Development and Application of Functional Magnetic Resonance Imaging in Paediatric Focal Epilepsy

There are two major applications of fMRI in paediatric focal epilepsy. The first is mapping of eloquent cortex. The second is the use of simultaneous EEG-fMRI to map the epileptogenic zone. The main methodological issues faced by these fMRI applications are: motion, physiological noise, quality assurance, and statistical analysis. To address the issues of subject motion and physiological noise we constructed a simple analytical biophysical model of Blood Oxygenation Level Dependent (BOLD) signal capable of identifying and correcting these artefacts (named FIACH). This model was validated in a sample of children performing a language task with high motion levels. FIACH outperformed 6 other competitive methods of noise control. In the second study, we characterized how metrics of quality assurance could predict the clinical utility of EEG-fMRI. We also quantified the impact of a natural stimulus (a cartoon) on reducing subject motion. During this analysis it was noted that the corrections for multiple comparisons employed using Random Field Theory (RFT) at an individual level were overly conservative. This led to an exploration of RFT sensitivity and its relationship to image smoothing and degrees of freedom. By reviewing over 150 papers published in 2016 it was possible to estimate that 80% of studies suffer from a similar loss in sensitivity. Simulations are provided to help identify and prevent this loss in sensitivity. In the final study we sought to use EEG-fMRI to characterize the relationship between the brain’s functional organization and Interictal Epileptiform Discharges (IEDs) in paediatric focal epilepsy. Interestingly, we identified increasing connectivity of the piriform cortex and caudate to the default mode network as a function of IEDs. This suggested a mechanism by which IEDs may propagate through functional networks in the brain

Testing covariance models for MEG source reconstruction of hippocampal activity

Beamforming is one of the most commonly used source reconstruction methods for magneto- and electroencephalography (M/EEG). One underlying assumption, however, is that distant sources are uncorrelated and here we tested whether this is an appropriate model for the human hippocampal data. We revised the Empirical Bayesian Beamfomer (EBB) to accommodate specific a-priori correlated source models. We showed in simulation that we could use model evidence (as approximated by Free Energy) to distinguish between different correlated and uncorrelated source scenarios. Using group MEG data in which the participants performed a hippocampal-dependent task, we explored the possibility that the hippocampus or the cortex or both were correlated in their activity across hemispheres. We found that incorporating a correlated hippocampal source model significantly improved model evidence. Our findings help to explain why, up until now, the majority of MEG-reported hippocampal activity (typically making use of beamformers) has been estimated as unilateral

Interference suppression techniques for OPM-based MEG: Opportunities and challenges

One of the primary technical challenges facing magnetoencephalography (MEG) is that the magnitude of neuromagnetic fields is several orders of magnitude lower than interfering signals. Recently, a new type of sensor has been developed – the optically pumped magnetometer (OPM). These sensors can be placed directly on the scalp and move with the head during participant movement, making them wearable. This opens up a range of exciting experimental and clinical opportunities for OPM-based MEG experiments, including paediatric studies, and the incorporation of naturalistic movements into neuroimaging paradigms. However, OPMs face some unique challenges in terms of interference suppression, especially in situations involving mobile participants, and when OPMs are integrated with electrical equipment required for naturalistic paradigms, such as motion capture systems. Here we briefly review various hardware solutions for OPM interference suppression. We then outline several signal processing strategies aimed at increasing the signal from neuromagnetic sources. These include regression-based strategies, temporal filtering and spatial filtering approaches. The focus is on the practical application of these signal processing algorithms to OPM data. In a similar vein, we include two worked-through experiments using OPM data collected from a whole-head sensor array. These tutorial-style examples illustrate how the steps for suppressing external interference can be implemented, including the associated data and code so that researchers can try the pipelines for themselves. With the popularity of OPM-based MEG rising, there will be an increasing need to deal with interference suppression. We hope this practical paper provides a resource for OPM-based MEG researchers to build upon

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)

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy.

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration

Modelling optically pumped magnetometer interference in MEG as a spatially homogeneous magnetic field

Here we propose that much of the magnetic interference observed when using optically pumped magnetometers for MEG experiments can be modeled as a spatially homogeneous magnetic field. We show that this approximation reduces sensor level variance and substantially improves statistical power. This model does not require knowledge of the underlying neuroanatomy nor the sensor positions. It only needs information about the sensor orientation. Due to the model's low rank there is little risk of removing substantial neural signal. However, we provide a framework to assess this risk for any sensor number, design or subject neuroanatomy. We find that the risk of unintentionally removing neural signal is reduced when multi-axis recordings are performed. We validated the method using a binaural auditory evoked response paradigm and demonstrated that removing the homogeneous magnetic field increases sensor level SNR by a factor of 3. Considering the model's simplicity and efficacy, we suggest that this homogeneous field correction can be a powerful preprocessing step for arrays of optically pumped magnetometers

