Tracking the neurodevelopmental trajectory of beta band oscillations with optically pumped magnetometer-based magnetoencephalography.

Neural oscillations mediate the coordination of activity within and between brain networks, supporting cognition and behaviour. How these processes develop throughout childhood is not only an important neuroscientific question but could also shed light on the mechanisms underlying neurological and psychiatric disorders. However, measuring the neurodevelopmental trajectory of oscillations has been hampered by confounds from instrumentation. In this paper, we investigate the suitability of a disruptive new imaging platform - optically pumped magnetometer-based magnetoencephalography (OPM-MEG) - to study oscillations during brain development. We show how a unique 192-channel OPM-MEG device, which is adaptable to head size and robust to participant movement, can be used to collect high-fidelity electrophysiological data in individuals aged between 2 and 34 years. Data were collected during a somatosensory task, and we measured both stimulus-induced modulation of beta oscillations in sensory cortex, and whole-brain connectivity, showing that both modulate significantly with age. Moreover, we show that pan-spectral bursts of electrophysiological activity drive task-induced beta modulation, and that their probability of occurrence and spectral content change with age. Our results offer new insights into the developmental trajectory of beta oscillations and provide clear evidence that OPM-MEG is an ideal platform for studying electrophysiology in neurodevelopment.

A Novel, Robust, and Portable Platform for Magnetoencephalography using Optically Pumped Magnetometers.

Magnetoencephalography (MEG) measures brain function via assessment of magnetic fields generated by neural currents. Conventional MEG uses superconducting sensors, which place significant limitations on performance, practicality, and deployment; however, the field has been revolutionised in recent years by the introduction of optically-pumped-magnetometers (OPMs). OPMs enable measurement of the MEG signal without cryogenics, and consequently the conception of 'OPM-MEG' systems which ostensibly allow increased sensitivity and resolution, lifespan compliance, free subject movement, and lower cost. However, OPM-MEG remains in its infancy with limitations on both sensor and system design. Here, we report a new OPM-MEG design with miniaturised and integrated electronic control, a high level of portability, and improved sensor dynamic range (arguably the biggest limitation of existing instrumentation). We show that this system produces equivalent measures when compared to an established instrument; specifically, when measuring task-induced beta-band, gamma-band and evoked neuro-electrical responses, source localisations from the two systems were highly comparable and temporal correlation was >0.7 at the individual level and >0.9 for groups. Using an electromagnetic phantom, we demonstrate improved dynamic range by running the system in background fields up to 8 nT. We show that the system is effective in gathering data during free movement (including a sitting-to-standing paradigm) and that it is compatible with simultaneous electroencephalography (EEG - the clinical standard). Finally, we demonstrate portability by moving the system between two laboratories. Overall, our new system is shown to be a significant step forward for OPM-MEG technology and offers an attractive platform for next generation functional medical imaging.

The neurodevelopmental trajectory of beta band oscillations: an OPM-MEG study.

Neural oscillations mediate the coordination of activity within and between brain networks, supporting cognition and behaviour. How these processes develop throughout childhood is not only an important neuroscientific question but could also shed light on the mechanisms underlying neurological and psychiatric disorders. However, measuring the neurodevelopmental trajectory of oscillations has been hampered by confounds from instrumentation. In this paper, we investigate the suitability of a disruptive new imaging platform - Optically Pumped Magnetometer-based magnetoencephalography (OPM-MEG) - to study oscillations during brain development. We show how a unique 192-channel OPM-MEG device, which is adaptable to head size and robust to participant movement, can be used to collect high-fidelity electrophysiological data in individuals aged between 2 and 34 years. Data were collected during a somatosensory task, and we measured both stimulus-induced modulation of beta oscillations in sensory cortex, and whole-brain connectivity, showing that both modulate significantly with age. Moreover, we show that pan-spectral bursts of electrophysiological activity drive task-induced beta modulation, and that their probability of occurrence and spectral content change with age. Our results offer new insights into the developmental trajectory of beta oscillations and provide clear evidence that OPM-MEG is an ideal platform for studying electrophysiology in neurodevelopment.

