Multimodal image analysis of the human brain

Gedurende de laatste decennia heeft de snelle ontwikkeling van multi-modale en niet-invasieve hersenbeeldvorming technologieën een revolutie teweeg gebracht in de mogelijkheid om de structuur en functionaliteit van de hersens te bestuderen. Er is grote vooruitgang geboekt in het beoordelen van hersenschade door gebruik te maken van Magnetic Reconance Imaging (MRI), terwijl Elektroencefalografie (EEG) beschouwd wordt als de gouden standaard voor diagnose van neurologische afwijkingen. In deze thesis focussen we op de ontwikkeling van nieuwe technieken voor multi-modale beeldanalyse van het menselijke brein, waaronder MRI segmentatie en EEG bronlokalisatie. Hierdoor voegen we theorie en praktijk samen waarbij we focussen op twee medische applicaties: (1) automatische 3D MRI segmentatie van de volwassen hersens en (2) multi-modale EEG-MRI data analyse van de hersens van een pasgeborene met perinatale hersenschade. We besteden veel aandacht aan de verbetering en ontwikkeling van nieuwe methoden voor accurate en ruisrobuuste beeldsegmentatie, dewelke daarna succesvol gebruikt worden voor de segmentatie van hersens in MRI van zowel volwassen als pasgeborenen. Daarenboven ontwikkelden we een geïntegreerd multi-modaal methode voor de EEG bronlokalisatie in de hersenen van een pasgeborene. Deze lokalisatie wordt gebruikt voor de vergelijkende studie tussen een EEG aanval bij pasgeborenen en acute perinatale hersenletsels zichtbaar in MRI

Visualisation of multi-dimensional medical images with application to brain electrical impedance tomography

Medical imaging plays an important role in modem medicine. With the increasing complexity and information presented by medical images, visualisation is vital for medical research and clinical applications to interpret the information presented in these images. The aim of this research is to investigate improvements to medical image visualisation, particularly for multi-dimensional medical image datasets. A recently developed medical imaging technique known as Electrical Impedance Tomography (EIT) is presented as a demonstration. To fulfil the aim, three main efforts are included in this work. First, a novel scheme for the processmg of brain EIT data with SPM (Statistical Parametric Mapping) to detect ROI (Regions of Interest) in the data is proposed based on a theoretical analysis. To evaluate the feasibility of this scheme, two types of experiments are carried out: one is implemented with simulated EIT data, and the other is performed with human brain EIT data under visual stimulation. The experimental results demonstrate that: SPM is able to localise the expected ROI in EIT data correctly; and it is reasonable to use the balloon hemodynamic change model to simulate the impedance change during brain function activity. Secondly, to deal with the absence of human morphology information in EIT visualisation, an innovative landmark-based registration scheme is developed to register brain EIT image with a standard anatomical brain atlas. Finally, a new task typology model is derived for task exploration in medical image visualisation, and a task-based system development methodology is proposed for the visualisation of multi-dimensional medical images. As a case study, a prototype visualisation system, named EIT5DVis, has been developed, following this methodology. to visualise five-dimensional brain EIT data. The EIT5DVis system is able to accept visualisation tasks through a graphical user interface; apply appropriate methods to analyse tasks, which include the ROI detection approach and registration scheme mentioned in the preceding paragraphs; and produce various visualisations

A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals

Spatio-temporal evolution of interictal epileptic activity : a study with unaveraged multichannel MEG data in association with MRIs.

This thesis addresses issues relating to MEG modelling, analysis and interpretation of results. A source model employing current density distributions, namely Magnetic Field Tomography (MET), is used to obtain the MEG results. The first issue of concern refers to the registration of MEG data with structural MR images in an attempt to improve the localisation capability of MEG/MET. Simulations testing some spatial and tem poral aspects of the reconstruction capability of MET are also provided. A novel way of conducting MET studies in depth is suggested and implemented: the iterative use of a source space designed to cover deep situated structures on either side of the brain. The main bulk of this thesis is concerned with research into interictal epileptic activity as recorded by means of multichannel MEG system s and analysed using MET. The major aim is to investigate whether or not MET analysis of unaveraged MEG data (single epochs) is feasible in cases of pathophysiological signals and more specifically interictal signals from patients with epilepsy of a complex partial type. The investigation is undertaken against the "traditional" view of the impropriety and absurdity of using single epoch records in the MEG analysis due to noise dominance; we provide evidence that analysis of single, unaveraged epileptic spikes is actually feasible: we demonstrate spatio-temporal coherence in the MET results of the various single interictal events and show that activity extracted from the "averaged event" is made up of activity contributions which occur intermittently and at variable latencies. Our statements are drawn from the study of both superficial and deep activity