Wearable neuroimaging: Combining and contrasting magnetoencephalography and electroencephalography

One of the most severe limitations of functional neuroimaging techniques, such as magnetoencephalography (MEG), is that participants must maintain a fixed head position during data acquisition. This imposes restrictions on the characteristics of the experimental cohorts that can be scanned and the experimental questions that can be addressed. For these reasons, the use of ‘wearable’ neuroimaging, in which participants can move freely during scanning, is attractive. The most successful example of wearable neuroimaging is electroencephalography (EEG), which employs lightweight and flexible instrumentation that makes it useable in almost any experimental setting. However, EEG has major technical limitations compared to MEG, and therefore the development of wearable MEG, or hybrid MEG/EEG systems, is a compelling prospect. In this paper, we combine and compare EEG and MEG measurements, the latter made using a new generation of optically-pumped magnetometers (OPMs). We show that these new second generation commercial OPMs, can be mounted on the scalp in an ‘EEG-like’ cap, enabling the acquisition of high fidelity electrophysiological measurements. We show that these sensors can be used in conjunction with conventional EEG electrodes, offering the potential for the development of hybrid MEG/EEG systems. We compare concurrently measured signals, showing that, whilst both modalities offer high quality data in stationary subjects, OPM-MEG measurements are less sensitive to artefacts produced when subjects move. Finally, we show using simulations that OPM-MEG offers a fundamentally better spatial specificity than EEG. The demonstrated technology holds the potential to revolutionise the utility of functional brain imaging, exploiting the flexibility of wearable systems to facilitate hitherto impractical experimental paradigms

Imaging the human hippocampus with optically-pumped magnetoencephalography

Optically-pumped (OP) magnetometers allow magnetoencephalography (MEG) to be performed while a participant’s head is unconstrained. To fully leverage this new technology, and in particular its capacity for mobility, the activity of deep brain structures which facilitate explorative behaviours such as navigation, must be detectable using OP-MEG. One such crucial brain region is the hippocampus. Here we had three healthy adult participants perform a hippocampal-dependent task – the imagination of novel scene imagery – while being scanned using OPMEG. A conjunction analysis across these three participants revealed a significant change in theta power in the medial temporal lobe. The peak of this activated cluster was located in the anterior hippocampus. We repeated the experiment with the same participants in a conventional SQUID-MEG scanner and found similar engagement of the medial temporal lobe, also with a peak in the anterior hippocampus. These OP-MEG findings indicate exciting new opportunities for investigating the neural correlates of a range of crucial cognitive functions in naturalistic contexts including spatial navigation, episodic memory and social interactions

Non-invasive measurements of ictal and interictal epileptiform activity using optically pumped magnetometers

Magneto- and electroencephalography (MEG/EEG) are important techniques for the diagnosis and pre-surgical evaluation of epilepsy. Yet, in current cryogen-based MEG systems the sensors are offset from the scalp, which limits the signal-to-noise ratio (SNR) and thereby the sensitivity to activity from deep structures such as the hippocampus. This effect is amplified in children, for whom adult-sized fixed-helmet systems are typically too big. Moreover, ictal recordings with fixed-helmet systems are problematic because of limited movement tolerance and/or logistical considerations. Optically Pumped Magnetometers (OPMs) can be placed directly on the scalp, thereby improving SNR and enabling recordings during seizures. We aimed to demonstrate the performance of OPMs in a clinical population. Seven patients with challenging cases of epilepsy underwent MEG recordings using a 12-channel OPM-system and a 306-channel cryogen-based whole-head system: three adults with known deep or weak (low SNR) sources of interictal epileptiform discharges (IEDs), along with three children with focal epilepsy and one adult with frequent seizures. The consistency of the recorded IEDs across the two systems was assessed. In one patient the OPMs detected IEDs that were not found with the SQUID-system, and in two patients no IEDs were found with either system. For the other patients the OPM data were remarkably consistent with the data from the cryogenic system, noting that these were recorded in different sessions, with comparable SNRs and IED-yields overall. Importantly, the wearability of OPMs enabled the recording of seizure activity in a patient with hyperkinetic movements during the seizure. The observed ictal onset and semiology were in agreement with previous video- and stereo-EEG recordings. The relatively affordable technology, in combination with reduced running and maintenance costs, means that OPM-based MEG could be used more widely than current MEG systems, and may become an affordable alternative to scalp EEG, with the potential benefits of increased spatial accuracy, reduced sensitivity to volume conduction/field spread, and increased sensitivity to deep sources. Wearable MEG thus provides an unprecedented opportunity for epilepsy, and given its patient-friendliness, we envisage that it will not only be used for presurgical evaluation of epilepsy patients, but also for diagnosis after a first seizure