Free and Interfacial Boundaries in Individual-Based Models of Multicellular Biological systems.

Coordination of cell behaviour is key to a myriad of biological processes including tissue morphogenesis, wound healing, and tumour growth. As such, individual-based computational models, which explicitly describe inter-cellular interactions, are commonly used to model collective cell dynamics. However, when using individual-based models, it is unclear how descriptions of cell boundaries affect overall population dynamics. In order to investigate this we define three cell boundary descriptions of varying complexities for each of three widely used off-lattice individual-based models: overlapping spheres, Voronoi tessellation, and vertex models. We apply our models to multiple biological scenarios to investigate how cell boundary description can influence tissue-scale behaviour. We find that the Voronoi tessellation model is most sensitive to changes in the cell boundary description with basic models being inappropriate in many cases. The timescale of tissue evolution when using an overlapping spheres model is coupled to the boundary description. The vertex model is demonstrated to be the most stable to changes in boundary description, though still exhibits timescale sensitivity. When using individual-based computational models one should carefully consider how cell boundaries are defined. To inform future work, we provide an exploration of common individual-based models and cell boundary descriptions in frequently studied biological scenarios and discuss their benefits and disadvantages.

Mathematical models of developmental vascular remodelling: A review.

Over the past 40 years, there has been a strong focus on the development of mathematical models of angiogenesis, while developmental remodelling has received little such attention from the mathematical community. Sprouting angiogenesis can be seen as a very crude way of laying out a primitive vessel network (the raw material), while remodelling (understood as pruning of redundant vessels, diameter control, and the establishment of vessel identity and hierarchy) is the key to turning that primitive network into a functional network. This multiscale problem is of prime importance in the development of a functional vasculature. In addition, defective remodelling (either during developmental remodelling or due to a reactivation of the remodelling programme caused by an injury) is associated with a significant number of diseases. In this review, we discuss existing mathematical models of developmental remodelling and explore the important contributions that these models have made to the field of vascular development. These mathematical models are effectively used to investigate and predict vascular development and are able to reproduce experimentally observable results. Moreover, these models provide a useful means of hypothesis generation and can explain the underlying mechanisms driving the observed structural and functional network development. However, developmental vascular remodelling is still a relatively new area in mathematical biology, and many biological questions remain unanswered. In this review, we present the existing modelling paradigms and define the key challenges for the field.

Choice of spatial discretisation influences the progression of viral infection within multicellular tissues.

There has been an increasing recognition of the utility of models of the spatial dynamics of viral spread within tissues. Multicellular models, where cells are represented as discrete regions of space coupled to a virus density surface, are a popular approach to capture these dynamics. Conventionally, such models are simulated by discretising the viral surface and depending on the rate of viral diffusion and other considerations, a finer or coarser discretisation may be used. The impact that this choice may have on the behaviour of the system has not been studied. Here we demonstrate that under realistic parameter regimes - where viral diffusion is small enough to support the formation of familiar ring-shaped infection plaques - the choice of spatial discretisation of the viral surface can qualitatively change key model outcomes including the time scale of infection. Importantly, we show that the choice between implementing viral spread as a cell-scale process, or as a high-resolution converged PDE can generate distinct model outcomes, which raises important conceptual questions about the strength of assumptions underpinning the spatial structure of the model. We investigate the mechanisms driving these discretisation artefacts, the impacts they may have on model predictions, and provide guidance on the design and implementation of spatial and especially multicellular models of viral dynamics. We obtain our results using the simplest TIV construct for the viral dynamics, and therefore anticipate that the important effects we describe will also influence model predictions in more complex models of virus-cell-immune system interactions. This analysis will aid in the construction of models for robust and biologically realistic modelling and inference.

Naturalistic Hyperscanning with Wearable Magnetoencephalography.

