Expanding the applicability of magnetoencephalography

Magnetoencephalography (MEG) offers a unique way to non-invasively monitor the neural activity in the human brain. MEG is based on measuring the very weak magnetic fields generated by the electric currents in the active neurons. Such measurements allow, with certain limitations, estimating the underlying current distribution and thus the locations and time courses of the neural generators with an excellent temporal resolution. The aim of this Thesis was to advance MEG to certain realms that have been considered difficult or even impossible for it. Specifically, the included studies contributed to the modelling of the neural generators, detection of activity in the deep brain areas, analysis of oscillatory activity, and characterisation of neural states related to bistable perception. Estimating the sources of MEG signals is non-trivial as multiple current constellations can give rise to the same observed magnetic fields. As a new solution to this problem, we introduced an automatic Bayesian tracking algorithm that recovers the locations and time courses of a set of focal neural current sources from MEG data. The majority of MEG experiments have concentrated on brain signals originating in the neocortex due to the rapid decrease of the MEG signals as a function increasing source depth. Here, we demonstrated that neural activity deep in the brainstem can be detected and accurately localised by MEG in favourable conditions. We also explored the utility of stochastic resonance in varying the salience of a cognitive stimulus, and showed that the detection accuracy of visually-presented words correlated better with the amplitudes of the late than early responses. The temporal resolution provided by MEG was exploited in novel ways. We showed that oscillatory 20-Hz signals from the primary and secondary somatosensory cortex were transiently phase-locked in response to a stimulus, possibly signifying functional connectivity. We also introduced a frequency-tagging method employing dynamical noise to separate brain activations elicited by different parts of a visual scene: monitoring these rhythmic signals with MEG enabled us to probe the neural engagement in the early visual brain areas during bistable perception and thus to link subjective perceptual states to brain states

EEG/MEG Sparse Source Imaging and Its Application in Epilepsy

This dissertation is a summary of my Ph.D. work on the development of sparse source imaging technologies based on electroencephalography (EEG) and magneto-encephalography (MEG) and their application to noninvasively reconstruct brain activation from external surface measurements. Conventional sparse source imaging (SSI) methods using the ℓ1-norm regularization to enforce sparseness in the original source domain leads to over-focused solutions and causes bias in estimating spatially extended brain sources. I address the over-focused issue in the ℓ1-norm regularization technique framework by exploring sparseness in the transform domains. First, I apply a SSI method that uses the variation transform, i.e. V-SSI, on clinical MEG interictal recordings from partial epilepsy patients. Estimated epileptic sources by V-SSI are validated using clinical pre-surgical evaluation data and surgical outcomes. Second, I implement a novel face-based wavelet transform, which can efficiently compress brain activation signals into sparse representations on a multi-resolution cortical source model, into the SSI technology framework. The proposed wavelet-based SSI (W-SSI) demonstrates a significantly improved ability in inferring both brain source locations and extents as compared with conventional ℓ2-norm regularizations in obtaining EEG/MEG inverse solutions and other SSI technologies. Furthermore, the face-based wavelet also indicates better performance than a previously reported vertex-based wavelet in W-SSI. I evaluate the W-SSI method and conduct the comparison studies using both simulations and real data collected from partial epilepsy patients. Lastly, I further propose the concept of using multiple transforms in the SSI technology framework and investigated a new SSI method by enforcing sparseness in both variation and face-based wavelet domains, termed as VW-SSI. I conduct simulation studies, which demonstrate that VW-SSI has significantly better detection accuracies in both source locations and extents than conventional ℓ2-norm regularizations and other SSI methods, including SSI, V-SSI, and W-SSI. I further validate the VW-SSI method using clinical MEG data from both language and motor experiments collected from epilepsy patients again to localize their important functional brain areas. The results indicate that VW-SSI provides a performance advantage in detecting neural phenomena that have been extremely difficult to recognize by other EEG/MEG inverse solutions. It thus suggests that the sparse source imaging technique is promising to serve as a non-invasive tool in assisting pre-surgical planning for partial epilepsy patients

