New solid phase microextraction (SPME) method was developed for brain tissue bioanalysis on a liquid chromatography mass spectrometry platform. To achieve set objectives, in vivo SPME desorption process was optimized for high throughput analysis through the development of a desorption device. Subsequently, new SPME coatings were developed for the extraction of polar neurotransmitters from biological matrices. In a targeted analysis, in vivo SPME was used to monitor of changes in the concentrations of endogenous compounds (multiple neurotransmitters) and exogenous drugs (carbamazepine and cimetidine) in the striatum of the rat brain extracellular fluid. For the first time, SPME was used for quantitative analysis of neurotransmitters and also study spacial distribution of other drugs in different regions of the brain extracellular fluid. A new approach was developed for improved metabolites coverage in a global non-targeted metabolomics studies. The proposed in vivo method showed how complementary results can be obtained through the combination of microdialysis and SPME for simultaneous sampling of the brain extracellular fluid. Finally, in a clinical application, SPME was used to monitor changes in the concentration of multiple neurotransmitters during deep brain stimulation of the pre-frontal cortex of the brain.

Trots att det har utvecklats skyddsutrustning som skyddar hjärnan mot farlig roterande kinematik inom flera områden, finns ännu ingen utrustning som skyddar boxare mot den typen av våld. Syftet med arbetet var att göra olympisk boxning och träning säkrare. Målet var att utveckla en handske som reducerar töjningen i hjärnan med minst 20 %. I det här arbetet utvecklades och testades ett antal boxningshandskar med implementerade glidskikt som skulle reducera töjningen i hjärnan som uppstår när huvudet utsätts för roterande kinematik. Testerna genomfördes med en linear impactor som slog handskarna mot ett testhuvud. Testhuvudet samlade mätdata med hjälp av nio accelerometrar. Två av prototyperna reducerade töjningen med mer än 20 % vid ett eller flera tester men de hade brister i användningsbarhet. Ingen av prototyperna uppfyllde alla mål och därför kan ingen prototyp rekommenderas för vidareutveckling men det kan konstateras att det finns potential i grundidén. / Although protective equipment has been developed that protects the brain against dangerous rotating kinematics in several areas, no equipment is yet available to protect boxers against this type of violence. The purpose of this work was to make Olympic boxing and training safer. The goal was to develop a glove that reduces the strain in the brain by at least 20 %. In this work, a number of boxing gloves with implemented sliding layers were developed and tested, which would reduce the strain in the brain that occurs when the head is subjected to rotational kinematics. In the tests a linear impactor was used, which hit the gloves against a test head. The test head collected data using nine accelerometers. Two of the prototypes reduced the strain by more than 20% in one or more tests, but they lacked in usability. None of the prototypes met all objectives and therefore no prototype can be recommended for further development, but it can be stated that there is potential in the basic idea. / <p>Betyg 2020-07-11</p>

Magnetic Resonance Imaging (MRI) is a cornerstone in neuroimaging for studying brain anatomy and functions. Anatomical MRI images, such as T1-weighted (T1-w) scans, allow the non-invasive visualization of the brain tissues, enabling the investigation of the brain morphology and facilitating the diagnosis of both acquired (e.g., tumors, stroke lesions, infections) and congenital (e.g., malformations) brain disorders. T1-w images provide a detailed representation of brain anatomy and accurate differentiation between the main brain structures, such as white matter (WM) and gray matter (GM), therefor they are frequently used in combination with advanced sequences such as diffusion MRI (dMRI) for the computation of the structural connectivity of the brain. In particular, from the processing of dMRI data, it is possible to investigate the structures of WM through tractography techniques, obtaining a virtual representation of the WM pathways called tractogram. Since the tractogram is a collection of digital fibers representing the neuronal axons connecting the brain's cortical areas, it is the fundamental element for studying the brain's structural connectivity. A critical step for processing the tractography data is the accurate labeling of the brain tissues, usually performed through brain tissue segmentation of T1-w images. Even though the gold standard is manual segmentation, it is time-consuming and prone to intra/inter-operator variability. Automated model-based methods produce more consistent and reliable results, however, they struggle with accuracy in the case of pathological brains due to reliance on priors based on normal anatomy. Recently, deep learning (DL) has shown the potential of supervised data-driven approaches for brain tissue segmentation by leveraging the information encoded in the signal intensity of T1-w images. As a first contribution of this thesis, we reported empirical evidence that a data-driven approach is effective for brain tissue segmentation in pathological brains. By implementing a DL network trained on a large dataset of only healthy subjects, we demonstrated improvements in segmenting the brain tissues compared to models based on healthy anatomical priors, especially on severely distorted brains. Additionally, we published a benchmark for enabling an open investigation into improving tissue segmentation of distorted brains, providing a training dataset of about one thousand healthy individuals with T1-w MR images and corresponding brain tissue labels, and a test dataset includes several tens of individuals with severe brain distortions. Another crucial aspect of processing tractography data for brain connectivity analysis is the correct alignment of the WM structures across different subjects or their normalization into a common reference space, usually performed as tractography alignment. The best practice is to perform the registration using T1-w images and then apply the resulting transformation to align the tractography, despite T1-w images lacking fiber orientation information. In light of this, various methods have been proposed to leverage the information of the WM from dMRI data, ranging from scalar diffusion maps to more complex models encoding fiber orientation in the voxels. As a second contribution to the thesis, we provide a comprehensive survey of methods for conducting tractogram alignment. Additionally, we include an empirical study with the results of a quantitative comparison among the main methods for which an implementation is available. From our findings, the use of increasingly complex diffusion models does not significantly improve the alignment of tractograms. Conversely, correspondence methods that use the fibers directly to compute the alignment outperform voxel-based methods, albeit with some limitations: not producing a deformation field, operating in an unsupervised manner, and avoiding using anatomical information. Recently, geometric deep learning (GDL) models have shown promising results in handling non-grid data like tractograms, offering new possibilities for WM structure alignment. The third main contribution of this thesis is implementing a GDL model for tractogram alignment through a supervised approach guided by fiber correspondence. The alignment is predicted as the displacement of fiber points, based on a GDL registration framework that combines graph convolutional networks and differentiable loopy belief propagation, incorporating the definition of fiber structure into the encoding of the graph. Our empirical analysis demonstrates the advantages of utilizing the proposed GDL framework over traditional volumetric registration, showcasing high alignment accuracy, low inference time, and good generalization capabilities. Overall, this thesis advances the methodology for processing MRI data for brain structural connectivity, addressing the challenges of tissue segmentation and tractography alignment, proving the potential of DL approaches also in the case of pathological brains.