The evolution of human cognitive function is reliant on complex social interactions which form the behavioural foundation of who we are. These social capacities are subject to dramatic change in disease and injury; yet their supporting neural substrates remain poorly understood. Hyperscanning employs functional neuroimaging to simultaneously assess brain activity in two individuals and offers the best means to understand the neural basis of social interaction. However, present technologies are limited, either by poor performance (low spatial/temporal precision) or an unnatural scanning environment (claustrophobic scanners, with interactions via video). Here, we describe hyperscanning using wearable magnetoencephalography (MEG) based on optically pumped magnetometers (OPMs). We demonstrate our approach by simultaneously measuring brain activity in two subjects undertaking two separate tasks-an interactive touching task and a ball game. Despite large and unpredictable subject motion, sensorimotor brain activity was delineated clearly, and the correlation of the envelope of neuronal oscillations between the two subjects was demonstrated. Our results show that unlike existing modalities, OPM-MEG combines high-fidelity data acquisition and a naturalistic setting and thus presents significant potential to investigate neural correlates of social interaction.

1,3-Diamine-Derived Catalysts: Design, Synthesis, and the Use in Enantioselective Mannich Reactions of Ketones.

1,3-Diamine-derived catalysts were designed, synthesized, and used in asymmetric Mannich reactions of ketones. The reactions catalyzed by one of the 1,3-diamine derivatives in the presence of acids afforded the Mannich products with high enantioselectivities under mild conditions. In most cases, bond formation occurred at the less-substituted α-position of the ketone carbonyl group. Our results indicate that the primary and the tertiary amines of the 1,3-diamine derivative cooperatively act for the catalysis.

Enabling ambulatory movement in wearable magnetoencephalography with matrix coil active magnetic shielding.

The ability to collect high-quality neuroimaging data during ambulatory participant movement would enable a wealth of neuroscientific paradigms. Wearable magnetoencephalography (MEG) based on optically pumped magnetometers (OPMs) has the potential to allow participant movement during a scan. However, the strict zero magnetic field requirement of OPMs means that systems must be operated inside a magnetically shielded room (MSR) and also require active shielding using electromagnetic coils to cancel residual fields and field changes (due to external sources and sensor movements) that would otherwise prevent accurate neuronal source reconstructions. Existing active shielding systems only compensate fields over small, fixed regions and do not allow ambulatory movement. Here we describe the matrix coil, a new type of active shielding system for OPM-MEG which is formed from 48 square unit coils arranged on two planes which can compensate magnetic fields in regions that can be flexibly placed between the planes. Through the integration of optical tracking with OPM data acquisition, field changes induced by participant movement are cancelled with low latency (25 ms). High-quality MEG source data were collected despite the presence of large (65 cm translations and 270° rotations) ambulatory participant movements.

Measurement of Frontal Midline Theta Oscillations using OPM-MEG.

Optically pumped magnetometers (OPMs) are an emerging lightweight and compact sensor that can measure magnetic fields generated by the human brain. OPMs enable construction of wearable magnetoencephalography (MEG) systems, which offer advantages over conventional instrumentation. However, when trying to measure signals at low frequency, higher levels of inherent sensor noise, magnetic interference and movement artefact introduce a significant challenge. Accurate characterisation of low frequency brain signals is important for neuroscientific, clinical, and paediatric MEG applications and consequently, demonstrating the viability of OPMs in this area is critical. Here, we undertake measurement of theta band (4-8 Hz) neural oscillations and contrast a newly developed 174 channel triaxial wearable OPM-MEG system with conventional (cryogenic-MEG) instrumentation. Our results show that visual steady state responses at 4 Hz, 6 Hz and 8 Hz can be recorded using OPM-MEG with a signal-to-noise ratio (SNR) that is not significantly different to conventional MEG. Moreover, we measure frontal midline theta oscillations during a 2-back working memory task, again demonstrating comparable SNR for both systems. We show that individual differences in both the amplitude and spatial signature of induced frontal-midline theta responses are maintained across systems. Finally, we show that our OPM-MEG results could not have been achieved without a triaxial sensor array, or the use of postprocessing techniques. Our results demonstrate the viability of OPMs for characterising theta oscillations and add weight to the argument that OPMs can replace cryogenic sensors as the fundamental building block of MEG systems.

