Bentham’s 1832 Greatest Happiness Principle states that the greatest happiness for the greatest amount of people should be the goal of public policy. When people are asked what they wish for in life, health and happiness are consistently mentioned. This thesis examines the relationship between health and happiness. However, as happiness is difficult to consistently operationalize across different studies and scientific disciplines, life satisfaction is used as a proxy for happiness. This thesis studies the relationship between health and life satisfaction with a particular focus on the directionality of the relationship and the tentative processes indicated to be involved with this process. This study is accomplished through a literary review of the scientific literature related to life satisfaction, its neural correlates and their relationship with physical health. This study is modelled on the top-down, bottom-up and bidirectional debate within the larger Subjective Well-Being (SWB) literature. The results indicate that the correlation between life satisfaction and health appears to be robust, but the exact directionality and causality is unclear and difficult to establish with a literary review, with only predictive ability of life satisfaction on later physical health or vice versa established. Furthermore, the results appear to indicate that the central process linking this relationship is resilience - the ability to adaptively respond to stressors. Enhancing resiliency through psychological interventions may be a method to promote happiness and health in individuals as well as in society as a whole.

Alzheimer’s disease (AD) is a neurodegenerative disease and the major cause of dementia, affecting more than 50 million people worldwide. Chronic pain is long-lasting, persistent pain that affects more than 1.5 billion of the world population. Overlapping and heterogenous symptoms of AD and chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms. To characterize disease pathology of AD, we measured the protein changes in the temporal neocortex region of the brain of AD subjects using mass spectrometry (MS). We found proteins involved in exo-endocytic and extracellular vesicle functions displaying altered levels in the AD brain, potentially resulting in neuronal dysfunction and cell death in AD. To detect novel biomarkers for AD, we used MS to analyze cerebrospinal fluid (CSF) of AD patients and found decreased levels of eight proteins compared to controls, potentially indicating abnormal activity of complement system in AD. By integrating new proteomics markers with absolute levels of Aβ42, total tau (t-tau) and p-tau in CSF, we improved the prediction accuracy from 83% to 92% of early diagnosis of AD. We found increased levels of chitinase-3-like protein 1 (CH3L1) and decreased levels of neurosecretory protein VGF (VGF) in AD compared to controls. By exploring the CSF proteome of neuropathic pain patients before and after successful spinal cord stimulation (SCS) treatment, we found altered levels of twelve proteins, involved in neuroprotection, synaptic plasticity, nociceptive signaling and immune regulation. To detect biomarkers for diagnosing a chronic pain state known as fibromyalgia (FM), we analyzed the CSF of FM patients using MS. We found altered levels of four proteins, representing novel biomarkers for diagnosing FM. These proteins are involved in inflammatory mechanisms, energy metabolism and neuropeptide signaling. Finally, to facilitate fast and robust large-scale omics data handling, we developed an e-infrastructure. We demonstrated that the e-infrastructure provides high scalability, flexibility and it can be applied in virtually any fields including proteomics. This thesis demonstrates that proteomics is a promising approach for gaining deeper insight into mechanisms of nervous system disorders and find biomarkers for diagnosis of such diseases.

The feeling of anxiety, a conscious experience, is associated with uneasiness, painfulness, or disturbing suspense. The current paper presents the phenomenology of anxiety disorders based on diagnostic criteria and reviews neuroimaging studies on anxiety including dissociation studies. Activity in the anterior cingulate cortex, medial prefrontal cortex, insula, temporal poles and amygdala suggest neural correlates of anxiety. The relevance of the neural correlates, how the feeling of anxiety differs from fear and worry, and the construct validity of anxiety are addressed. Anxiety and pain correlate with activity in the anterior cingulate cortex, which warrants further studies on the painfulness–anxiety relationship.

