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Att kunna uppskatta antal är en grundläggande förmåga som återfinns hos många djur förutom männinskan. Trippelkodmodellen (TKM) för numerisk kognition säger att antal representeras på tre olika sätt, som (arabiska) siffror, som sifferord och som ickesymboliska magnituder, vilka associeras till separata, men delvis överlappande, neurala substrat. Denna studie undersökte för första gången alla tre koder samtidigt på barn. 10 barn mellan 10-12 år genomgick fMRT-skanning för att söka neurala korrelat till antalsuppfattning. Oberoende uppgift > kontroll-kontraster bekräftade delvis TKM, såsom funktionellt olika neurala substrat, ett fronto-parietalt nätverk och att barn nyttjar det ventrala uppmärksamhetsnätet mer än vuxna på grund av mindre automatisering. Därtill fanns aktiveringar i visuella områden V2 och V3 liksom i primära somatosensoriska området vilket överensstämmer med föreslagna kompletteringar av TKM. Parametriska kontraster kunde i viss mån bekräfta distanseffekten som innebär större kognitiv belastning vid särskiljning av närliggande antal jämfört med att skilja på tydligt olika antal. / Being able to approximate numbers is a basic skill present in many animals, including man. The Triple Code Model (TCM) of numerical cognition suggests that numerosity is represented in three different codes, each subserved by functionally dissociated, but partly overlapping, neural substrates. The codes are (arabic) numbers, number words, and non-symbolic magnitude. This study examined all three codes in children for the first time. 10 healthy children, 10-12 years old, had an fMRI in order to detect neural correlates to numerosity processing. Independent task-control contrasts partly confirmed the TCM as functionally dissociated neural substrates, with a fronto-parietal network and the fact that children, having automatized functions less, more heavily depends on the ventral attention network. Furthermore, activations in the visual areas V2 and V3 as well as in primary somatosensory cortex is in accordance with recent suggestions of updates to the TCM. Parametric contrasts did, to some extent, confirm the distance effect, where it is more difficult to discriminate closely spaced numbers than numbers of more different magnitude.

Kleine Levin Syndrome (KLS) is a hypersomniac disease of episodic nature that affects only 1-5 per million individuals globally. In addition to extensive periods of sleep (> 20 hours) patients experience a wide range of symptoms during an episode, which occur approximately 1-12 times a year with a median of 10 days. The etiology and pathophysiology of the disease is unknown. Diagnostic criteria (The International Classification of Sleep disorders, third addition) rely solemnly on symptomatic characteristics. Misdiagnosis is unfortunately common. The potential of using hypocretin-1, amyloid-beta/tau and the IgG index in the CSF as potential disease biomarkers was investigated. Measurements were taken during the asymptomatic and/or symptomatic phase of the disease. All values were within the normal range. Lower hypocretin-1 values were observed in the asymptomatic phase compared to the symptomatic phase in two of the three patients, although not statistically significant.

Mild Cognitive Impairment (MCI) refers to a transitional stage between normal aging and dementia. The purpose of this study was to predict the development of MCI patients based on cognitive function. 222 MCI patients were studied at baseline and at a follow-up of 2 years. Using discriminant analysis, they were predicted into four diagnostic groups: Improved, Stable MCI, Dementia of the Alzheimer’s Type (AD) and Other Dementia. Using four tests - Rey-Osterrieth Complex Figure Test recall, Auditory-Verbal Learning Test recall, TMTB time and Digit Symbol – overall 62.6% of cases were correctly classified after cross-validation. The rate of prediction in this study was 1.8 times better than chance, which is better than reported in most other studies. The model did best for the AD group with 80% of cases correctly classified. However, most cases in the Other Dementia group were also classified as AD.

Recurrent processing is the corticocortical activity that appears after the feedforward sweep of information processing in the brain. According to Victor Lamme, this process is directly connected to visual awareness. Our consciousness can be divided into phenomenal and reflective consciousness. The underlying process of phenomenal consciousness is suggested to be localized recurrent processing. Widespread recurrent processing to motor and frontal regions correlates with reflective consciousness. Recent electroencephalographic studies have shown visual awareness negativity correlating with localized recurrent processing in both a temporal and spatial aspect. If we accept that localized recurrent processing is consciousness, we get the controversial implications that we can be conscious of something without being able to introspect.

