ABSTRACT Gliomas are the most common type of brain tumours and are often diffusely localised in areas that give permanent functional symptoms, so called eloquent areas. These areas partly control speech and language. Low-grade glioma (LGG) is the most suitable type of tumour for awake surgery. By performing surgery while the patient is awake, intra-operative testing of language and speech is possible and a more secure tumour resection can be performed. Patients that are to undergo such surgery execute a pre-operative speech and language testing, done by a speech and language pathologist, which is later used as a reference for the intra- and post-operative assessment. In this study the pre- and post-operative results for 20 patients with gliomas, who underwent awake surgery on 23 occasions at the Akademiska hospital in Uppsala from June 2013 until August 2015 were analysed. The aim of this study was to evaluate how the tumour resection affected speech and language. Furthermore, possible correlations between language deficits and tumour localisation were investigated. The results showed considerable variations in whether the patients improved and/or deteriorated. Overall, more patients deteriorated than improved. More pronounced deficits were shown for naming and verbal fluency pre- and post-operatively. A correlation analysis showed that patients with a tumour located in insula had greater difficulties with naming than patients with other tumour locations. This study provides an evaluation of the language outcomes of patients who underwent awake surgery in Uppsala. Additionally, the study resulted in an overview of the development of speech and language pathologists’ assessments since the start of awake surgery in 2013, and specific recommendations for improvement.   Keywords: Low-grade gliomas, awake surgery, pre- and post-operative speech and language testing, speech and language pathology, naming, verbal fluency, insula SAMMANFATTNING Gliom är den vanligaste typen av hjärntumör och är ofta diffust lokaliserad i områden som ger bestående funktionsnedsättning vid skada, så kallade elokventa områden. Dessa områden kontrollerar bland annat tal och språk. Av dessa är det de lågmaligna/låggradiga gliomen (LGG) som oftast är aktuella för resektion i vaket tillstånd. Genom att utföra operationen när patienten är vaken tillåts intraoperativ testning av tal och språk vilket leder till säkrare resektion. Alla patienter som ska genomgå denna typ av operation utför preoperativ tal- och språkbedömning hos logoped, som senare används som referenspunkt för den intra- och postoperativa bedömningen. I denna studie analyserades pre- och postoperativa resultat för 20 patienter med gliom som opererats vid 23 olika tillfällen på Akademiska sjukhuset i Uppsala sedan verksamheten startade juni 2013. Två frågeställningar skulle besvaras: Hur har tumörresektionen påverkat tal- och språkförmågan hos patienter som genomgått kirurgi i vaket tillstånd? Finns det något samband mellan språkliga symptom och tumörlokalisation? Resultatet visade stora variationer i huruvida patienterna förbättrades och/eller försämrades i sin tal- och språkfunktion efter operation. Generellt noterades dock fler försämringar än förbättringar. Benämning och verbalt ordflöde var de två parametrar där störst svårigheter påvisades både pre- och postoperativt. Korrelationsanalys visade att patienter med tumörer i insula hade större svårigheter med benämning än patienter med övriga tumörlokalisationer. Förutom att beskriva det språkliga utfallet för de patienter som genomgått kirurgi i vaket tillstånd så har denna studie resulterat i en översikt av hur logopedbedömningarna sett ut pre- och postoperativt sedan vakenkirurgin infördes i Uppsala, och även förslag på hur de kan förbättras i framtiden.   Nyckelord: Lågmaligna gliom, vakenkirurgi, pre- och postoperativ tal- och språkbedömning, logopedi, benämning, verbalt ordflöde, insula

This review has examined the spatial and temporal neural activation of speech comprehension. Six theories on speech comprehension were selected and reviewed. The most fundamental structures for speech comprehension are the superior temporal gyrus, the fusiform gyrus, the temporal pole, the temporoparietal junction, and the inferior frontal gyrus. Considering temporal aspects of processes, the N400 ERP effect indicates semantic violations, and the P600 indicates re-evaluation of a word due to ambiguity or syntax error. The dual-route processing model provides the most accurate account of neural correlates and streams of activation necessary for speech comprehension, while also being compatible with both the reviewed studies and the reviewed theories. The integrated theory of language production and comprehension provides a contemporary theory of speech production and comprehension with roots in computational neuroscience, which in conjunction with the dual-route processing model could drive the fields of language and neuroscience even further forward.

