Magnetoencephalography for the investigation and diagnosis of Mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI), (or concussion), is the most common type of brain injury. Despite this, it often goes undiagnosed and can cause long term disability—most likely caused by the disruption of axonal connections in the brain. Objective methods for diagnosis and prognosis are needed but clinically available neuroimaging modalities rarely show structural abnormalities, even when patients suffer persisting functional deficits. In the past three decades, new powerful techniques to image brain structure and function have shown promise in detecting mTBI related changes. Magnetoencephalography (MEG), which measures electrical brain activity by detecting magnetic fields outside the head generated by neural currents, is particularly sensitive and has therefore gained interest from researchers. Numerous studies are proposing abnormal low-frequency neural oscillations and functional connectivity—the statistical interdependency of signals from separate brain regions—as potential biomarkers for mTBI. However, typically small sample sizes, the lack of replication between groups, the heterogeneity of the cohorts studied, and the lack of longitudinal studies impedes the adoption of MEG as a clinical tool in mTBI management. In particular, little is known about the acute phase of mTBI. In this thesis, some of these gaps will be addressed by analysing MEG data from individuals with mTBI, using novel as well as conventional methods. The potential future of MEG in mTBI research will also be addressed by testing the capabilities of a wearable MEG system based on optically pumped magnetometers (OPMs). The thesis contains three main experimental studies. In study 1, we investigated the signal dynamics underlying MEG abnormalities, found in a cohort of subjects scanned within three months of an mTBI, using a Hidden Markov Model (HMM), as growing evidence suggests that neural dynamics are (in part) driven by transient bursting events. Applying the HMM to resting-state data, we show that previously reported findings of diminished intrinsic beta amplitude and connectivity in individuals with mTBI (compared to healthy controls) can be explained by a reduction in the beta-band content of pan-spectral bursts and a loss in the temporal coincidence of bursts respectively. Using machine learning, we find the functional connections driving group differences and achieve classification accuracies of 98%. In a motor task, mTBI resulted in reduced burst amplitude, altered modulation of burst probability during movement and decreased connectivity in the motor network. In study 2, we further test our HMM-based method in a cohort of subjects with mTBI and non-head trauma—scanned within two weeks of injury—to ensure specificity of any observed effects to mTBI and replicate our previous finding of reduced connectivity and high classification accuracy, although not the reduction in burst amplitude. Burst statistics were stable over both studies—despite data being acquired at different sites, using different scanners. In the same cohort, we applied a more conventional analysis of delta-band power. Although excess low-frequency power appears to be a promising candidate marker for persistently symptomatic mTBI, insufficient data exist to confirm this pattern in acute mTBI. We found abnormally high delta power to be a sensitive measure for discriminating mTBI subjects from healthy controls, however, similarly elevated delta amplitude was found in the cohort with non-head trauma, suggesting that excess delta may not be specific to mTBI, at least in the acute stage of injury. Our work highlights the need for longitudinal assessment of mTBI. In addition, there appears to be a need to investigate naturalistic paradigms which can be tailored to induce activity in symptom-relevant brain networks and consequently are likely to be more sensitive biomarkers than the resting state scans used to date. Wearable OPM-MEG makes naturalistic scanning possible and may offer a cheaper and more accessible alternative to cryogenic MEG, however, before deploying OPMs clinically, or in pitch-side assessment for athletes, for example, the reliability of OPM-derived measures needs to be verified. In the third and final study, we performed a repeatability study using a novel motor task, estimating a series of common MEG measures and quantifying the reliability of both activity and connectivity derived from OPM-MEG data. These initial findings—presently limited to a small sample of healthy controls—demonstrate the utility of OPM-MEG and pave the way for this technology to be deployed on patients with mTBI