Study of cortical rhythmic activity and connectivity with magnetoencephalography

Intracranial recordings in animals and neuroimaging studies on humans have indicated that oscillatory activity and its modulations may play a fundamental role in large-scale neural information processing. Furthermore, rhythmic interactions between cortical areas have been detected across a variety of tasks with electroencephalography (EEG) and magnetoencephalography (MEG). This kind of coupling has been proposed to be a key mechanism through which information is integrated across segregated areas. So far, rhythmic interactions have been analyzed primarily at the EEG/MEG sensor level, without explicit knowledge of cortical areas involved. In this thesis work we developed new methods that can be used to image oscillatory activity and coherence at the cortical level with MEG. Dynamic Imaging of Coherent Sources (DICS) enables localization of interacting areas both using external reference signals and directly from the MEG data. When the interacting areas have been determined it is possible to use additional measures beyond coherence to further quantify interactions within the networks. DICS was originally designed for study of continuous data; its further development into event-related DICS (erDICS) adds the possibility to image modulations of rhythmic activity that are locked to stimulus or movement timing. Furthermore, permutation testing incorporated into erDICS allows the evaluation of the statistical significance of the results. Analysis of simulated and real data showed that DICS and erDICS yield accurate localization and quantification of oscillatory activity and coherence. Comparison of DICS to other methods of localizing oscillatory activity revealed that it is equally accurate and that it can better separate the activity originating from two nearby areas. We applied DICS to two datasets, recorded from groups of subjects while they performed slow finger movements and when they were reading continuously. In both cases, we were able to systematically identify interacting cortico-cortical networks and, using phase coupling and causality measures, to quantify the manner in which the nodes within these networks influenced each other. Furthermore, we compared the identified reading network to results reported in neurophysiological and hemodynamic activation studies. In addition to areas typically detected in activation studies of reading the network included areas that are normally found in language production rather than perception tasks, indicating more extensive networking of neural systems than usually observed in activation studies

Bayesian inversion in biomedical imaging

Biomedizinische Bildgebung ist zu einer Schlüsseltechnik geworden, Struktur oder Funktion lebender Organismen nicht-invasiv zu untersuchen. Relevante Informationen aus den gemessenen Daten zu rekonstruieren erfordert neben mathematischer Modellierung und numerischer Simulation das verlässliche Lösen schlecht gestellter inverser Probleme. Um dies zu erreichen müssen zusätzliche a-priori Informationen über die zu rekonstruierende Größe formuliert und in die algorithmischen Lösungsverfahren einbezogen werden. Bayesianische Invertierung ist eine spezielle mathematische Methodik dies zu tun. Die vorliegende Arbeit entwickelt eine aktuelle Übersicht Bayesianischer Invertierung und demonstriert die vorgestellten Konzepte und Algorithmen in verschiedenen numerischen Studien, darunter anspruchsvolle Anwendungen aus der biomedizinischen Bildgebung mit experimentellen Daten. Ein Schwerpunkt liegt dabei auf der Verwendung von Dünnbesetztheit/Sparsity als a-priori Information.Biomedical imaging techniques became a key technology to assess the structure or function of living organisms in a non-invasive way. Besides innovations in the instrumentation, the development of new and improved methods for processing and analysis of the measured data has become a vital field of research. Building on traditional signal processing, this area nowadays also comprises mathematical modeling, numerical simulation and inverse problems. The latter describes the reconstruction of quantities of interest from measured data and a given generative model. Unfortunately, most inverse problems are ill-posed, which means that a robust and reliable reconstruction is not possible unless additional a-priori information on the quantity of interest is incorporated into the solution method. Bayesian inversion is a mathematical methodology to formulate and employ a-priori information in computational schemes to solve the inverse problem. This thesis develops a recent overview on Bayesian inversion and exemplifies the presented concepts and algorithms in various numerical studies including challenging biomedical imaging applications with experimental data. A particular focus is on using sparsity as a-priori information within the Bayesian framework. <br

Characterising population variability in brain structure through models of whole-brain structural connectivity

Models of whole-brain connectivity are valuable for understanding neurological function. This thesis seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically acquired diffusion data. We propose new approaches for studying these models. The aim is to develop techniques which can take models of brain connectivity and use them to identify biomarkers or phenotypes of disease. The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections are traced between 77 regions of interest, automatically extracted by label propagation from multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data. These are compared in subsequent studies. To date, most whole-brain connectivity studies have characterised population differences using graph theory techniques. However these can be limited in their ability to pinpoint the locations of differences in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include a spectral clustering approach for comparing population differences in the clustering properties of weighted brain networks. In addition, machine learning approaches are suggested for the first time. These are particularly advantageous as they allow classification of subjects and extraction of features which best represent the differences between groups. One limitation of the proposed approach is that errors propagate from segmentation and registration steps prior to tractography. This can cumulate in the assignment of false positive connections, where the contribution of these factors may vary across populations, causing the appearance of population differences where there are none. The final contribution of this thesis is therefore to develop a common co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject into a single probabilistic model of diffusion for the population. This allows tractography to be performed only once, ensuring that there is one model of connectivity. Cross-subject differences can then be identified by mapping individual subjects’ anisotropy data to this model. The approach is used to compare populations separated by age and gender