A 90-channel triaxial magnetoencephalography system using optically pumped magnetometers.

Magnetoencephalography (MEG) measures the small magnetic fields generated by current flow in neural networks, providing a noninvasive metric of brain function. MEG is well established as a powerful neuroscientific and clinical tool. However, current instrumentation is hampered by cumbersome cryogenic field-sensing technologies. In contrast, MEG using optically pumped magnetometers (OPM-MEG) employs small, lightweight, noncryogenic sensors that provide data with higher sensitivity and spatial resolution, a natural scanning environment (including participant movement), and adaptability to any age. However, OPM-MEG is new and the optimum way to design a system is unknown. Here, we construct a novel, 90-channel triaxial OPM-MEG system and use it to map motor function during a naturalistic handwriting task. Results show that high-precision magnetic field control reduced background fields to ∼200 pT, enabling free participant movement. Our triaxial array offered twice the total measured signal and better interference rejection compared to a conventional (single-axis) design. We mapped neural oscillatory activity to the sensorimotor network, demonstrating significant differences in motor network activity and connectivity for left-handed versus right-handed handwriting. Repeatability across scans showed that we can map electrophysiological activity with an accuracy ∼4 mm. Overall, our study introduces a novel triaxial OPM-MEG design and confirms its potential for high-performance functional neuroimaging.

Multiscale modelling of desquamation in the interfollicular epidermis.

Maintenance of epidermal thickness is critical to the barrier function of the skin. Decreased tissue thickness, specifically in the stratum corneum (the outermost layer of the tissue), causes discomfort and inflammation, and is related to several severe diseases of the tissue. In order to maintain both stratum corneum thickness and overall tissue thickness it is necessary for the system to balance cell proliferation and cell loss. Cell proliferation in the epidermis occurs in the basal layer and causes constant upwards movement in the tissue. Cell loss occurs when dead cells at the top of the tissue are lost to the environment through a process called desquamation. Desquamation is thought to occur through a gradual reduction in adhesion between cells, due to the cleaving of adhesion proteins by enzymes, in the stratum corneum. In this paper we will investigate combining a (mass action) subcellular model of desquamation with a three dimensional (cell centre based) multicellular model of the interfollicular epidermis to better understand maintenance of epidermal thickness. Specifically, our aim is to determine if a hypothesised biological model for the degradation of cell-cell adhesion, from the literature, is sufficient to maintain a steady state tissue thickness. These investigations show the model is able to provide a consistent rate of cell loss in the multicellular model. This loss balances proliferation, and hence maintains a homeostatic tissue thickness. Moreover, we find that multiple proliferative cell populations in the basal layer can be represented by a single proliferative cell population, simplifying investigations with this model. The model is used to investigate a disorder (Netherton Syndrome) which disrupts desquamation. The model shows how biochemical changes can cause disruptions to the tissue, resulting in a reduced tissue thickness and consequently diminishing the protective role of the tissue. A hypothetical treatment result is also investigated: we compare the cases of a partially effective homogeneous treatment (where all cells partially recover) and a totally effective heterogeneous treatment (in which a proportion of the cells totally recover) with the aim to determine the difference in the response of the tissue to these different scenarios. Results show an increased benefit to corneum thickness from the heterogeneous treatment over the homogeneous treatment.

Modelling realistic 3D deformations of simple epithelia in dynamic homeostasis.