Alzheimers sjukdom (AD) är den vanligaste formen av demens och kännetecknas av intracellulärt neurofibrillärt trassel (NFT) bestående av proteinet tau och extracellulära plack, uppbyggda av peptiden amyloid beta (Aβ). En växande skara studier har börjat peka mot att AD är en hjärnspecifik typ av diabetes. Insulinresistens följt av hyperinsulinemi och hyperglykemi är kännetecken för diabetes mellitus typ 2 (DMT2) och har visat sig vara en riskfaktor för AD. Insulin, ett hormon som kontrollerar glukoshomeostasen i perifera nervsystemet (PNS) och är viktigt för minne och inlärning, transporteras över blod-hjärnbarriären i en mättnadsbar transportmekanism och dess koncentration i centrala nervsystemet (CNS) minskar vid DMT2 och AD. Insulin-like growth factor 1 (IGF-1), ett neuronskyddande protein som minskar ogynnsam β-sekretasklyvning av amyloid precursor protein (APP) i amyloidkaskadhypotesen, minskar i koncentration i hjärnan när mycket insulin transporteras in i CNS. γ-sekretas ökar sin aktivitet på APP vid höga halter kolesterol som är vanligt vid DMT2, Aβ fungerar då som en negativ inhibitor till HMG-Coa reduktas (HMGR), enzymet som bildar kolesterol och kan därmed reglera kolesterolhalterna. Regleringssystem för Aβ i blod-hjärnbarriären (BBB) som p-GP, LRP-1 och RAGE rubbas vid DMT2. Aβ och insulin delar samma degraderingssystem, insulin degrading enzyme (IDE), som reglerar halterna Aβ och insulin. Dessutom har Aβ oligomerer visat sig kunna bryta ned insulinreceptorer (IR). Vidare har läkemedel mot diabetes visat sig lindra demens hos AD patienter. I den här rapporten gås de molekylärfysiologiska sambanden igenom i detalj. Slutligen finns det fog för ett samband mellan metabolt syndrom, en riskfaktor för DMT2, och AD.

Alzheimers sjukdom är den vanligaste orsaken till demens och i samband med att befolkningen blir större och allt äldre ökar även antalet patienter. Vid sjukdomen sker en hjärnatrofi och de mikroskopiska fynd man ser är extracellulära plack av β-amyloid, intracellulära neurofibriller av fosforylerat tau och förlust av nervcellsutskott, axoner, synapser och dendriter. Några av de tidiga patologiska förändringarna man kan se är störningar i nervcellernas lysosomala system som fyller en viktig roll vid nedbrytning av makromolekyler. I en tidigare studie har man påvisat förhöjda nivåer av proteiner från det lysosomala systemet i cerebrospinalvätska. Syftet med den här studien var att mäta nivåer av det lysosomala systemets proteiner i human hjärnvävnad från patienter med Alzheimer och jämföra dessa med kontrollprover. De sex proteiner som analyserades med Western blot var EEA1, PICALM, LAMP-1, LAMP-2, LC3 och TFEB. Resultaten visar på signifikant ökning i temporala cortex av LAMP-1 och LAMP-2 och en signifikant minskning av LC3 och EEA1 hos patienter med Alzheimers sjukdom. För att kunna dra riktiga slutsatser kring hur de ökade nivåerna i cerebrospinalvätska speglar de olika sjukdomsmekanismerna i hjärnan krävs vidare analyser av fler patientprover samt prover från andra områden i hjärnan. / Alzheimer's disease is the most common cause of dementia, and when the population becomes larger and older also the number of patients increase. A cerebral atrophy and microscopic findings of extracellular plaques of β-amyloid, intracellular neurofibrillary of phosphorylated tau and loss of nerve cell protrusions, axons, synapses and dendrites are seen during the disease. One of the early pathological changes is the disruption of the neuronal lysosomal network that plays an important role in the degradation of macromolecules. In a previous study elevated levels of proteins of the lysosomal network in cerebrospinal fluid from Alzheimer’s disease patients was demonstrated. The purpose of this study was to measure levels of the lysosomal network system in the brain. The six proteins EEA1, PICALM, LAMP-1, LAMP -2, LC3 and TFEB were analyzed in human brain tissue from five Alzheimer's disease cases and five control cases by Western blot. The results show a significant increase in the temporal cortex of LAMP-1 and LAMP -2 and a significant decrease of LC3 and EEA1 in patients with Alzheimer's disease. In order to draw proper conclusions about how the increased levels in cerebrospinal fluid reflect the different disease mechanisms in the brain it requires further analysis of more patient samples and from other areas of the brain.

