The current thesis addresses some of the unresolved predictions of recent models of the semantic brain system, such as the hub-and-spokes model. In particular, we tackle different aspects of the hypothesis that a widespread network of interacting heteromodal (hub(s)) and unimodal (spokes) cortices underlie semantic cognition. For this purpose, we use connectivity analyses, measures of graph theory and permutation-based statistics with source reconstructed Electro-/MagnetoEncephaloGraphy (EEG/MEG) data in order to track dynamic modulations of activity and connectivity within the semantic networks while a concept unfolds in the brain. Moreover, in order to obtain more accurate connectivity estimates of the semantic networks, we propose novel methods for some of the challenges associated with EEG/MEG connectivity analysis in source space. We utilised data-driven analyses of EEG/MEG recordings of visual word recognition paradigms and found that: 1) Bilateral Anterior Temporal Lobes (ATLs) acted as potential processor hubs for higher-level abstract representation of concepts. This was reflected in modulations of activity by multiple contrasts of semantic variables; 2) ATL and Angular Gyrus (AG) acted as potential integrator hubs for integration of information produced in distributed semantic areas. This was observed using Dynamic Causal Modelling of connectivity among the main left-hemispheric candidate hubs and modulations of functional connectivity of ATL and AG to semantic spokes by word concreteness. Furthermore, examining whole-brain connectomes using measures of graph theory revealed modules in the right ATL and parietal cortex as global hubs; 3) Brain oscillations associated with perception and action in low-level cortices, in particular Alpha and Gamma rhythms, were modulated in response to words with those sensory-motor attributes in the corresponding spokes, shedding light on the mechanism of semantic representations in spokes; 4) Three types of hub-hub, hub-spoke and spoke-spoke connectivity were found to underlie dynamic semantic graphs. Importantly, these results were obtained using novel approaches proposed to address two challenges associated with EEG/MEG connectivity. Firstly, in order to find the most suitable of several connectivity metrics, we utilised principal component analysis (PCA) to find commonalities and differences of those methods when applied to a dataset and identified the most suitable metric based on the maximum explained variance. Secondly, reconstruction of EEG/MEG connectomes using anatomical or fMRI-based parcellations can be significantly contaminated by spurious leakage-induced connections in source space. We, therefore, utilised cross-talk functions in order to optimise the number, size and locations of cortical parcels, obtaining EEG/MEG-adaptive parcellations. In summary, this thesis proposes approaches for optimising EEG/MEG connectivity analyses and applies them to provide the first empirical evidence regarding some of the core predictions of the hub-and-spokes model. The key findings support the general framework of the hub(s)-and-spokes, but also suggest modifications to the model, particularly regarding the definition of semantic hub(s).

The aim of this doctoral thesis was to study the influence of memory, pain, age and education on the regional cerebral blood flow (rCBF), i.e. brain function, in early Alzheimer's disease (AD) and in chronic neck pain patients in comparison to healthy controls and in healthy elderly per se. This was done by optimizing single photon emission computed tomography (SPECT) as a method to study rCBF with the tracer Technetium-99m (99mTc) hexamethylpropyleneamine oxime (HMPAO) and by matching all image data to a brain atlas before evaluation. The rCBF-SPECT was evaluated and developed to obtain higher diagnostic accuracy in AD and in chronic neck pain patients it was used to study basic pain related cerebral processes in chronic pain of different origin. A new semimanual registration method, based on fiducial marker, suitable for investigations with low spatial resolution was developed. The method was used to reconstruct images with an improved attenuation and scatter correction by using an attenuation-map calculated from the patients' previously acquired CT images. The influence of age and education on rCBF was evaluated with