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

Magnetic Field Mapping and Correction for Moving OP-MEG

Background: Optically pumped magnetometers (OPMs) have made moving, wearable magnetoencephalography (MEG) possible. The OPMs typically used for MEG require a low background magnetic field to operate, which is achieved using both passive and active magnetic shielding. However, the background magnetic field is never truly zero Tesla, and so the field at each of the OPMs changes as the participant moves. This leads to position and orientation dependent changes in the measurements, which manifest as low frequency artefacts in MEG data. Objective: We modelled the spatial variation in the magnetic field and used the model to predict the movement artefact found in a dataset. Methods: We demonstrate a method for modelling this field with a triaxial magnetometer, then showed that we can use the same technique to predict the movement artefact in a real OPM-based MEG (OP-MEG) dataset. Results: Using an 86-channel OP-MEG system, we found that this modelling method maximally reduced the power spectral density of the data by 27.8 0.6 dB at 0 Hz, when applied over 5 s non-overlapping windows. Conclusion: The magnetic field inside our state-of-the art magnetically shielded room can be well described by low-order spherical harmonic functions. We achieved a large reduction in movement noise when we applied this model to OP-MEG data. Significance: Real-time implementation of this method could reduce passive shielding requirements for OP-MEG recording and allow the measurement of low-frequency brain activity during natural participant movement

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

Magnetic Field Mapping and Correction for Moving OP-MEG

Background: Optically pumped magnetometers (OPMs) have made moving, wearable magnetoencephalography (MEG) possible. The OPMs typically used for MEG require a low background magnetic field to operate, which is achieved using both passive and active magnetic shielding. However, the background magnetic field is never truly zero Tesla, and so the field at each of the OPMs changes as the participant moves. This leads to position and orientation dependent changes in the measurements, which manifest as low frequency artefacts in MEG data. Objective: We model the spatial variation in the magnetic field and use the model to predict the movement artefact found in a dataset. Methods: We demonstrate a method for modelling this field with a triaxial magnetometer, then show that we can use the same technique to predict the movement artefact in a real OPM-based MEG (OP-MEG) dataset. Results: Using an 86-channel OP-MEG system, we found that this modelling method maximally reduced the power spectral density of the data by 27.8 ± 0.6 dB at 0 Hz, when applied over 5 s non-overlapping windows. Conclusion: The magnetic field inside our state-of-the art magnetically shielded room can be well described by low-order spherical harmonic functions. We achieved a large reduction in movement noise when we applied this model to OP-MEG data. Significance: Real-time implementation of this method could reduce passive shielding requirements for OP-MEG recording and allow the measurement of low-frequency brain activity during natural participant movement

Building Mental Experiences: From Scenes to Events

Mental events are central to everyday cognition, be it our continuous perception of the world, recalling autobiographical memories, or imagining the future. Little is known about the fine-grained temporal dynamics of these processes. Given the apparent predominance of scene imagery across cognition, in this thesis I used magnetoencephalography to investigate whether and how activity in the hippocampus and ventromedial prefrontal cortex (vmPFC) supports the mental construction of scenes and the events to which they give rise. In the first experiment, participants gradually imagined scenes and also closely matched non-scene arrays; this allowed me to assess whether any brain regions showed preferential responses to scene imagery. The anterior hippocampus and vmPFC were particularly engaged by the construction of scene imagery, with the vmPFC driving hippocampal activity. In the second experiment, I found that certain objects – those that were space-defining – preferentially engaged the vmPFC and superior temporal gyrus during scene construction, providing insight into how objects affect the creation of scene representations. The third experiment involved boundary extension during scene perception, permitting me to examine how single scenes might be prepared for inclusion into events. I observed changes in evoked responses just 12.5-58 ms after scene onset over fronto-temporal sensors, with again the vmPFC exerting a driving influence on other brain regions, including the hippocampus. In the final experiment, participants watched brief movies of events built from a series of scenes or non-scene patterns. A difference in evoked responses between the two event types emerged during the first frame of the movies, the primary source of which was shown to be the hippocampus. The enduring theme of the results across experiments was scene-specific engagement of the hippocampus and vmPFC, with the latter being the driving influence. Overall, this thesis provides insights into the neural dynamics of how scenes are built, made ready for inclusion into unfolding mental episodes, and then linked to produce our seamless experience of the world