Karakterizacija predkliničnega tumorskega ksenograftnega modela z uporabo multiparametrične MR

Introduction: In small animal studies multiple imaging modalities can be combined to complement each other in providing information on anatomical structure and function. Non-invasive imaging studies on animal models are used to monitor progressive tumor development. This helps to better understand the efficacy of new medicines and prediction of the clinical outcome. The aim was to construct a framework based on longitudinal multi-modal parametric in vivo imaging approach to perform tumor tissue characterization in mice. Materials and Methods: Multi-parametric in vivo MRI dataset consisted of T1-, T2-, diffusion and perfusion weighted images. Image set of mice (n=3) imaged weekly for 6 weeks was used. Multimodal image registration was performed based on maximizing mutual information. Tumor region of interested was delineated in weeks 2 to 6. These regions were stacked together, and all modalities combined were used in unsupervised segmentation. Clustering methods, such as K-means and Fuzzy C-means together with blind source separation technique of non-negative matrix factorization were tested. Results were visually compared with histopathological findings. Results: Clusters obtained with K-means and Fuzzy C-means algorithm coincided with T2 and ADC maps per levels of intensity observed. Fuzzy C-means clusters and NMF abundance maps reported most promising results compared to histological findings and seem as a complementary way to asses tumor microenvironment. Conclusions: A workflow for multimodal MR parametric map generation, image registration and unsupervised tumor segmentation was constructed. Good segmentation results were achieved, but need further extensive histological validation.Uvod Eden izmed pomembnih stebrov znanstvenih raziskav v medicinski diagnostiki predstavljajo eksperimenti na živalih v sklopu predkliničnih študij. V teh študijah so eksperimenti izvedeni za namene odkrivanja in preskušanja novih terapevtskih metod za zdravljenje človeških bolezni. Rak jajčnikov je eden izmed glavnih vzrokov smrti kot posledica rakavih obolenj. Potreben je razvoj novih, učinkovitejših metod, da bi lahko uspešneje kljubovali tej bolezni. Časovno okno aplikacije novih terapevtikov je ključni dejavnik uspeha raziskovane terapije. Tumorska fiziologija se namreč razvija med napredovanjem bolezni. Eden izmed ciljev predkliničnih študij je spremljanje razvoja tumorskega mikro-okolja in tako določiti optimalno časovno okno za apliciranje razvitega terapevtika z namenom doseganja maksimalne učinkovitosti. Slikovne modalitete so kot raziskovalno orodje postale izjemno popularne v biomedicinskih in farmakoloških raziskavah zaradi svoje neinvazivne narave. Predklinične slikovne modalitete imajo nemalo prednosti pred tradicionalnim pristopom. Skladno z raziskovalno regulativo, tako za spremljanje razvoja tumorja skozi daljši čas ni potrebno žrtvovati živali v vmesnih časovnih točkah. Sočasno lahko namreč s svojim nedestruktivnim in neinvazivnim pristopom poleg anatomskih informacij podajo tudi molekularni in funkcionalni opis preučevanega subjekta. Za dosego slednjega so običajno uporabljene različne slikovne modalitete. Pogosto se uporablja kombinacija več slikovnih modalitet, saj so medsebojno komplementarne v podajanju željenih informacij. V sklopu te naloge je predstavljeno ogrodje za procesiranje različnih modalitet magnetno resonančnih predkliničnih modelov z namenom karakterizacije tumorskega tkiva. Metodologija V študiji Belderbos, Govaerts, Croitor Sava in sod. [1] so z uporabo magnetne resonance preučevali določitev optimalnega časovnega okna za uspešno aplikacijo novo razvitega terapevtika. Poleg konvencionalnih magnetno resonančnih slikovnih metod (T1 in T2 uteženo slikanje) sta bili uporabljeni tudi perfuzijsko in difuzijsko uteženi tehniki. Zajem slik je potekal tedensko v obdobju šest tednov. Podatkovni seti, uporabljeni v predstavljenem delu, so bili pridobljeni v sklopu omenjene raziskave. Ogrodje za