Mind-wandering was until recently not a mainstream topic of research. The aim of this literature review is to present current views on the definition of mind-wandering and how the phenomenon is experienced. Furthermore, it gives an account of the implications of mind-wandering on cognitive performance, as well as its neurological correlates. In addition, the methods used to study mind-wandering are reviewed.The study of mind-wandering reveals a highly frequent phenomenon with practical consequences on a broad scale, both disruptive and supportive to goal-related behaviour and wellbeing in general. Originating from the default network, and its regions related to representations of self, memory, Theory of Mind, empathy and creativity, mind-wandering is hypothesized to be a function for planning one’s future life. Suggested further research concerns how mind-wandering can be countered, detected from the outside and whether it alters the physical feature of the brain.

Post-traumatic stress disorder (PTSD) is a disabling condition that afflicts 1-10% of the general population, with twice as high lifetime prevalence for women than men. Treatments exist, but none have proven reliable and consistent efficacy. A large minority of patients remain treatment-resistant despite undergoing several different types of treatment over extended periods of time. Recently completed studies in the U.S. and in Switzerland have demonstrated the potential of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment-resistant PTSD. One of the major problems of treating PTSD is the patients’ fear state and inability to form a therapeutic alliance. Both these issues can be facilitated through administration of MDMA; the psychological effects - such as heightened empathy, increased openness and diminished anxiety – seem well-suited for therapeutic purposes. The rationale behind treating PTSD with MDMA has been indicated in neuroimaging studies; MDMA affects some of the neural structures altered in patients with PTSD, most notably the amygdala and the ventromedial prefrontal cortex. Using the Schedule 1 substance MDMA for this purpose is however controversial; animal studies have indicated that MDMA is neurotoxic, although no adverse effects on humans related to incidental use of MDMA in a controlled setting have been found. In conclusion, the data support that MDMA may be an efficient tool for treating PTSD, as well as safe and effective to use in a clinical context.

Injury and neurodegenerative conditions of the spinal cord can lead to paralysis and loss of sensation. Cell therapeutic approaches can restore sensory innervation of the spinal cord following injury and protect spinal cord cells from degeneration. This thesis primarily focuses on the restoration of deaffarented sensory fibres following injury to the dorsal root and spinal cord. These injuries lead to the formation of a non-permissive glial scar that prevents sensory axons from reinnervating spinal cord targets. It takes advantage of a dorsal root injury model that closely mimics spinal root avulsion injuries occurring in humans. In the first part of the thesis, three different neural progenitor types from human or murine sources are tested for their regenerative properties following their transplantation to the site of dorsal root avulsion injury. In the second part, the ability of murine neural progenitors to protect spinal motor neurons from a neurodegenerative process is tested. In the first original research article, I show that human embryonic stem cell derived neural progenitors are able to restore sensorimotor functions, mediated by the formation of a tissue bridge that allows ingrowth of sensory axons into the spinal cord. In the second research article, I present that murine boundary cap neural crest stem cells, a special type of neural progenitor that governs the entry of sensory axons into the spinal cord during development, are unable to form a permissive tissue bridge. This is possibly caused by the contribution of transplant derived ingrowth non-permissive glial cells. In the third research article, I show that human neural progenitors derived from foetal sources are capable of stimulating sensory ingrowth and that they ameliorate the glial scar. When this approach is combined with the delivery of sensory outgrowth stimulating neurotrophic factors, these cells fail to form a permissive tissue bridge and fail to modify the glial scar. In the final research article, murine boundary cap neural crest stem cells are shown to protect motor neurons, which harbor an amyotrophic lateral sclerosis causing mutation, from oxidative stress. Oxidative stress is a pathological component of amyotrophic lateral sclerosis in human patients. Taken together, this thesis provides first evidence that sensory regeneration following a spinal root avulsion injury can be achieved by transplantation of human neural progenitors. In addition, it introduces murine boundary cap neural crest stem cells as interesting candidates for the cell therapeutic treatment of amyotrophic lateral sclerosis.