statistical parametric mapping, SPM in healthy elderly. The main findings were age related changes in rCBF in regions close to interlobar and interhemispheric space but not in regions typically affected in early AD, except for the medial temporal lobe. The theory of a 'cognitive reserve' in individuals with a longer education was supported with findings in the lateral temporal lobe, a region related to semantic memory, and in the frontal lobe. A cross-sectional study of chronic neck pain patients showed extensive rCBF changes in coping related regions in a non-traumatic pain patients compared to both healthy and a pain group with a traumatic origin, i.e. whiplash syndrome. The whiplash group displayed no significant differences in rCBF in comparison with the healthy controls. This suggests different pain mechanisms in these groups. The AD-patients showed a significantly lower rCBF in temporoparietal regions including left hippocampus. These changes were associated to episodic memory performance, and especially to face recognition. The diagnostic sensitivity for AD was high. The face recognition test (episodic memory) was used in AD patients to improve the sensitivity of method, i.e. memory-provoked rCBF-SPECT (MP-SPECT). The results were compared to healthy controls and the reductions of rCBF in temporoparietal regions were more pronounced in mild AD during provocation. Memory provocation increased the sensitivity of AD-related rCBF changes at group level. If a higher sensitivity for AD at the individual level is verified in future studies, a single MP-SPECT study might then be of help to set diagnosis earlier. In conclusion rCBF in temporoparietal regions are associated to an impaired episodic memory in early AD. Changes in these regions do not have a strong connection to chronological age. The diagnostic sensitivity of rCBF-SPECT in AD is high and there is a potentially higher sensitivity if memory provoked investigations are used. The findings in this thesis have given an increased knowledge of underlying cerebral pain processing in non-traumatic and traumatic (whiplash) neck pain. Preliminary results supporting the theory of 'cognitive reserve' by showing a correlation between long education and preserved rCBF was found in healthy elderly.

A combined view of the human brain and computer-generated virtual realities is motivated by recent developments in cognitive neuroscience and human-computer interaction (HCI). The emergence of new theories of human brain function, together with an increasing use of realistic human-computer interaction, give reason to believe that a better understanding of the relationship between human brains and virtual realities is both possible and valuable. The concept of “presence”, described as the subjective feeling of being in a place that feels real, can serve as a cornerstone concept in the development of such an understanding, as computer-generated presence is tightly related to how human brains work in virtual realities. In this thesis, presence is related both to theoretical discussions rooted in theories of human brain function, and to measurements of brain activity during realistic interaction. The practical implications of such results are further developed by considering potential applications. This includes the development and evaluation of a prototype application, motivated by presented principles. The theoretical conception of presence in this thesis relies on general principles of brain function, and describes presence as a general cognitive function, not specifically related to virtual realities. Virtual reality (VR) is an excellent technology for investigating and taking advantage of all aspects of presence, but a more general interpretation allows the same principles to be applied to a wide range of applications. Functional magnetic resonance imaging (fMRI) was used to study the working human brain in VR. Such data can inform and constrain further discussion about presence. Using two different experimental designs we have investigated both the effect of basic aspects of VR interaction, as well as the neural correlates of disrupted presence in a naturalistic environment. Reality-based brain-computer interaction (RBBCI) is suggested as a concept for summarizing the motivations for, and the context of, applications building on an understanding of human