Dopamine replacement therapy is the main method of treating Parkinson’s Disease (PD), however over time this treatment causes increasingly abnormal, involuntary movements. This symptom, known as Levodopa-Induced-Dyskinesia (LID) is associated with aberrant, high frequency oscillations (HFOs) in the motor cortex and basal ganglia, as demonstrated with implanted electrodes in human Parkinson’s patients as well as in a rat model of Parkinson’s Disease. However, despite efforts to determine if the same high frequency oscillations are also present during dyskinesia in the widespread 6-OHDA mouse model of Parkinson’s Disease, studies have been unable to do so. By building and implanting a 64-channel multi-electrode array into a unilateral 6-OHDA lesioned mouse, we were able to record HFOs at 80Hz and >100Hz in the motor cortex, basal ganglia and thalamus in the lesioned hemisphere during LID. We also recorded bilateral HFOs at >100Hz in the intact hemisphere. With this work we show that the same HFOs that are present in the motor cortex and basal ganglia of rats and humans are also present in mice during dyskinesia. This work will act to further validate the 6-OHDA PD-model in mice and provide opportunities to investigate new treatments for Parkinson’s Disease, dyskinesia and other neurological conditions. It will also serve as a model to study a purposed mechanism underlying the information processing in populations of neurons. / Dopaminbehandling är den mest förekommande metoden för att behandla Parkinsons sjukdom men detta orsakar dessvärre en bieffekt i form av gradvis förvärrande ofrivilliga rörelser. Detta beteendemönster kallas för Levodopa-Inducerad-Dyskinesi (LID) och med hjälp av elektrodimplantat i hjärnan, på parkinsonpatienter och djurmodeller av parkinsons, har man kunnat se att beteendet är förknippat med högfrekventa oscilleringar (HFO) av hjärnaktivitet i motorcortex och basala ganglierna. Trots försök att kartlägga om dessa högfrekventa oscilleringar också är närvarande i den populära 6-OHDA musmodellen av Parkinsons sjukdom, så har man hittills inte lyckats demonstrera detta. Genom att bygga och implantera ett elektrodimplantat med 64 kanaler i en ensidigt-leisonerad 6-OHDA musmodell av Parkinsons sjukdom så kunde vi åskådliggöra HFO i motor cortex, basala ganglierna och thalamus i den lesionerade hjärnhalvan under LID. Vi kunde också påvisa HFO som sträckte sig över till den intakta hjärnhalvan, med frekvenser över 100 Hz. Denna forskning ger stöd att 6-OHDA modellen för Parkinsons i möss är valid och ger möjlighet till nya metoder att utforska och behandla Parkinsons, dyskinesi och andra neurologiska åkommor. Studien lägger också grunden för framtida studier som ämnar att undersöka föreslagna mekanismer bakom sättet populationer av neuroner bearbetar information. / ingår i ett projekt finansierat av Vetenskapsrådet #2018-02717

Background: Glioblastoma (GBM) is the most common and malignant primary brain tumor. It is a rapidly progressing tumor that infiltrates the adjacent healthy brain tissue and is difficult to treat. Despite modern treatment including surgical resection followed by radiochemotherapy and adjuvant chemotherapy, the outcome remains poor. The median overall survival is 10-12 months. Neuroimaging is the most important diagnostic tool in the assessment of GBMs and the current imaging standard is contrast-enhanced magnetic resonance imaging (MRI). Positron emission tomography (PET) has been recommended as a complementary imaging modality. PET provides additional information to MRI, in biological behavior and aggressiveness of the tumor. This study aims to investigate if the combination of PET and MRI can improve the diagnostic assessment of these tumors. Patients and methods: In this study, 