procesiranje je narejeno v okolju Matlab (MathWorks, verzija R2019b) in omogoča tako samodejno kot ročno procesiranje slikovnih podatkov. V prvem koraku je pred generiranjem parametričnih map uporabljenih modalitet, potrebno izluščiti parametre uporabljenih protokolov iz priloženih tekstovnih datotek in zajete slike pravilno razvrstiti glede na podano anatomijo. Na tem mestu so slike tudi filtrirane in maskirane. Filtriranje je koristno za izboljšanje razmerja med koristnim signalom (slikanim živalskim modelom) in ozadjem, saj je skener za zajem slik navadno podvržen različnim izvorom slikovnega šuma. Uporabljen je bil filter ne-lokalnih povprečij Matlab knjižnice za procesiranje slik. Prednost maskiranja se potrdi v naslednjem koraku pri generiranju parametričnih map, saj se ob primerno maskiranem subjektu postopek bistveno pospeši z mapiranjem le na želenem področju. Za izdelavo parametričnih map je uporabljena metoda nelinearnih najmanjših kvadratov. Z modeliranjem fizikalnih pojavov uporabljenih modalitet tako predstavimo preiskovan živalski model z biološkimi parametri. Le-ti se komplementarno dopolnjujejo v opisu fizioloških lastnosti preučevanega modela na ravni posameznih slikovnih elementov. Ključen gradnik v uspešnem dopolnjevanju informacij posameznih modalitet je ustrezna poravnava parametričnih map. Posamezne modalitete so zajete zaporedno, ob različnih časih. Skeniranje vseh modalitet posamezne živali skupno traja več kot eno uro. Med zajemom slik tako navkljub uporabi anestetikov prihaja do majhnih premikov živali. V kolikor ti premiki niso pravilno upoštevani, prihaja do napačnih interpretacij skupnih informacij večih modalitet. Premiki živali znotraj modalitet so bili modelirani kot toge, med različnimi modalitetami pa kot afine preslikave. Poravnava slik je izvedena z lastnimi Matlab funkcijami ali z uporabo funkcij iz odprtokodnega ogrodja za procesiranje slik Elastix. Z namenom karakterizacije tumorskega tkiva so bile uporabljene metode nenadzorovanega razčlenjevanja. Bistvo razčlenjevanja je v združevanju posameznih slikovnih elementov v segmente. Elementi si morajo biti po izbranem kriteriju dovolj medsebojno podobni in se hkrati razlikovati od elementov drugih segmentov. Za razgradnjo so bile izbrane tri metode: metoda K-tih povprečij, kot ena izmed enostavnejšihmetoda mehkih C-tih povprečij, s prednostjo mehke razčlenitvein kot zadnja, nenegativna matrična faktorizacija. Slednja ponuja pogled na razčlenitev tkiva kot produkt tipičnih več-modalnih značilk in njihove obilice za vsak posamezni slikovni element. Za potrditev izvedenega razčlenjevanja z omenjenimi metodami je bila izvedena vizualna primerjava z rezultati histopatološke analize. Rezultati Na ustvarjene parametrične mape je imela poravnava slik znotraj posameznih modalitet velik vpliv. Zaradi dolgotrajnega zajema T1 uteženih slik nemalokrat prihaja do premikov živali, kar brez pravilne poravnave slik negativno vpliva na mapiranje modalitet in kasnejšo segmentacijo slik. Generirane mape imajo majhno odstopanje od tistih, narejenih s standardno uporabljenimi odprtokodnimi programi. Klastri pridobljeni z metodama K-tih in mehkih C-tih povprečij dobro sovpadajo z razčlenbami glede na njihovo inteziteto pri T2 in ADC mapah. Najobetavnejše rezultate po primerjavi s histološkimi izsledki podajata metoda mehkih C-povprečij in nenegativna matrična faktorizacija. Njuni segmentaciji se dopolnjujeta v razlagi tumorskega mikro-okolja. Zaključek Z izgradnjo ogrodja za procesiranje slik magnetne resonance in segmentacijo tumorskega tkiva je bil cilj magistrske naloge dosežen. Zasnova ogrodja omogoča poljubno dodajanje drugih modalitet in uporabo drugih živalskih modelov. Rezultati razčlenitve tumorskega tkiva so obetavni, vendar je potrebna nadaljna primerjava z rezultati histopatološke analize. Možna nadgradnja je izboljšanje robustnosti poravnave slik z uporabo modela netoge (elastične) preslikave. Prav tako je smiselno preizkusiti dodatne metode nenadzorovane segmentacije in dobljene rezultate primerjati s tukaj predstavljenimi