Sammanfattning Syfte Syftet med denna studie var att ta reda på om akut visuell biofeedback i form av EMG, från qudriceps och hamstrings kan öka knäextensorernas muskelaktivitet samt styrkeutvecklingen, vid en maximal viljemässig isokinetisk benspark (20o.s-1).   Metod Totalt deltog 19 aktiva och motiverade försökspersoner, 9 kvinnor och 10 män, i denna studie. Försökspersonerna rekryterades under förutsättningarna att de inte hade några knäskador samt att de inte bedrev någon typ av kontinuerlig styrketräning för benen. Testet bestod av två omgångar koncentriska och excentriska maximala viljemässiga isokinetiska muskelaktioner (MVC) för respektive ben. Knävinkelhastigheten var 20o.s-1 och rörelseomfånget var 60o, från120o till 180o där 180o motsvarar sträckt knä. EMG-feedback från knämuskulaturen visades endast i omgång två då försökspersonen utförde kontraktioner med höger ben. Styrkan i knäextensorerna, den viljemässiga aktiveringsgraden samt EMG från quadriceps och hamstrings mättes under hela rörelseomfånget (60o).   Resultat Biofeedback i form av EMG-rms ökade styrkeutvecklingen signifikant i knäextensorerna (10 %) från 144 ± 48 till 158 ± 53 Nm. Beträffande den viljemässiga aktiveringen av knäextensorerna så ökade den signifikant (9 %) från 75 ±15 % till 81 ± 15 % då feedback gavs. Biofeedback påverkade dock inte till en minskad EMG aktiviteten i hamstringsmuskulaturen.   Slutsats Sammanfattningsvis så visar denna studie att fullt friska aktiva personer kan öka sin styrkeutveckling vid maximala viljemässiga knäextensioner med hjälp av visuell realtidsfeedback i form av EMG-rms från quadriceps och hamstrings. Vidare så visade studien att den viljemässiga aktiveringsförmågan ökade signifikant då feedback tillfördes. Dock visade studien ingen minskad hamstringsaktivering då feedback gavs till försökspersonen och styrkeökningen beror således snarare på ökad quadricepsaktivering än minskad hamstringsaktivering. / Abstract Aim The aim of this study was to investigate whether or not EMG-feedback from quadriceps and hamstrings has any acute effects on muscle activation and strength during a voluntary maximal isokinetic knee extensor action (eccentric and concentric) (20o.s-1).   Method Nineteen healthy subjects, 9 female and 10 male, participated in the study. They reported no previous knee injuries and were not involved in strength training for the leg muscles. Subjects performed two sets of maximal voluntary unilateral knee extensor actions at a velocity of 20o.s-1 through a 60o range of motion of the knee joint 120o to 180o, with 180o representing a fully extended knee. EMG-feedback from the knee muscles was only given for the right leg during the second set. Knee extensor strength, level of activation and electromyographic activity of quadriceps and hamstrings were recorded during the whole range of motion (60o).   Results The results of this study showed that the knee extensor strength increased significantly (by 10 %) from 144 ± 48 with no feedback to 158 ± 53 Nm with feedback. With regard to the level of activation of the knee extensors it increased significantly (by 9%) from 75 ±15 % with no feedback to 81 ± 15 % with feedback. However, biofeedback did not contribute to decreased levels of hamstrings activity.   Conclusions The main findings of the study were that the EMG-rms feedback acutely increased the strength and voluntary activation of quadriceps during a maximal voluntary isokinetic knee extensor action. However, the study showed no reduction in hamstring activation when feedback was given during the knee extensor actions. Therefore, the increased strength output was likely related to the enhanced activation of quadriceps and not a result of decreased hamstrings activation.

Spina bifida myelomeningocele (SBM) is the most common and severe type of spina bifida which is a neural tube defect (NTD). Additionally to the defect of the spinal cord most cases of SBM develop an Arnold-Chiari-II malformation, which is the main reason behind the common development of hydrocephalus. Children with SBM have a rather different cognitive profile than typically developing children. Hence, this thesis reviews the neurological impact on the cognitive profile and its relation to the social impairments found for this population. The Arnold-Chiari-II malformation is a malformation of the hindbrain which affects structures of the hindbrain, midbrain, ventricular system and subcortical gray matter. These deficits lead to impairments in the cognitive domains of executive functioning, visual-spatial working memory, intelligence, language, and learning. The consequences of these cognitive deficits are often on the social aspects of life. Two aspects affected are education and work, projecting in less academic success and a higher rate of unemployment. By clarifying the relationship between all of these aspects there is hope to improve the life of these individuals, especially on an educational basis.