brains in virtual realities. The RBBCI prototype application we developed did not achieve the set goals, but much remains to be investigated and lessons from our evaluation point to possible ways forward. A developed use of methods and techniques from computer gaming is of particular interest. / Ett kombinerat perspektiv på den mänskliga hjärnan och datorgenererade virtuella verkligheter motiveras av den senaste utvecklingen inom kognitiv neurovetenskap och människa-datorinteraktion (MDI). Framväxten av nya teorier om den mänskliga hjärnan, tillsammans med en ökande användning av realistisk människa-datorinteraktion, gör det troligt att en bättre förståelse för relationen mellan mänskliga hjärnor och virtuella verkligheter är både möjlig och värdefull. Begreppet "närvaro", som i detta sammanhang beskrivs som den subjektiva känslan av att vara på en plats som känns verklig, kan fungera som en hörnsten i utvecklingen av en sådan förståelse, då datorgenererad närvaro är tätt kopplat till hur mänskliga hjärnor fungerar i virtuella verkligheter. I denna avhandling kopplas närvaro både till teoretiska diskussioner grundade i teorier om den mänskliga hjärnan, och till mätningar av hjärnans aktivitet under realistisk interaktion. De praktiska konsekvenserna av sådana resultat utvecklas vidare med en närmare titt på potentiella tillämpningar. Detta inkluderar utveckling och utvärdering av en prototypapplikation, motiverad av de presenterade principerna. Den teoretiska diskussionen av närvaro i denna avhandling bygger på allmänna principer för hjärnans funktion, och beskriver känslan av närvaro som en generell kognitiv funktion, inte specifikt relaterad till virtuella verkligheter. Virtuell verklighet (virtual reality, VR) är en utmärkt teknik för att undersöka och dra nytta av alla aspekter av närvaro, men en mer allmän tolkning gör att samma principer kan tillämpas på ett brett spektrum av applikationer. Funktionell hjärnavbildning (fMRI) användes för att studera den arbetande mänskliga hjärnan i VR. Sådant data kan informera och begränsa en vidare diskussion av närvaro. Med hjälp av två olika försöksdesigner har vi har undersökt både effekten av grundläggande aspekter av VR-interaktion, och neurala korrelat av störd närvaro i en naturalistisk miljö. Verklighets-baserad hjärna-dator interaktion (reality-based brain-computer interaction, RBBCI) föreslås som ett begrepp för att sammanfatta motiv och kontext för applikationer som bygger på en förståelse av den mänskliga hjärnan i virtuella verkligheter. Den prototypapplikation vi utvecklade uppnådde inte de uppsatta målen, men mycket återstår att utforska och lärdomar från vår utvärdering pekar på möjliga vägar framåt. En vidare användning av metoder och tekniker från dataspel är speciellt intressant.

<p>Mice have become the preferred model system for studying brain function and disease. With the powerful genetic tools available, mouse models can be created to study the underlying molecular basis of neurobiology in vivo. Just as magnetic resonance imaging is the dominant tool for evaluating the human brain, high-resolution MRI--magnetic resonance microscopy (MRM)--is a useful tool for studying the brain of mouse models. However, the need for high spatial resolution limits the signal-to-noise ratio (SNR) of the MRM images. To address this problem, T1-shortening contrast agents can be used, which not only improve the tissue contrast-to-noise ratio (CNR) but also increase SNR by allowing the MR signal to recover faster between pulses. By "actively staining" the tissue with these T1-shortening agents, MRM can be performed with higher resolution, greater contrast, and shorter scan times. In this work, active staining with T1-shortening agents was used to enhance three types of in vivo mouse brain MRM: (1) angiographic imaging of the neurovasculature, (2) anatomical imaging of the brain parenchyma, and (3) functional imaging of neuronal activity.</p> <p></p> <p>For magnetic resonance angiography (MRA) of the mouse, typical contrast agents are not useful because they are quickly cleared by the body and/or extravasate from the blood pool before a high-resolution image can be acquired. To address these limitations, a novel contrast agent--SC-Gd liposomes--has been developed, which is cleared slowly by the body and is too large to extravasate from the blood pool. In this work, MRA protocols were optimized for both the standard technique (time-of-flight contrast) and SC-Gd liposomes. When the blood was stained with SC-Gd liposomes, small vessel CNR improved to 250% that of time-of-flight. The SC-Gd liposomes could also be used to reduce scan time by 75% while still improving CNR by 32%.