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Since the first human spaceflight in 1961, hundreds of humans have been in space. Microgravity and high radiation are the main spaceflight hazards. The space environment is known to impact several aspects of human health, such as bone density and cognitive performance. However, the effects of long­duration spaceflights on a cellular and molecular level, utilizing biosamples and multiomic approaches, is poorly studied. In this project, the method Spatial Transcriptomics has been utilized to compare brain tissue from the hippocampus region of mice that have been in space with a control group of mice that have stayed on Earth. Spatial Transcriptomics allow for the quantification of gene expression, while maintaining the spatial information of the transcriptome. The results of this study suggest that spaceflights cause mitochondrial stress.   This thesis work is part of a more extensive study in collaboration with NASA, and more studies will be conducted to investigate the effects of spaceflights further. If these findings are confirmed, medicines used on Earth to treat patients with mitochondrial dysfunction could increase the well­being of astronauts in space. / Sedan den första människan skickades till rymden år 1961, har hundratals astronauter lämnat jordens atmosfär.   De mest signifikanta hälsoriskerna i rymden är mikrogravitation och hög strålning och rymdmiljön har stor påverkan på oss. Exempelvis upplever astronauter ofta minskad benmassa och nedsatt kognitiv funktion. Men kunskapen kring hur människor påverkas av långtidresor i rymden är begränsad. Särskilt få experiment har genomförts på stora dataset från biologiska prover, på en molekylär och cellulär nivå. I detta projekt har genuttryck hos möss som varit i rymden jämförts med en kontrollgrupp av möss som stannat på jorden. Metoden Spatial Transcriptomics (ST) har använts för att undersöka vävnadssnitt från hippocampus i mushjärna. Med ST är det möjligt att undersöka RNA­molekyler och kartlägga deras position i vävnaden. Resultatet från denna studie indikerar att miljön i rymden leder till dysfunktion i mitokondrierna. Detta arbete är en del av en större studie i samarbete med NASA och fler experiment kommer genomföras för att undersöka hur vi påverkas av miljön i rymden. Om fler studier stödjer detta resultat, kan mediciner som använts på jorden för att behandla patienter med dysfunktion i mitokondrierna, användas i förebyggande syfte för astronauter.

As of today, Alzheimer’s disease is the leading cause of dementia among neurodegenerative disorders, affecting many millions of people worldwide. As the average life span of populations increase, more and more people succumb to the illness each year. Like other neurodegenerative disorders, Alzheimer’s disease can be attributed to the accumulation of protein aggregates in the brain. These amyloid-β peptides and tau proteins can presumably be detected in the brain many years before the onset of clinical symptoms. Development of fluorescent ligands, capable of binding to these neuropathological hallmarks and highlighting them, could serve as molecular diagnostic tools and facilitate an early diagnosis of the disease. The method could also be useful in studying disease progression and evaluating the effects of novel treatments. One such ligand is HS-259. The aim of this project was to synthetize different analogues of HS-259, and test their selectivity towards the aforementioned aggregates in brain tissue from an individual with Alzheimer’s disease. Staining of tissue samples with analogue solution enables visualization of aggregate sites through fluorescence imaging. In the end, five analogues were synthetized, albeit in relatively low overall yields. Synthetic methods included Suzuki-Miyara cross-couplings, Ullmann-type arylations and condensations. Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) were used for analysis of the compounds. Two of the five analogues could be tested for staining of aggregates and assessed for photophysical characteristics, i.e. absorption- and emission spectra. One analogue stained both amyloid-β aggregates and some tau aggregates, whereas the other stained neither. Since only two analogues were tested and rendered inconsistent results, further studies are needed to assess the binding properties of HS-259 analogues in general.