The end is just the beginning:Unraveling the postictal state

Epilepsy is one of the most common neurological disorders worldwide. Postictal symptoms, occurring after seizures, often form a great burden for patients and their caregivers. Approximately one-third of patients do not achieve seizure freedom with proper treatment (i.e., antiepileptic medication or surgical removal of epileptic tissue). These patients suffer from the seizure aftermath each time they have a seizure. Until today, it is unclear how we can treat the postictal state effectively. Promising findings from animal studies showed that acetaminophen (in The Netherlands better known as ‘paracetamol’) or nimodipine (vasodilator) could improve postictal symptoms in rats. We highlight that a clear definition for the postictal state was still lacking, which is why we provided a new definition that includes its manifestation (i.e., clinical and electroencephalography [EEG]) as well as temporal variability. ECT appears to be a useful human model to investigate seizures and postictal states because clinical and EEG characteristics (i.e., spatiotemporal dynamics) show sufficient similarities between both epilepsy and ECT patients. With ECT, ictal and postictal phenomena can be studied in a well-controlled environment, increasing practical feasibility of clinical studies. We describe that the postictal EEG shows a clear pattern of frequencies that return to baseline levels at approximately 1h after the seizure, which depends on seizure duration. Longer clinical reorientation time and repeated exposure to seizures are associated with longer postictal EEG recovery.We examined postictal cerebral blood flow, measured with arterial spin labeling magnetic resonance imaging (ASL-MRI), and show clear patterns of hypoperfusion in some patients, while in others, discrete local hyperperfusion is seen. These opposite patterns depend on seizure duration. Using functional MRI, we show that postictal mean network connectivity strength decreases in the left central executive network and in the auditory network compared to baseline and controlled for network connectivity changes in healthy controls. Finally, with our prospective clinical trial with randomized three-condition cross-over design, we fail to replicate findings from animal models, possibly because our chosen doses of pre-ECT administered acetaminophen or nimodipine (much lower than in the animal studies) do not improve postictal EEG recovery, clinical reorientation time and postictal ASL-MRI perfusion

Machine Learning for Biomedical Application

Biomedicine is a multidisciplinary branch of medical science that consists of many scientific disciplines, e.g., biology, biotechnology, bioinformatics, and genetics; moreover, it covers various medical specialties. In recent years, this field of science has developed rapidly. This means that a large amount of data has been generated, due to (among other reasons) the processing, analysis, and recognition of a wide range of biomedical signals and images obtained through increasingly advanced medical imaging devices. The analysis of these data requires the use of advanced IT methods, which include those related to the use of artificial intelligence, and in particular machine learning. It is a summary of the Special Issue “Machine Learning for Biomedical Application”, briefly outlining selected applications of machine learning in the processing, analysis, and recognition of biomedical data, mostly regarding biosignals and medical images

Automated Extraction of Biomarkers for Alzheimer's Disease from Brain Magnetic Resonance Images

In this work, different techniques for the automated extraction of biomarkers for Alzheimer's disease (AD) from brain magnetic resonance imaging (MRI) are proposed. The described work forms part of PredictAD (www.predictad.eu), a joined European research project aiming at the identification of a unified biomarker for AD combining different clinical and imaging measurements. Two different approaches are followed in this thesis towards the extraction of MRI-based biomarkers: (I) the extraction of traditional morphological biomarkers based on neuronatomical structures and (II) the extraction of data-driven biomarkers applying machine-learning techniques. A novel method for a unified and automated estimation of structural volumes and volume changes is proposed. Furthermore, a new technique that allows the low-dimensional representation of a high-dimensional image population for data analysis and visualization is described. All presented methods are evaluated on images from the Alzheimer's Disease Neuroimaging Initiative (ADNI), providing a large and diverse clinical database. A rigorous evaluation of the power of all identified biomarkers to discriminate between clinical subject groups is presented. In addition, the agreement of automatically derived volumes with reference labels as well as the power of the proposed method to measure changes in a subject's atrophy rate are assessed. The proposed methods compare favorably to state-of-the art techniques in neuroimaging in terms of accuracy, robustness and run-time