Characterisation of the ghrelinergic system in human models of neurodegenerative diseases

Calorie restriction (CR) has well established neuroprotective properties across species and is known to prevent cognitive deficits in several mouse models and in aged humans. Our group and others have shown that CR beneficial effects are dependent on the circulating hormone acyl-ghrelin (AG), that promotes hippocampal memory function and protects against neurodegeneration in rodents. Indeed, ghrelin knockout (KO) mice show defects in memory task performance and plasma ghrelin levels are significantly reduced in aged humans. Because of its connection to memory and ageing, AG has been studied in mouse models of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the two most common causes of dementia in the aged population. However, very few of these studies have been performed in human models. This project aimed to determine the expression of key regulatory proteins of the ghrelin pathway in the young and aged healthy human brain, as well as brain of AD and PD patients, combining immunohistochemistry, RNA in situ hybridization, and molecular biology. My findings show that the key enzymes of the ghrelinergic axis – GHS-R1a, GOAT and APT1 – are highly expressed in the aged healthy human hippocampus, but their expression level is impaired in PD with dementia . Further studies are needed to determine a potential correlation between the activity of ghrelin in the brain and the level of cognitive impairment and dementia. On the contrary, very little difference is observed between early and late stage of AD, suggesting that the ghrelinergic system may not be impaired in these patients. The second aim was to characterize the effects of AG on a human neuronal cell line treated with rotenone or amyloid-β oligomers (AβOs) to simulate oxidative stress from PD and AD, respectively. Using confocal microscopy and molecular biology techniques, I assessed neuronal cell death and mitochondrial function and reported significant mitochondrial toxicity in these models, that worsen by chronic pre-treatment with the inactive form of AG, unacylated ghrelin (UAG). Ultimately, this project supports the ghrelinergic axis as a potential target for future studies aiming to identify treatments to limit the progression of dementia in humans

Towards naturalistic scanning environments for wearable magnetoencephalography

Magnetoencephalography (MEG) is a neuroimaging technique that probes human brain function, by measuring the magnetic fields generated at the scalp by current flow in assemblies of neurons. A direct measure of neural activity, MEG offers high spatiotemporal resolution, but limitations imposed by superconducting sensor technologies impede its clinical utility. Specifically, neuromagnetic fields are up to a billion times smaller than that of the Earth, meaning MEG must be performed inside a magnetically shielded room (MSR), which is typically expensive, heavy, and difficult to site. Furthermore, current MEG systems employ superconducting quantum interference devices (SQUIDs) to detect these tiny magnetic fields, however, these sensors require cryogenic cooling with liquid helium. Consequently, scanners are bulky, expensive, and the SQUIDs must be arranged in a fixed, one-size-fits-all array. Any movement relative to the fixed sensors impacts data quality, meaning participant movement in MEG is severely restricted. The development of technology to enable a wearable MEG system allowing free participant movement would generate a step change for the field. Optically-pumped magnetometers (OPMs) are an alternative magnetic field detector recently developed with sufficient sensitivity for MEG measurements. Operating at body temperature, in a small and lightweight sensor package, OPMs offer the potential for a wearable MEG scanner that allows participant movement, with sensors mounted on the scalp in a helmet or cap. However, OPMs operate around a zero-field resonance, resulting in a narrow dynamic range that may be easily exceeded by movement of the sensor within a background magnetic field. Enabling a full range of participant motion during an OPM-MEG scan therefore presents a significant challenge, requiring precise control of the background magnetic field. This thesis describes the development of techniques to better control the magnetic environment for OPM-MEG. This includes greater reduction of background magnetic fields over a fixed region to minimise motion artefacts and facilitate larger movements, and the application of novel, multi-coil active magnetic shielding systems to enable flexibility in participant positioning within the MSR. We outline a new approach to map background magnetic fields more accurately, reducing the remnant magnetic field to <300 pT and yielding a five-fold reduction in motion artefact, to allow detection of a visual steady-state evoked response during continuous head motion. Employing state-of-the-art, triaxial OPMs alongside this precision magnetic field control technique, we map motor function during a handwriting task involving naturalistic head movements and investigate the advantages of triaxial sensitivity for MEG data analysis. Using multi-coil active magnetic shielding, we map motor function consistently in the same participant when seated and standing, and demonstrate the first OPM-MEG hyperscanning experiments. Finally, we outline how the integration of a multi-coil system into the walls of a lightweight MSR, when coupled with field control over a larger volume, provides an open scanning environment. In sum, these developments represent a significant step towards realising the full potential of OPM-MEG as a wearable functional neuroimaging technology