22 patients fulfilled the inclusion criteria, diagnosed with GBM, and participated in all four 18F-fluorothymidine (FLT)-PET/MR examinations. FLT-PET/MR examinations were performed preoperative (baseline), before the start of the oncological therapy, at two and six weeks into therapy. Optimization of an adaptive thresholding algorithm, a batch processing pipeline, and image feature extraction algorithms were developed and implemented in MATLAB and the analyzing tool imlook4d. Results: There was a significant difference in radiochemotherapy treatment response between long-term and short-term survivors’ tumor volume in MRI (p<0.05), and marginally significant (p<0.10) for maximum standard uptake value (SUVmax), PET tumor volume, and total lesion activity (TLA). Preoperative short-term survivors had on average larger tumor volume, higher SUV, and total lesion activity (TLA). The overall trend seen was that long-term survivors had a better treatment response in both MRI and PET than short-term survivors.  During radiochemotherapy, long-term survivors displayed shrinking MR tumor volume after two weeks, and almost no remaining tumor volume was left after six weeks; the short-term survivors display marginal tumor volume reduction during radiochemotherapy. In PET, long-term survivors mean tumor volumes start to decrease two weeks into radiochemotherapy. Short-term survivors do not show any PET volume reduction two and six weeks into radiochemotherapy. For patients with more or less than 200 days progression-free survival, PET volume and TLA were significantly different, and MR volume only marginally significant, suggesting that PET possibly could have added value. Conclusion: The combination of PET and MRI can be used to predict radiochemotherapy response between two and six weeks, predicting overall survival and progression-free survival using MR and PET volume, SUVmax, and TLA. This study is limited by small sample size and further research with greater number of participants is recommended.

Retinoic acid (RA) is a well-known neurodevelopmental signaling molecule. It is reported to induce effects on neurite formation in differentiating neurons and to interfere with the actin cytoskeleton. Therefore, this project aimed to investigate the mechanisms behind effects of RA on the actin cytoskeleton of developing neurons using the C17.2 neural progenitor cells (NPCs) in vitro model. The goal was to evaluate the morphological effects the growth cone had upon exposure to RA agonist and antagonist, and to analyze the expression of three genes: Coronin actin-binding protein 1C(Coro1c), Cdc42 effector protein 4 gene (Cdc42), and Fibronectin (Fn1). These genes were selected because of their relation to actin dynamics and/or their regulation by the Wnt pathway, which regulates/affects actin reorganization. Since the Wnt pathway was also shown to be affected by RA, this study aimed to investigate the relationship between RA and actin through the Wnt pathway. Cdc42 and Fn1 are related to both the Wnt pathway and actin dynamics, whereas Coro1cis a known actin-related protein. The expressions showed significant increase with Coro1c, while Cdc42 and Fn1 had a similar overall trend increase with the RA agonist. The RA antagonist showed no significant effect, except a trend decrease in all the genetic expressions. All genetic expression effects subside with the increase of RA agonist and antagonist concentrations. The results suggest the changes in actin filaments are related to a low dose effect of RA. The findings indicate a possibility of a regulation mechanism that controls actin-related gene expression in response to RA. This mechanism is possibly not restricted to the Wnt pathway seeing that a non-Wnt related gene was affected as well.