High Precision Anatomy for MEG

Magnetoencephalography (MEG) is a non-invasive brain imaging method with high temporal resolution but relatively poor spatial resolution as compared to some other non-invasive techniques. This thesis examines how the spatial resolution of MEG can be improved using new recording paradigms in which the subject’s head position is fixed and known in advance. This is accomplished by using subject-specific head casts made using a combination of structural MRI and 3D printing technology. The resulting high-precision spatial models allow one to make inference at spatial scales of the order of cortical laminae. This thesis outlines the design of the head casts and examines the potential theoretical and empirical advances they offer. Specifically I outline simulation and then empirical investigations showing it is possible to non-invasively distinguish between electrophysiological signals in different layers of the cortex

Spatio-temporal analysis in functional brain imaging

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 119-137).Localizing sources of activity from electroencephalography (EEG) and magnetoencephalography (MEG) measurements involves solving an ill-posed inverse problem, where infinitely many source distribution patterns can give rise to identical measurements. This thesis aims to improve the accuracy of source localization by incorporating spatio-temporal models into the reconstruction procedure. First, we introduce a novel method for current source estimation, which we call the l₁l₂-norm source estimator. The underlying model captures the sparseness of the active areas in space while encouraging smooth temporal dynamics. We compute the current source estimates efficiently by solving a second-order cone programming problem. By considering all time points simultaneously, we achieve accurate and stable results as confirmed by the experiments using simulated and human MEG data. Although the l₁l₂-norm estimator enables accurate source estimation, it still faces challenges when the current sources are close to each other in space. To alleviate problems caused by the limited spatial resolution of EEG/MEG measurements, we introduce a new method to incorporate information from functional magnetic resonance imaging (fMRI) into the estimation algorithm.(cont.) Whereas EEG/MEG record neural activity, fMRI reflects hemodynamic activity in the brain with high spatial resolution. We examine empirically the neurovascular coupling in simultaneously recorded MEG and diffuse optical imaging (DOI) data, which also reflects hemodynamic activity and is compatible with MEG recordings. Our results suggest that the neural activity and hemodynamic responses are aligned in space. However, the relationship between the temporal dynamics of the two types of signals is non-linear and varies from region to region. Based on these findings, we develop the fMRI-informed regional EEG/MEG source estimator (FIRE). This method is based on a generative model that encourages similar spatial patterns but allows for differences in time courses across imaging modalities. Our experiments with both Monte Carlo simulation and human fMRI-EEG/MEG data demonstrate that FIRE significantly reduces ambiguities in source localization and accurately captures the timing of activation in adjacent functional regions.by Wanmei Ou.Ph.D

Differential contributions of synaptic and intrinsic inhibitory currents to speech segmentation via flexible phase-locking in neural oscillators

Current hypotheses suggest that speech segmentation-the initial division and grouping of the speech stream into candidate phrases, syllables, and phonemes for further linguistic processing-is executed by a hierarchy of oscillators in auditory cortex. Theta (∼3-12 Hz) rhythms play a key role by phase-locking to recurring acoustic features marking syllable boundaries. Reliable synchronization to quasi-rhythmic inputs, whose variable frequency can dip below cortical theta frequencies (down to ∼1 Hz), requires "flexible" theta oscillators whose underlying neuronal mechanisms remain unknown. Using biophysical computational models, we found that the flexibility of phase-locking in neural oscillators depended on the types of hyperpolarizing currents that paced them. Simulated cortical theta oscillators flexibly phase-locked to slow inputs when these inputs caused both (i) spiking and (ii) the subsequent buildup of outward current sufficient to delay further spiking until the next input. The greatest flexibility in phase-locking arose from a synergistic interaction between intrinsic currents that was not replicated by synaptic currents at similar timescales. Flexibility in phase-locking enabled improved entrainment to speech input, optimal at mid-vocalic channels, which in turn supported syllabic-timescale segmentation through identification of vocalic nuclei. Our results suggest that synaptic and intrinsic inhibition contribute to frequency-restricted and -flexible phase-locking in neural oscillators, respectively. Their differential deployment may enable neural oscillators to play diverse roles, from reliable internal clocking to adaptive segmentation of quasi-regular sensory inputs like speech