Decoding the Encoding of Functional Brain Networks: an fMRI Classification Comparison of Non-negative Matrix Factorization (NMF), Independent Component Analysis (ICA), and Sparse Coding Algorithms

Brain networks in fMRI are typically identified using spatial independent component analysis (ICA), yet mathematical constraints such as sparse coding and positivity both provide alternate biologically-plausible frameworks for generating brain networks. Non-negative Matrix Factorization (NMF) would suppress negative BOLD signal by enforcing positivity. Spatial sparse coding algorithms ($L1$ Regularized Learning and K-SVD) would impose local specialization and a discouragement of multitasking, where the total observed activity in a single voxel originates from a restricted number of possible brain networks. The assumptions of independence, positivity, and sparsity to encode task-related brain networks are compared; the resulting brain networks for different constraints are used as basis functions to encode the observed functional activity at a given time point. These encodings are decoded using machine learning to compare both the algorithms and their assumptions, using the time series weights to predict whether a subject is viewing a video, listening to an audio cue, or at rest, in 304 fMRI scans from 51 subjects. For classifying cognitive activity, the sparse coding algorithm of $L1$ Regularized Learning consistently outperformed 4 variations of ICA across different numbers of networks and noise levels (p$<$0.001). The NMF algorithms, which suppressed negative BOLD signal, had the poorest accuracy. Within each algorithm, encodings using sparser spatial networks (containing more zero-valued voxels) had higher classification accuracy (p$<$0.001). The success of sparse coding algorithms may suggest that algorithms which enforce sparse coding, discourage multitasking, and promote local specialization may capture better the underlying source processes than those which allow inexhaustible local processes such as ICA

A Novel Synergistic Model Fusing Electroencephalography and Functional Magnetic Resonance Imaging for Modeling Brain Activities

Study of the human brain is an important and very active area of research. Unraveling the way the human brain works would allow us to better understand, predict and prevent brain related diseases that affect a significant part of the population. Studying the brain response to certain input stimuli can help us determine the involved brain areas and understand the mechanisms that characterize behavioral and psychological traits. In this research work two methods used for the monitoring of brain activities, Electroencephalography (EEG) and functional Magnetic Resonance (fMRI) have been studied for their fusion, in an attempt to bridge together the advantages of each one. In particular, this work has focused in the analysis of a specific type of EEG and fMRI recordings that are related to certain events and capture the brain response under specific experimental conditions. Using spatial features of the EEG we can describe the temporal evolution of the electrical field recorded in the scalp of the head. This work introduces the use of Hidden Markov Models (HMM) for modeling the EEG dynamics. This novel approach is applied for the discrimination of normal and progressive Mild Cognitive Impairment patients with significant results. EEG alone is not able to provide the spatial localization needed to uncover and understand the neural mechanisms and processes of the human brain. Functional Magnetic Resonance imaging (fMRI) provides the means of localizing functional activity, without though, providing the timing details of these activations. Although, at first glance it is apparent that the strengths of these two modalities, EEG and fMRI, complement each other, the fusion of information provided from each one is a challenging task. A novel methodology for fusing EEG spatiotemporal features and fMRI features, based on Canonical Partial Least Squares (CPLS) is presented in this work. A HMM modeling approach is used in order to derive a novel feature-based representation of the EEG signal that characterizes the topographic information of the EEG. We use the HMM model in order to project the EEG data in the Fisher score space and use the Fisher score to describe the dynamics of the EEG topography sequence. The correspondence between this new feature and the fMRI is studied using CPLS. This methodology is applied for extracting features for the classification of a visual task. The results indicate that the proposed methodology is able to capture task related activations that can be used for the classification of mental tasks. Extensions on the proposed models are examined along with future research directions and applications