Magnetoencephalography for the investigation and diagnosis of Mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI), (or concussion), is the most common type of brain injury. Despite this, it often goes undiagnosed and can cause long term disability—most likely caused by the disruption of axonal connections in the brain. Objective methods for diagnosis and prognosis are needed but clinically available neuroimaging modalities rarely show structural abnormalities, even when patients suffer persisting functional deficits. In the past three decades, new powerful techniques to image brain structure and function have shown promise in detecting mTBI related changes. Magnetoencephalography (MEG), which measures electrical brain activity by detecting magnetic fields outside the head generated by neural currents, is particularly sensitive and has therefore gained interest from researchers. Numerous studies are proposing abnormal low-frequency neural oscillations and functional connectivity—the statistical interdependency of signals from separate brain regions—as potential biomarkers for mTBI. However, typically small sample sizes, the lack of replication between groups, the heterogeneity of the cohorts studied, and the lack of longitudinal studies impedes the adoption of MEG as a clinical tool in mTBI management. In particular, little is known about the acute phase of mTBI. In this thesis, some of these gaps will be addressed by analysing MEG data from individuals with mTBI, using novel as well as conventional methods. The potential future of MEG in mTBI research will also be addressed by testing the capabilities of a wearable MEG system based on optically pumped magnetometers (OPMs). The thesis contains three main experimental studies. In study 1, we investigated the signal dynamics underlying MEG abnormalities, found in a cohort of subjects scanned within three months of an mTBI, using a Hidden Markov Model (HMM), as growing evidence suggests that neural dynamics are (in part) driven by transient bursting events. Applying the HMM to resting-state data, we show that previously reported findings of diminished intrinsic beta amplitude and connectivity in individuals with mTBI (compared to healthy controls) can be explained by a reduction in the beta-band content of pan-spectral bursts and a loss in the temporal coincidence of bursts respectively. Using machine learning, we find the functional connections driving group differences and achieve classification accuracies of 98%. In a motor task, mTBI resulted in reduced burst amplitude, altered modulation of burst probability during movement and decreased connectivity in the motor network. In study 2, we further test our HMM-based method in a cohort of subjects with mTBI and non-head trauma—scanned within two weeks of injury—to ensure specificity of any observed effects to mTBI and replicate our previous finding of reduced connectivity and high classification accuracy, although not the reduction in burst amplitude. Burst statistics were stable over both studies—despite data being acquired at different sites, using different scanners. In the same cohort, we applied a more conventional analysis of delta-band power. Although excess low-frequency power appears to be a promising candidate marker for persistently symptomatic mTBI, insufficient data exist to confirm this pattern in acute mTBI. We found abnormally high delta power to be a sensitive measure for discriminating mTBI subjects from healthy controls, however, similarly elevated delta amplitude was found in the cohort with non-head trauma, suggesting that excess delta may not be specific to mTBI, at least in the acute stage of injury. Our work highlights the need for longitudinal assessment of mTBI. In addition, there appears to be a need to investigate naturalistic paradigms which can be tailored to induce activity in symptom-relevant brain networks and consequently are likely to be more sensitive biomarkers than the resting state scans used to date. Wearable OPM-MEG makes naturalistic scanning possible and may offer a cheaper and more accessible alternative to cryogenic MEG, however, before deploying OPMs clinically, or in pitch-side assessment for athletes, for example, the reliability of OPM-derived measures needs to be verified. In the third and final study, we performed a repeatability study using a novel motor task, estimating a series of common MEG measures and quantifying the reliability of both activity and connectivity derived from OPM-MEG data. These initial findings—presently limited to a small sample of healthy controls—demonstrate the utility of OPM-MEG and pave the way for this technology to be deployed on patients with mTBI

Mild traumatic brain injury impairs the coordination of intrinsic and motor-related neural dynamics

Mild traumatic brain injury (mTBI) poses a considerable burden on healthcare systems. Whilst most patients recover quickly, a significant number suffer from sequelae that are not accompanied by measurable structural damage. Understanding the neural underpinnings of these debilitating effects and developing a means to detect injury, would address an important unmet clinical need. It could inform interventions and help predict prognosis. Magnetoencephalography (MEG) affords excellent sensitivity in probing neural function and presents significant promise for assessing mTBI, with abnormal neural oscillations being a potential specific biomarker. However, growing evidence suggests that neural dynamics are (at least in part) driven by transient, pan-spectral bursting and in this paper, we employ this model to investigate mTBI. We applied a Hidden Markov Model to MEG data recorded during resting state and a motor task and show that previous findings of diminished intrinsic beta amplitude in individuals with mTBI are largely due to the reduced beta band spectral content of bursts, and that diminished beta connectivity results from a loss in the temporal coincidence of burst states. In a motor task, mTBI results in diminished burst amplitude, altered modulation of burst probability during movement, and a loss in connectivity in motor networks. These results suggest that, mechanistically, mTBI disrupts the structural framework underlying neural synchrony, which impairs network function. Whilst the damage may be too subtle for structural imaging to see, the functional consequences are detectable and persist after injury. Our work shows that mTBI impairs the dynamic coordination of neural network activity and proposes a potent new method for understanding mTBI