</p> <p>For MRM of the mouse brain parenchyma, active staining has been used to make dramatic improvements in the imaging of ex vivo specimens. However for in vivo imaging, the blood-brain barrier (BBB) prevents T1-shortening agents from entering the brain parenchyma. In this work, a noninvasive technique was developed for BBB opening with microbubbles and ultrasound (BOMUS). Using BOMUS, the parenchyma of the brain could be actively stained with the T1-shortening contrast agent, Gd-DTPA, and MRM images could be acquired in vivo with unprecedented resolution (52 x 52 x 100 micrometers3) in less than 1 hour.</p> <p>Functional MRI (fMRI), which uses blood oxygen level dependant (BOLD) contrast to detect neuronal activity, has been a revolutionary technique for studying brain function in humans. However, in mice, BOLD contrast has been difficult to detect and thus routine fMRI in mice has not been feasible. An alternative approach for detecting neuronal activity uses manganese (Mn2+). Mn2+ is a T1-shortening agent that can enter depolarized neurons via calcium channels. Thus, Mn2+ is a functional contrast agent with affinity for active neurons. In this work, Mn2+ (administered with the BOMUS technique) was used to map the neuronal response to stimulation of the vibrissae. The resultant activation map showed close agreement to published maps of the posterior-lateral and anterior-medial barrel field of the primary sensory cortex.</p> <p>The use of T1-shortening agents to actively stain tissues of interest--blood, brain parenchyma, or active neurons--will facilitate the use of MRM for studying mouse models of brain development, function, and disease.</p> / Dissertation

Photoacoustic tomography (PAT), as well as thermoacoustic tomography (TAT), utilize electromagnetic radiation in its visible, near infrared, microwave, and radiofrequency forms, respectively, to induce acoustic waves in biological tissues for imaging purposes. Combining the advantages of both the high image contrast that results from electromagnetic absorption and the high resolution of ultrasound imaging, these new imaging modalities could be the next successful imaging techniques in biomedical applications. Basic research on PAT and TAT, and the relevant physics, is presented in Chapter I. In Chapter II, we investigate the imaging mechanisms of TAT in terms of signal generation, propagation and detection. We present a theoretical analysis as well as simulations of such imaging characteristics as contrast and resolution, accompanied by experimental results from phantom and tissue samples. In Chapter III, we discuss the further application of TAT to the imaging of biological tissues. The microwave absorption difference in normal and cancerous breast tissues, as well as its influence on thermoacoustic wave generation and the resulting transducer response, is investigated over a wide range of electromagnetic frequencies and depths of tumor locations. In Chapter IV, we describe the mechanism of PAT and the algorithm used for image reconstruction. Because of the broad bandwidth of the laser-induced ultrasonic waves and the limited bandwidth of the single transducer, multiple ultrasonic transducers, each with a different central frequency, are employed for simultaneous detection. Chapter V further demonstrates PAT’s ability to image vascular structures in biological tissue based on blood’s strong light absorption capability. The photoacoustic images of rat brain tumors in this study clearly reveal the angiogenesis that is associated with tumors. In Chapter VI, we report on further developing PAT to image deeply embedded optical heterogeneity in biological tissues. The improved imaging ability is attributed to better penetration by NIR light, the use of the optical contrast agent ICG (indocyanine green) and a new detection scheme of a circular scanning configuration. Deep penetrating PAT, which is based on a tissue’s intrinsic contrast using laser light of 532 nm green light and 1.06 µm near infrared light, is also presented.