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Bakgrund och syfte. Ordflödestest undersöker en persons förmåga att generera så många ord som möjligt under en minut. Orden kan börja på en viss bokstav eller tillhöra en särskild kategori. FAS är ett vanligt ordflödestest där orden som ska genereras börjar på bokstäverna F, A och S. Exempel på kategoriska ordflödestest är djurflöde, som går ut på att säga så många djur som möjligt, samt verbflöde där instruktionen är att säga så många saker man kan göra (handlingar). Forskare har undersökt vilka mentala färdigheter som ligger till grund för ordflödesförmågan, framför allt planerande och reglerande (exekutiva) funktioner samt språklig förmåga. I forskning används ofta FAS och djurflöde för att undersöka olika delar av den språkliga förmågan. Även verbflöde har undersökts i dessa sammanhang, men inte i lika stor utsträckning. Däremot har verbflöde en större roll i forskning på planerande och reglerande funktioner hos äldre personer som har exempelvis Alzheimers eller Parkinson. Forskningen har lett till att ordflödestest används i kliniska sammanhang som en del i utredningen av dessa sjukdomar. I praktiken används även FAS och djurflöde vid utredningar av dyslexi, språkstörning och koncentrations-/hyperaktivitetssvårigheter (ADHD). Forskning har visat motstridiga resultat om vilka typer av ordflödestest som är nedsatta vid dyslexi och språkstörning, eller vilka mentala förmågor som är viktiga vid genomförande av ordflödestest. I denna studie undersöks FAS, djurflöde och verbflöde hos studenter inom högre utbildning med och utan dyslexi. Syftet är att utreda om ordflödesförmågan är nedsatt hos studenter med dyslexi. Studien undersöker om ordflöde kan bidra till att förklara spridningen i läsförmåga. Metod. I undersökningen deltog 42 studenter, varav 16 hade dyslexidiagnos och 26 kontroller utan dyslexidiagnos. Deltagarna genomförde test som undersöker läsförmåga, fonologisk förmåga, snabb benämning samt ordflöde av FAS, djur och verb. Resultat. Prestationen på ordflödesförmåga var signifikant nedsatt hos studenter med dyslexi jämfört med kontrollgruppen. En multipel regression med bakåteliminering genomfördes för att undersöka om FAS, djurflöde och verbflöde kunde förutsäga spridningen i läsförmåga när fonologisk medvetenhet och snabb benämning kontrollerades för. Regressionsanalysen visade att verbflöde, tillsammans med fonologisk medvetenhet, kunde förutsäga läsförmåga hos studenter med och utan dyslexi. Diskussion. Den nedsatta ordflödesförmågan hos studenter med dyslexi diskuteras utifrån faktorer som utbildning och andra mentala förmågor. Resultatet pekar på ett unikt samband mellan verbflöde och läsförmåga hos studenter med och utan dyslexi. De strukturer i hjärnan som aktiveras vid verbflöde är även strukturer som ligger till grund för andra mentala förmågor. Dessa mentala förmågor har även visats vara nedsatta hos personer med dyslexi. Generellt indikerar dessa nya fynd att verbflöde har en betydelse i förhållande till läsförmåga och dyslexi som behöver undersökas vidare. Resultatet diskuteras även utifrån ett kliniskt perspektiv. / Verbal fluency is commonly measured in cognitive assessments and has been shown to measure aspects of verbal ability and executive function, as well as to involve specific cortical areas during performance. Verbal fluency tasks, in which participants generate words during a given time limit, have been used in research and assessments of neurobiological disorders and impairments. Dyslexia is a neurobiologically based reading disorder that is characterized by difficulties in word decoding and spelling. Research on verbal fluency in individuals with dyslexia shows that semantic and letter fluency is impaired. However, studies show inconsistent results. This study examines performance on semantic fluency (animals), action fluency (verbs), and letter fluency (FAS) in 42 students with developmental dyslexia (DD, n = 16) and a control group with typical reading development (TD, n = 26). Participants also perform a test battery that measures reading and phonological abilities, amongst others. Additionally, it is examined if verbal fluency performance can contribute to predicting reading ability, when phonological awareness and rapid automatized naming (RAN) are taken into account. Results show that verbal fluency performance was impaired in the DD group, and that action and letter fluency were relatively more impaired than semantic fluency. A backward elimination regression showed that action fluency and phonological awareness were significant predictors of reading ability, together explaining 48 % of the variance. The impaired verbal fluency ability is discussed in relation to factors such as education and cognitive abilities. Further, the findings point to a possible unique connection between action fluency and reading ability in students, in addition to phonological awareness. The possibility that the relationship between action fluency and reading may be partly explained by common neurocognitive underpinnings is discussed. These novel findings indicate that action fluency has a pertinent role in reading ability and dyslexia, which should be further examined.