Mapping Interictal activity in epilepsy using a hidden Markov model: A magnetoencephalography study

Abstract: Epilepsy is a highly heterogeneous neurological disorder with variable etiology, manifestation, and response to treatment. It is imperative that new models of epileptiform brain activity account for this variability, to identify individual needs and allow clinicians to curate personalized care. Here, we use a hidden Markov model (HMM) to create a unique statistical model of interictal brain activity for 10 pediatric patients. We use magnetoencephalography (MEG) data acquired as part of standard clinical care for patients at the Children's Hospital of Philadelphia. These data are routinely analyzed using excess kurtosis mapping (EKM); however, as cases become more complex (extreme multifocal and/or polymorphic activity), they become harder to interpret with EKM. We assessed the performance of the HMM against EKM for three patient groups, with increasingly complicated presentation. The difference in localization of epileptogenic foci for the two methods was 7 ± 2 mm (mean ± SD over all 10 patients); and 94% ± 13% of EKM temporal markers were matched by an HMM state visit. The HMM localizes epileptogenic areas (in agreement with EKM) and provides additional information about the relationship between those areas. A key advantage over current methods is that the HMM is a data‐driven model, so the output is tuned to each individual. Finally, the model output is intuitive, allowing a user (clinician) to review the result and manually select the HMM epileptiform state, offering multiple advantages over previous methods and allowing for broader implementation of MEG epileptiform analysis in surgical decision‐making for patients with intractable epilepsy

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

GalvAnalyze: Streamlining Data Analysis of Galvanostatic Battery Cycling

We present GalvAnalyze, a software tool developed in Python, that processes data collected using a variety of battery cyclers and creates a set of outputs that greatly reduce the inefficiencies associated with manual or semi-manual analysis of galvanostatic cycling data. An experiment is carried out by 10 participants with varying degrees of experience processing galvanostatic cycling data, enabling quantitative analysis of the processing time benefit that GalvAnalyze enables. The functionality of GalvAnalyze includes handling data where the applied current density varies, separating the data into individual charge-discharge cycle pairs, and producing hysteresis plots using a simple graphical user interface. The executable can be downloaded at https://www.thenamilab.com/ and is built to be accessible, with no prior coding expertise required. In the interest of transparency, and to allow future contributions to the functionality of GalvAnalyze by the wider community, the source code can be found on GitHub (https://github.com/LukasRier/GalvAnalyze)

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

Test-Retest Reliability of the Human Connectome: An OPM-MEG study

Magnetoencephalography with optically pumped magnetometers (OPM-MEG) offers a new way to record electrophysiological brain function, with significant advantages over conventional MEG, including adaptability to head shape/size, free movement during scanning, increased signal amplitude, and no reliance on cryogenics. However, OPM-MEG remains in its infancy, with significant questions to be answered regarding the optimal system design. Here, we present an open-source dataset acquired using a newly constructed OPM-MEG system with a triaxial sensor design, 168 channels, OPM-optimised magnetic shielding, and active background field control. We measure the test-retest reliability of the human connectome, which was computed using amplitude envelope correlation to measure whole-brain (parcellated) functional connectivity, in 10 individuals while they watch a 600 s move clip. Our results show high repeatability between experimental runs at the group level, with a correlation coefficient of 0.81 in the θ, 0.93 in α⁠, and 0.94 in β frequency ranges. At the individual subject level, we found marked differences between individuals, but high within-subject robustness (correlations of 0.56 ± 0.25, 0.72 ± 0.15, and 0.78 ± 0.13 in α⁠, θ, and β respectively). These results compare well to previous findings using conventional MEG and show that OPM-MEG is a viable way to robustly characterise connectivity