Includes vita. / Title from PDF of title page. / Document formatted into pages; contains 222 pages. / Includes bibliographical references. / Text (Electronic thesis) in PDF format. / ABSTRACT: This dissertation presents a knowledge-guided expert system that is capable of applying routinesfor multispectral analysis, (un)supervised clustering, and basic image processing to automatically detect and segment brain tissue abnormalities, and then label glioblastoma-multiforme brain tumors in magnetic resonance volumes of the human brain. The magnetic resonance images used here consist of three feature images (T1-weighted, proton density, T2-weighted) and the system is designed to be independent of a particular scanning protocol. Separate, but contiguous 2D slices in the transaxial plane form a brain volume. This allows complete tumor volumes to be measured and if repeat scans are taken over time, the system may be used to monitor tumor response to past treatments and aid in the planning of future treatment. Furthermore, once processing begins, the system is completely unsupervised, thus avoiding the problems of human variability found in supervised segmentation efforts.Each slice is initially segmented by an unsupervised fuzzy c-means algorithm. The segmented image, along with its respective cluster centers, is then analyzed by a rule-based expert system which iteratively locates tissues of interest based on the hierarchy of cluster centers in feature space. Model-based recognition techniques analyze tissues of interest by searching for expected characteristics and comparing those found with previously defined qualitative models. Normal/abnormal classification is performed through a default reasoning method: if a significant model deviation is found, the slice is considered abnormal. Otherwise, the slice is considered normal. Tumor segmentation in abnormal slices begins with multispectral histogram analysis and thresholding to separate suspected tumor from the rest of the intra-cranial region. The tumor is then refined with a variant of seed growing, followed by spatial component analysis and a final thresholding step to remove non-tumor pixels.The knowledge used in this system was extracted from general principles of magnetic resonance imaging, the distributions of individual voxels and cluster centers in feature space, and anatomical information. Knowledge is used both for single slice processing and information propagation between slices. A standard rule-based expert system shell (CLIPS) was modified to include the multispectral analysis, clustering, and image processing tools.A total of sixty-three volume data sets from eight patients and seventeen volunteers (four with and thirteen without gadolinium enhancement) were acquired from a single magnetic resonance imaging system with slightly varying scanning protocols were available for processing. All volumes were processed for normal/abnormal classification. Tumor segmentation was performed on the abnormal slices and the results were compared with a radiologist-labeled ground truth' tumor volume and tumor segmentations created by applying supervised k-nearest neighbors, a partially supervised variant of the fuzzy c-means clustering algorithm, and a commercially available seed growing package. The results of the developed automatic system generally correspond well to ground truth, both on a per slice basis and more importantly in tracking total tumor volume during treatment over time. / System requirements: World Wide Web browser and PDF reader. / Mode of access: World Wide Web.

Résumé Les premières études électrophysiologiques et anatomiques ont établi le rôle crucial du cortex somatosensoriel primaire et secondaire (SI et SII) dans le traitement de l'information somatosensorielle. Toutefois, les récentes avancées en techniques d’imagerie cérébrale ont mis en question leur rôle dans la perception somatosensorielle. La réorganisation du cortex somatosensoriel est un phénomène qui a été proposé comme cause de la douleur du membre fantôme chez les individus amputés. Comme la plupart des études se sont concentrées sur le rôle du SI, une étude plus approfondie est nécessaire. La présente série d'expériences implique une exploration du rôle des régions somatosensorielles dans la perception des stimuli douleureux et non-douleureux chez des volontaires sains et patients avec des douleurs de membre fantôme. La première étude expérimentale présentée dans le chapitre 3 est une méta-analyse des études de neuro-imagerie employant des stimuli nociceptifs chez des volontaires sains. En comparaison aux précédentes, la présente étude permet la génération de cartes quantitatives probabilistes permettant la localisation des régions activées en réponse à des stimuli nociceptifs. Le rôle du cortex somatosensoriel dans la perception consciente de stimuli chauds a été étudié dans le chapitre 4 grâce à une étude d'imagerie par résonance magnétique fonctionnelle, dans laquelle des stimuli thermiques douloureux et non-douloureux ont été administrés de manière contrebalancée. Grâce à cette procédure, la perception de la chaleur fut atténuée par les stimuli douloureux, ce qui permit la