Differential contributions of synaptic and intrinsic inhibitory currents to speech segmentation via flexible phase-locking in neural oscillators

Current hypotheses suggest that speech segmentation-the initial division and grouping of the speech stream into candidate phrases, syllables, and phonemes for further linguistic processing-is executed by a hierarchy of oscillators in auditory cortex. Theta (∼3-12 Hz) rhythms play a key role by phase-locking to recurring acoustic features marking syllable boundaries. Reliable synchronization to quasi-rhythmic inputs, whose variable frequency can dip below cortical theta frequencies (down to ∼1 Hz), requires "flexible" theta oscillators whose underlying neuronal mechanisms remain unknown. Using biophysical computational models, we found that the flexibility of phase-locking in neural oscillators depended on the types of hyperpolarizing currents that paced them. Simulated cortical theta oscillators flexibly phase-locked to slow inputs when these inputs caused both (i) spiking and (ii) the subsequent buildup of outward current sufficient to delay further spiking until the next input. The greatest flexibility in phase-locking arose from a synergistic interaction between intrinsic currents that was not replicated by synaptic currents at similar timescales. Flexibility in phase-locking enabled improved entrainment to speech input, optimal at mid-vocalic channels, which in turn supported syllabic-timescale segmentation through identification of vocalic nuclei. Our results suggest that synaptic and intrinsic inhibition contribute to frequency-restricted and -flexible phase-locking in neural oscillators, respectively. Their differential deployment may enable neural oscillators to play diverse roles, from reliable internal clocking to adaptive segmentation of quasi-regular sensory inputs like speech.Wellcome Trust; P50 MH109429 - NIMH NIH HHS; R01 MH111439 - NIMH NIH HHS; 098353 - Wellcome TrustPublished versio

Differential contributions of synaptic and intrinsic inhibitory currents to speech segmentation via flexible phase-locking in neural oscillators

Now published in PLOS Computational Biology doi: 10.1371/journal.pcbi.1008783.Current hypotheses suggest that speech segmentation – the initial division and grouping of the speech stream into candidate phrases, syllables, and phonemes for further linguistic processing – is executed by a hierarchy of oscillators in auditory cortex. Theta (~3-12 Hz) rhythms play a key role by phase-locking to recurring acoustic features marking syllable boundaries. Reliable synchronization to quasi-rhythmic inputs, whose variable frequency can dip below cortical theta frequencies (down to ~1 Hz), requires “flexible” theta oscillators whose underlying neuronal mechanisms remain unknown. Using biophysical computational models, we found that the flexibility of phase-locking in neural oscillators depended on the types of hyperpolarizing currents that paced them. Simulated cortical theta oscillators flexibly phase-locked to slow inputs when these inputs caused both (i) spiking and (ii) the subsequent buildup of outward current sufficient to delay further spiking until the next input. The greatest flexibility in phase-locking arose from a synergistic interaction between intrinsic currents that was not replicated by synaptic currents at similar timescales. Flexibility in phase-locking enabled improved entrainment to speech input, optimal at mid-vocalic channels, which in turn supported syllabic-timescale segmentation through identification of vocalic nuclei. Our results suggest that synaptic and intrinsic inhibition contribute to frequency-restricted and -flexible phase-locking in neural oscillators, respectively. Their differential deployment may enable neural oscillators to play diverse roles, from reliable internal clocking to adaptive segmentation of quasi-regular sensory inputs like speech. Author summary: Oscillatory activity in auditory cortex is believed to play an important role in auditory and speech processing. One suggested function of these rhythms is to divide the speech stream into candidate phonemes, syllables, words, and phrases, to be matched with learned linguistic templates. This requires brain rhythms to flexibly synchronize with regular acoustic features of the speech stream. How neuronal circuits implement this task remains unknown. In this study, we explored the contribution of inhibitory currents to flexible phase-locking in neuronal theta oscillators, believed to perform initial syllabic segmentation. We found that a combination of specific intrinsic inhibitory currents at multiple timescales, present in a large class of cortical neurons, enabled exceptionally flexible phase-locking, which could be used to precisely segment speech by identifying vowels at mid-syllable. This suggests that the cells exhibiting these currents are a key component in the brain’s auditory and speech processing architecture.https://journals.plos.org/ploscompbiol/article/peerReview?id=10.1371/journal.pcbi.100878