Cell-penetrating peptides (CPPs) have for a little bit more than a decade been employed as delivery vectors for a wide range of cargoes, ranging from gold particles to entire plasmids. Although CPP are well studied and utilized in numerous publications, our knowledge about CPP mediated transport is still poor. The articles presented in this thesis all consider different aspects of CPP mediated delivery. The first two papers are evaluating and improving already known techniques. In paper I, standard polyethyleneimine (PEI) transfection is improved by conjugating the CPP TP10 to the cationic polymer. In paper II, the same CPP is employed to deliver a dsDNA decoy oligo, resulting in decreased activity of the transcription factor c-Myc. The third paper is a more general overview of the delivery efficiency of well known CPPs and how the delivered cargo influences the CPP mediated toxicity. The study shows that different CPPs are suitable for different cargos and that toxic side effects depend heavily on the cargo and coupling strategy used. In Paper IV, a novel CPP, M918, is evaluated as a delivery vector for a transposon based non-viral gene therapy system. M918 display simultaneous delivery of a plasmid carrying a selection gene and a transposase into cultured cells. This is the first study where two so vastly different molecules as a cationic protein and an anionic plasmid, are simultaneously transported into cells by a peptide vector. The method might be a first step towards a safe peptide based non-viral gene therapy platform. Taken together, the results presented in this thesis might help to improve already existing techniques, increase our understandings about CPP mediated delivery and, at the same time, develop new CPP based delivery systems.

In neuroscience, zebrafish can be used as a model organism to study cognitive deficits and human physiology. Previous methods to study behavior in animal models have relied on manual observations, which can lack repeatability, until recently when automatic operant boxes have been developed. Due to the automated testing, automatic operant boxes are a robust method with high throughput and minimal handling which reduce stress in the animal. The aim of this study was to establish and optimize a method and a protocol for studying reversal learning in Zantiks AD units (an automatic operant box). The Zantiks AD unit was controlled by predefined scripts and the purpose of the script was supposed to make the fish associate a visual stimulus with a positive reinforcement, in this study, dry food. Three pilot studies were made, each with one parameter in focus (habituation days, intertrial time and motivation) to see if there was any impact on learning, between two groups. Neither the habituation days (pilot 1) nor the intertrial time (pilot 2) seemed to have a pronounced effect but the impact of motivation (pilot 3) did. The impact of motivation needs to be analyzed further, where different types of food could be compared.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is characterized by formation of amyloid plaques in the brain. The major constituent of these plaques is the hydrophobic peptide Aβ. Aβ accumulation is considered to be the main cause of the pathology seen in AD brains. Aβ is produced through sequential cleavage of the amyloid precursor protein (APP). APP can be processed by two different enzymatic pathways. Formation of Aβ requires cleavage of APP by β- and γ-secretase. However, most proteolytic processing of APP does not result in Aβ formation. Instead, APP is mainly cleaved by α-secretase, which not only precludes formation of the toxic Aβ peptide but also generates the neuroprotective sAPPα fragment. Increasing the α-secretase processing of APP is thereby a potential therapeutic strategy for AD. APP is a member of a conserved gene family, also including the APP-like proteins-1 and -2 (APLP1 and APLP2). The APP family members have essential and overlapping functions and have been reported to be processed in a similar way by the same enzymes. The processing of all APP family members is increased in response to several stimuli, including retinoic acid (RA) and insulin-like growth factor-1 (IGF-1), which also induce a shift towards α-secretase processing. The aim of this thesis was to investigate the mechanisms and signaling involved in induced α-secretase processing of the APP family. The main α-secretase candidates are ADAM10 and TACE. In this thesis we wanted to study the effects on expression levels of ADAM10 and TACE during RA treatment. We also wanted to investigate the mechanism behind IGF-1-induced processing of APP and APLP2. We found that both ADAM10 and TACE are up-regulated in response to RA, but that the signaling pathways involved differed between the two enzymes. Similarly, we showed that IGF-1-induced processing of APLP2, but not of APP, is dependent on PKC. Furthermore, we showed that ADAM10 is the main α-secretase for APP, whereas TACE cleaves APLP2 in response to IGF-1. We conclude that although APP and APLP2 proteolytic processing are induced by the same stimuli, the processing is dependent on different signaling pathways and processing enzymes, which in turn are differentially regulated.