comparaison des stimuli consciemment perçus avec ceux qui ne le furent pas. Les résultats ont montrés que les stimulations chaudes perçues ont engendré l’activation de l’aire SI controlatérale, ainsi que de la région SII. Grâce à l’évaluation clinique de patients amputés présentant une altération de leurs perceptions somatosensorielles, il est également possible de dessiner un aperçu des régions corticales qui sous-tendent ces modifications perceptuelles. Dans le chapitre 5 nous avons émis l'hypothèse proposant que les sensations du membre fantôme représentent un corrélat perceptuel de la réorganisation somatotopique des représentations sensorielles corticales. En effet, la réorganisation des sensations peut donner des indices sur les régions impliquées dans la genèse des sensations référées. Ainsi, un protocole d’évaluation sensoriel a été administré à un groupe de patients affligés de douleur au niveau du membre fantôme. Les résultats ont montré que, contrairement aux études précédentes, les sensations diffèrent grandement selon le type et l'intensité des stimuli tactiles, sans évidence de la présence d’un modèle spatialement localisé. Toutefois, les résultats actuels suggèrent que les régions corticales à champs récepteurs bilatéraux présentent également des modifications en réponse à une déafférentation. Ces études présentent une nouvelle image des régions corticales impliquées dans la perception des stimuli somatosensoriels, lesquelles comprennent les aires SI et SII, ainsi que l'insula. Les résultats sont pertinents à notre compréhension des corrélats neurologiques de la perception somatosensorielle consciente. / Abstract Early anatomical and single-unit recording studies established a crucial role for the primary and secondary somatosensory cortices (SI & SII) in processing somatosensory information. However, recent advances in brain imaging and analysis techniques have called into question their role in somatosensation. Findings from this recent research are relevant to the study of the reorganizational changes occurring in the somatosensory cortices that have been causally linked to the genesis of pain in amputee patients. These patients continue to perceive and experience pain in the absent limb, which is usually referred to as phantom-limb pain; but little research on this phenomenon has focused on other regions outside SI, and further study is needed. The present series of experiments involve an exploration of the roles of the somatosensory cortices in the perception of noxious and innocuous tactile stimuli in healthy volunteers and patients with phantom-limb pain. The first experimental study in Chapter 3 is a meta-analytic review of neuroimaging studies examining noxious stimuli evoked activation in healthy volunteers. In comparison to previous reviews that have merely reported the prevalence of pain-related activation, the present study yields quantitative probabilistic maps that permit localization of the likelihood of obtaining activation in response to noxious stimuli within any brain region. The role of the somatosensory cortices in the conscious perception of brief warm stimuli was explored in Chapter 4 using functional magnetic resonance imaging, where noxious and innocuous thermal stimuli were counterbalanced within the experimental protocol. This procedure allowed a gating of the somatosensory system in which the perception of warm stimuli was attenuated by painful stimuli, thus permitting the comparison of detected with undetected stimuli. Results showed that detected warm stimuli significantly activated SI and SII. It is also possible to draw insight regarding which cortical regions subserve somatosensory processing and its organization by clinical assessment of amputee patients, who demonstrate altered somatosensation. To date, few studies have explored the relationship between referred sensations to the phantom and cortical reorganization. In Chapter 5 we hypothesized that referred sensations to phantom limbs are a perceptual correlates of a somatotopic reorganization of sensory representations. Derangements in referred sensations can give clues to the regions involved in referred sensations genesis. Thus, a quantitative sensory testing protocol was administered to a group of phantom-limb pain patients. Results showed that, contrary to previous reports, referred sensations to the phantom differed greatly based on the type and intensity of the tactile stimuli applied to the body, with no evidence of a spatially localized pattern. Previous reports of referred sensations have solely focused on plastic changes in SI. However, the present results suggest that other cortical regions with bilateral receptive fields also undergo reorganizational changes in response to deafferentation. These studies present an emerging picture of the cortical regions involved in the perception of somatosensory stimuli, which include SI and SII, as well as the insula. Findings are relevant to our understanding of the neural correlates of conscious perception of somatosensation and the formation of the mental representation of stimuli applied to the body.

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