The maintenance of tissue and organ structures during dynamic homeostasis is often not well understood. In order for a system to be stable, cell renewal, cell migration and cell death must be finely balanced. Moreover, a tissue's shape must remain relatively unchanged. Simple epithelial tissues occur in various structures throughout the body, such as the endothelium, mesothelium, linings of the lungs, saliva and thyroid glands, and gastrointestinal tract. Despite the prevalence of simple epithelial tissues, there are few models which accurately describe how these tissues maintain a stable structure. Here, we present a novel, 3D, deformable, multilayer, cell-centre model of a simple epithelium. Cell movement is governed by the minimisation of a bending potential across the epithelium, cell-cell adhesion, and viscous effects. We show that the model is capable of maintaining a consistent tissue structure while undergoing self renewal. We also demonstrate the model's robustness under tissue renewal, cell migration and cell removal. The model presented here is a valuable advancement towards the modelling of tissues and organs with complex and generalised structures.

A lightweight magnetically shielded room with active shielding.

Magnetically shielded rooms (MSRs) use multiple layers of materials such as MuMetal to screen external magnetic fields that would otherwise interfere with high precision magnetic field measurements such as magnetoencephalography (MEG). Optically pumped magnetometers (OPMs) have enabled the development of wearable MEG systems which have the potential to provide a motion tolerant functional brain imaging system with high spatiotemporal resolution. Despite significant promise, OPMs impose stringent magnetic shielding requirements, operating around a zero magnetic field resonance within a dynamic range of ± 5 nT. MSRs developed for OPM-MEG must therefore effectively shield external sources and provide a low remnant magnetic field inside the enclosure. Existing MSRs optimised for OPM-MEG are expensive, heavy, and difficult to site. Electromagnetic coils are used to further cancel the remnant field inside the MSR enabling participant movements during OPM-MEG, but present coil systems are challenging to engineer and occupy space in the MSR limiting participant movements and negatively impacting patient experience. Here we present a lightweight MSR design (30% reduction in weight and 40-60% reduction in external dimensions compared to a standard OPM-optimised MSR) which takes significant steps towards addressing these barriers. We also designed a 'window coil' active shielding system, featuring a series of simple rectangular coils placed directly onto the walls of the MSR. By mapping the remnant magnetic field inside the MSR, and the magnetic field produced by the coils, we can identify optimal coil currents and cancel the remnant magnetic field over the central cubic metre to just |B|= 670 ± 160 pT. These advances reduce the cost, installation time and siting restrictions of MSRs which will be essential for the widespread deployment of OPM-MEG.

Composition of Pinot Noir Wine from Grapevine Red Blotch Disease-Infected Vines Managed with Exogenous Abscisic Acid Applications.

Grapevine red blotch disease (GRBD) has negative effects on grape development and impacts berry ripening. Abscisic acid (ABA) is a plant growth regulator involved in the initiation of berry ripening. Exogenous abscisic acid application was compared to an unsprayed control on GRBD-positive Pinot noir vines during two vintages, and the total monomeric anthocyanin, total phenolics, phenolic composition, and volatile profile were measured in wines. In addition, untargeted metabolites were profiled using high-resolution LC-MS/MS. Results showed that the wine composition varied by vintage year and was not consistent with ABA application. Wines from the ABA treatment had a lower total anthocyanin and total phenolic content in one year. The untargeted high-resolution LC-MS/MS analysis showed a higher abundance of phenolic compounds in ABA wines in 2019, but lower in 2018. The wine volatile compounds of ABA treatments varied by vintage. There were higher levels of free ß-damascenone, ß-ionone, nerol, and several fermentation-derived esters, acids, and alcohols in ABA wines, but these were not observed in 2019. Lower 3-isobutyl-2-methoxypyrazine (IBMP) was also observed in wines with ABA treatment in 2019. The results demonstrated that ABA application to the fruit zones did not consistently mitigate the adverse impacts of GRBD on Pinot noir wines.

Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling.

Angiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 receptor within the mouse retina which disrupts flow-migration coupling, creating mixed populations of ECs polarised with/against flow which aggregate into arteriovenous malformations (AVMs). The lack of live imaging options in vivo means that the collective EC dynamics that drive AVM and the consequences of mixed populations of polarity remain a mystery. Therefore, our goal is to present a novel agent-based model to provide theoretical insight into EC force transmission and collective dynamics during angiogenic remodelling. Force transmission between neighbouring agents consists of extrusive forces which maintain spacing and cohesive forces which maintain the collective. We performed migration simulations within uniformly polarised populations (against flow) and mixed polarity (with/against flow). Within uniformly polarised populations, extrusive forces stabilised the plexus by facilitating EC intercalation which ensures that cells remained evenly distributed. Excess cohesion disrupts intercalation, resulting in aggregations of cells and functional shunting. Excess cohesion between ECs prevents them from resolving diameter balances within the plexus, leading to prolonged flow reversals which exert a critical behaviour change within the system as they switch the direction of cell migration and traffic patterns at bifurcations. Introducing mixtures of cell polarity dramatically changed the role of extrusive forces within the system. At low extrusion, opposing ECs were able to move past each other; however, at high extrusion the pushing between cells resulted in migration speeds close to zero, forming traffic jams and disrupting migration. In our study, we produced vascular malformations and functional shunting with either excess cohesion between ECs or mixtures of cell polarity. At the centre of both these mechanisms are cell-cell adherens junctions, which are involved in flow sensing/polarity and must remodelling dynamically to allow rearrangements of cells during vascular patterning. Thus, our findings implicate junctional dysfunction as a new target in the treatment and prevention of vascular disease and AVMs.

How quickly does a wound heal? Bayesian calibration of a mathematical model of venous leg ulcer healing.

Chronic wounds, such as venous leg ulcers, are difficult to treat and can reduce the quality of life for patients. Clinical trials have been conducted to identify the most effective venous leg ulcer treatments and the clinical factors that may indicate whether a wound will successfully heal. More recently, mathematical modelling has been used to gain insight into biological factors that may affect treatment success but are difficult to measure clinically, such as the rate of oxygen flow into wounded tissue. In this work, we calibrate an existing mathematical model using a Bayesian approach with clinical data for individual patients to explore which clinical factors may impact the rate of wound healing for individuals. Although the model describes group-level behaviour well, it is not able to capture individual-level responses in all cases. From the individual-level analysis, we propose distributions for coefficients of clinical factors in a linear regression model, but ultimately find that it is difficult to draw conclusions about which factors lead to faster wound healing based on the existing model and data. This work highlights the challenges of using Bayesian methods to calibrate partial differential equation models to individual patient clinical data. However, the methods used in this work may be modified and extended to calibrate spatiotemporal mathematical models to multiple data sets, such as clinical trials with several patients, to extract additional information from the model and answer outstanding biological questions.

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

Using OPM-MEG in contrasting magnetic environments.

Magnetoencephalography (MEG) has been revolutionised by optically pumped magnetometers (OPMs). "OPM-MEG" offers higher sensitivity, better spatial resolution, and lower cost than conventional instrumentation based on superconducting quantum interference devices (SQUIDs). Moreover, because OPMs are small, lightweight, and portable they offer the possibility of lifespan compliance and (with control of background field) motion robustness, dramatically expanding the range of MEG applications. However, OPM-MEG remains nascent technology; it places stringent requirements on magnetic shielding, and whilst a number of viable systems exist, most are custom made and there have been no cross-site investigations showing the reliability of data. In this paper, we undertake the first cross-site OPM-MEG comparison, using near identical commercial systems scanning the same participant. The two sites are deliberately contrasting, with different magnetic environments: a "green field" campus university site with an OPM-optimised shielded room (low interference) and a city centre hospital site with a "standard" (non-optimised) MSR (higher interference). We show that despite a 20-fold difference in background field, and a 30-fold difference in low frequency interference, using dynamic field control and software-based suppression of interference we can generate comparable noise floors at both sites. In human data recorded during a visuo-motor task and a face processing paradigm, we were able to generate similar data, with source localisation showing that brain regions could be pinpointed with just ∼10 mm spatial discrepancy and temporal correlations of > 80%. Overall, our study demonstrates that, with appropriate field control, OPM-MEG systems can be sited even in city centre hospital locations. The methods presented pave the way for wider deployment of OPM-MEG.