sources. Virtual electrode analyses were used to reconstruct the time series at each source. FFTs of the virtual electrode time series were calculated to obtain the amplitude and phase characteristics of each source identified in the beamforming analyses. Multivariate Hotelling's T(2) statistics were used to determine the statistical significance of these reconstructed ASSRs. The results suggest that the ability of auditory cortex to phase-lock to FM is dependent on the FM pulse rate and that the ASSR to FM is lateralised to the right hemisphere.

Temporal dynamics of sinusoidal and non-sinusoidal amplitude modulation.

Previous behavioural studies in human subjects have demonstrated the importance of amplitude modulations to the process of intelligible speech perception. In functional neuroimaging studies of amplitude modulation processing, the inherent assumption is that all sounds are decomposed into simple building blocks, i.e. sinusoidal modulations. The encoding of complex and dynamic stimuli is often modelled to be the linear addition of a number of sinusoidal modulations and so, by investigating the response of the cortex to sinusoidal modulation, an experimenter can probe the same mechanisms used to encode speech. The experiment described in this paper used magnetoencephalography to measure the auditory steady-state response produced by six sounds, all modulated in amplitude at the same frequency but which formed a continuum from sinusoidal to pulsatile modulation. Analysis of the evoked response shows that the magnitude of the envelope-following response is highly non-linear, with sinusoidal amplitude modulation producing the weakest steady-state response. Conversely, the phase of the steady-state response was related to the shape of the modulation waveform, with the sinusoidal amplitude modulation producing the shortest latency relative to the other stimuli. It is shown that a point in auditory cortex produces a strong envelope following response to all stimuli on the continuum, but the timing of this response is related to the shape of the modulation waveform. The results suggest that steady-state response characteristics are determined by features of the waveform outside of the modulation domain and that the use of purely sinusoidal amplitude modulations may be misleading, especially in the context of speech encoding.