Background: Performing aerobic exercise and maintaining high levels of aerobic fitness may have positive effects on both brain structure and function in older adults. Despite decades of research however, there is still a rather poor understanding of the neurocognitive mechanisms explaining the positive effects of aerobic exercise on cognition. Changes in prefrontal gray matter as well as dopaminergic neurotransmission in striatum are both candidate neurocognitive mechanisms. The main aims of this thesis are: 1. To investigate the effects of aerobic exercise and fitness on cognition and magnetic resonance imaging (MRI) derived gray matter volumes using data from a 6 month physical exercise intervention in older adults (Study I). 2. To simulate the effect of atrophy in longitudinal positron emission tomography (PET) which could pose a challenge to interpreting changes in longitudinal PET imaging (Study II). 3. To study the influence of aerobic exercise and fitness on the dopamine D2-receptor (D2R) system in striatum using [11C]raclopride PET as a potential mechanism for improved cognition (Study III). Results: In Study I, aerobic exercise was found to improve cognitive performance in a broad, rather than domain-specific sense. Moreover, aerobic fitness was related to prefrontal cortical thickness, and improved aerobic fitness over 6 months was related to increased hippocampal volume. In Study II, we identified areas in the striatum vulnerable to the effect of shrinkage, which should be considered in longitudinal PET imaging. Finally, in Study III, the effect of being aerobically fit, and improving fitness levels was found to impact dopaminergic neurotransmission in the striatum, which in turn mediated fitness-induced improvements in working memory updating performance. Conclusion: The findings in this thesis provide novel evidence regarding the neurocognitive mechanisms of aerobic exercise-induced improvements in cognition, and impacts the interpretation of longitudinal PET imaging. Performing aerobic exercise and staying aerobically fit at an older age have positive effects on cognition and brain systems important for memory and cognition. Specifically, fitness-induced changes to the dopaminergic system stands out as one novel neurocognitive mechanism explaining the positive effects of aerobic fitness on working-memory performance in healthy older adults.

Solute carriers (SLCs) constitute the largest family of membrane-bound transporter proteins in humans, and they convey transport of nutrients, ions, drugs and waste over cellular membranes via facilitative diffusion, co-transport or exchange. Several SLCs are associated with diseases and their location in membranes and specific substrate transport makes them excellent as drug targets. However, as 30 % of the 430 identified SLCs are still orphans, there are yet numerous opportunities to explain diseases and discover potential drug targets. Among the novel proteins are 29 atypical SLCs of major facilitator superfamily (MFS) type. These share evolutionary history with the remaining SLCs, but are orphans regarding expression, structure and/or function. They are not classified into any of the existing 52 SLC families. The overall aim in this thesis was to study the atypical SLCs with a focus on their phylogenetic clustering, evolutionary conservation, structure, protein expression in mouse brains and if and how their gene expressions were affected upon changed food intake. In Papers I-III, the focus was on specific proteins, MFSD5 and MFSD11 (Paper I), MFSD1 and MFSD3 (Paper II), and MFSD4A and MFSD9 (Paper III). They all shared neuronal expression, and their transcription levels were altered in several brain areas after subjecting mice to food deprivation or a high-fat diet. In Paper IV, the 29 atypical SLCs of MFS type were examined. They were divided into 15 families, based on phylogenetic analyses and sequence identities, to facilitate functional studies. Their sequence relationships with other SLCs were also established. Some of the proteins were found to be well conserved with orthologues down to nematodes and insects, whereas others emerged at first in vertebrates. The atypical SLCs of MFS type were predicted to have the common MFS structure, composed of 12 transmembrane segments. With single-cell RNA sequencing and in situ proximity ligation assay, co-expression of atypical SLCs was analysed to get a comprehensive understanding of how membrane-bound transporters interact.   In conclusion, the atypical SLCs of MFS type are suggested to be novel SLC transporters, involved in maintaining nutrient homeostasis through substrate transport.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery. / Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindring och det är oftast förstahandsval vid behandling av patienter med PS. Flera faktorer påverkar tillgängligheten av LD, bl.a. den hastighet som magsäcken tömmer sig med och denna verkar förlångsammad hos personer med PS vilket ger sämre tillgänglighet av LD i blodet och därmed i hjärnan. LD bryts även ner i hög grad av olika enzym ute i kroppen vilket leder till mindre mängd LD som hamnar i hjärnan och till fler nedbrytningsprodukter som orsakar biverkningar. Tillägg av enzymhämmare leder till ökad mängd LD som kan nå hjärnan och omvandlas till DA. Det anses viktigt att undvika höga toppar av LD i hjärnan då dessa verkar bidra till utvecklandet av besvärliga motoriska komplikationer hos patienter med PS. Om LD ges mer kontinuerligt, exempelvis som en kontinuerlig infusion in i tarmen eller i blodet, så minskar dessa motoriska komplikationer. Inopererande av stimulatorer i vissa delar av hjärnan (DBS) har också visat sig minska dessa motoriska komplikationer och även resultera i att man kan minska LD-dosen. Huvudsyftet med den här avhandlingen är att studera LD hos patienter med PS; i blod och fettvävnad då LD ges i tablettform och se om det finns något samband med LD-upptag och hastigheten på magsäckstömningen (MT) och om kontinuerligt given LD påverkar LD-upptaget eller MT; i blod och i ryggmärgsvätska då enzymhämmarna entakapon och karbidopa tillsätts LD; i hjärna vid behandling med DBS och då LD ges både som tablett och som infusion i blodet. Sammanfattningsvis kan vi se att LD-upptaget är mer gynnsamt hos patienter med PS i tidigare skede av sjukdomens komplikationsfas. MT är förlångsammad hos patienter med PS och det är inget tydligt samband mellan LD-upptag och MT eller mellan MT och sjukdomsgrad. Kontinuerligt given LD minskar LDnivåerna. Enzymhämmaren entakapon ökar den maximala koncentrationen av LD i blod och ryggmärgsvätska och effekten är mer tydlig vid tillägg av karbidopa vilket är viktigt att ta i beaktande vid behandling av PS för att undvika höga toppar av LD i hjärnan. LD ökar i hjärnan då man behandlar med LD i tablettform och som infusion i blodet och DA-nivåerna i hjärnan följer LD väl vilket visar på att patienter med PS fortfarande kan omvandla LD till DA trots trolig uttalad brist av de DA-producerande nervcellerna i hjärnan. DBS verkar öka DA i vissa områden i hjärnan och tillsammans med LD-infusion i blodet verkar det även öka LD i hjärnan och det kan förklara varför man kan sänka LDdosen efter DBS-operation.

Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD. The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models. In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats.  Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol. In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993. In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model. Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol. In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.

Bakgrund: De intrinsica fotmusklerna (IFM) har potential att påverka idrottslig prestation som hopp, sprint samt balans direkt genom påverkan av muskelstyrkan eller indirekt genom påverkan på det mediala-longitudinella fotvalvet. Ett växande antalet studier visar samband mellan träning av IFM och idrottslig prestation, dock råder ingen konsensus och motstridiga resultat finns. Syfte: Syftet med studien var att kritiskt granska litteratur och undersöka det aktuella vetenskapliga kunskapsläget för sambandet mellan muskelstyrka i IFM och friska individers sprint- och hopprestanda samt balans. Metod: En litteratursökning med noga valda sökord genomfördes i fyra databaser. Efter genomgång av in- och exkluderingskriterier inkluderades 10 studier vilka kvalitetsmässigt bedömdes med Joanna Briggs Institute granskningsmall för tvärsnittsstudier. En narrativ syntetiserande analys genomfördes. Resultat: Kvalitén i inkluderade studier bedömdes i genomsnitt vara medelgod. Det som främst drog ner betyget var hanteringen av confounders och användandet av ej valida mätinstrument. Generellt visade inkluderade studier på ett samband mellan tåflexor styrka/storlek och hopp- och sprintprestanda samt balans. Svårigheten att isolerat mäta IFM försvårar möjligheten att utreda IFMs betydelse för inkluderade studiers utfallsmått. Slutsats: Genomförd litteraturstudie visar möjliga samband mellan styrka/tåflexorstorlek och prestation i hopp och sprint såväl som balans. För att nå en ökad förståelse för hur IFM påverkar idrottslig prestation och balans behövs en större kunskap om hur IFM styrka direkt eller indirekt kan mätas isolerat och hur muskelstorlek kan översättas till styrka. Genomförd litteraturgranskning stödjer ett redan identifierat behov av valida mätinstrument för att nå en ökad förståelse av IFMs betydelse för idrottslig prestation och balans. / Background: The intrinsic foot muscles (IFM) have the potential to improve sprint, jump and balance performance by direct muscle power or indirectly by supporting the medial longitudinal arch. A growing number of studies show the association between exercising the IFM and athletic performance. However, there is no consensus if athletes can benefit from IFM training and inconsistent results are published. Aim: The aim of this study was to conduct a critical systematic review to evaluate the current knowledge of the association between IFM strength and performance in jump sprint and balance in healthy individual’s. Methods: Four data bases were searched for eligible studies. After screening for exclusion and inclusion criteria ten studies were included. The scientific quality was analyzed using the Joanna Briggs Institute ”Critical Appraisal tools” for Cross Sectional Studies, and a narrative synthesis was conducted. Results: The average quality score for the included studies was “moderately good”. The main reason for the low scores was insufficient attention to confounders and the use of non-valid instruments. An association was found in most of the studies between toe flexor strength/size and jump, sprint and balance performance. Difficulties in selectively measuring the IFM activity complicated the possibility to evaluate the impact of IFM on studied outcome measures. Conclusion: The presented study shows an association between toe flexor strength/size and athletic performance. However, to understand how IFM strength training affects athletic performance, both directly and indirectly, more studies focused on how to measure the IFM using valid methods for isolated IFM measures of strength and size is needed.