Towards naturalistic scanning environments for wearable magnetoencephalography

Magnetoencephalography (MEG) is a neuroimaging technique that probes human brain function, by measuring the magnetic fields generated at the scalp by current flow in assemblies of neurons. A direct measure of neural activity, MEG offers high spatiotemporal resolution, but limitations imposed by superconducting sensor technologies impede its clinical utility. Specifically, neuromagnetic fields are up to a billion times smaller than that of the Earth, meaning MEG must be performed inside a magnetically shielded room (MSR), which is typically expensive, heavy, and difficult to site. Furthermore, current MEG systems employ superconducting quantum interference devices (SQUIDs) to detect these tiny magnetic fields, however, these sensors require cryogenic cooling with liquid helium. Consequently, scanners are bulky, expensive, and the SQUIDs must be arranged in a fixed, one-size-fits-all array. Any movement relative to the fixed sensors impacts data quality, meaning participant movement in MEG is severely restricted. The development of technology to enable a wearable MEG system allowing free participant movement would generate a step change for the field. Optically-pumped magnetometers (OPMs) are an alternative magnetic field detector recently developed with sufficient sensitivity for MEG measurements. Operating at body temperature, in a small and lightweight sensor package, OPMs offer the potential for a wearable MEG scanner that allows participant movement, with sensors mounted on the scalp in a helmet or cap. However, OPMs operate around a zero-field resonance, resulting in a narrow dynamic range that may be easily exceeded by movement of the sensor within a background magnetic field. Enabling a full range of participant motion during an OPM-MEG scan therefore presents a significant challenge, requiring precise control of the background magnetic field. This thesis describes the development of techniques to better control the magnetic environment for OPM-MEG. This includes greater reduction of background magnetic fields over a fixed region to minimise motion artefacts and facilitate larger movements, and the application of novel, multi-coil active magnetic shielding systems to enable flexibility in participant positioning within the MSR. We outline a new approach to map background magnetic fields more accurately, reducing the remnant magnetic field to <300 pT and yielding a five-fold reduction in motion artefact, to allow detection of a visual steady-state evoked response during continuous head motion. Employing state-of-the-art, triaxial OPMs alongside this precision magnetic field control technique, we map motor function during a handwriting task involving naturalistic head movements and investigate the advantages of triaxial sensitivity for MEG data analysis. Using multi-coil active magnetic shielding, we map motor function consistently in the same participant when seated and standing, and demonstrate the first OPM-MEG hyperscanning experiments. Finally, we outline how the integration of a multi-coil system into the walls of a lightweight MSR, when coupled with field control over a larger volume, provides an open scanning environment. In sum, these developments represent a significant step towards realising the full potential of OPM-MEG as a wearable functional neuroimaging technology