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Alpha-mannosidosis is a rare lysosomal storage disease caused by lysosomal α-mannosidase deficiency. In human patients the disease is characterized by an array of physical and physiological symptoms as well as psychiatric disease. This master thesis will focus on the psychiatric symptoms. Patients may show recurrent episodes of confusion and psychosis, delusions, auditory and visual hallucinations, anxiety and depression. In addition, these symptoms are often preceded by a physical or psychological stressor. A mouse model of alpha-mannosidosis was created that mimicked the human features of the milder form of this disease. However, psychopathological behaviour alterations in this mouse model have not been described elaborately yet, nor has the influence of environmental stress been assessed in this mouse model of alpha-mannosidosis. Therefore, the goal of this master thesis is to make up a psychopathological behaviour profile of alpha-mannosidosis mice and assess its relationship to environmental stress. In addition, as the efficacy of enzyme replacement therapy for the correction of storage in alpha-mannosidosis has been proved in several animal studies of alpha-mannosidosis mice, a second objective is to assess the effects of enzyme replacement therapy on psychopathological behaviour in these alpha-mannosidosis mice. Two groups of alpha-mannosidase knock-out mice and control mice were used. The first group comprised an experimental group of 17 4-to-5-month-old alpha-mannosidosis mice and a control group of 17 age-matched control mice. Before these mice were assessed in a behavioural test battery, a genotype mixed group of 17 out of these 34 mice underwent a stress conditioning procedure in order to elicit chronic stress. Then, all mice were assessed in a comprehensive behavioural test battery comprised of seven behavioural paradigms, including depression, anxiety, explorative behaviour, sensorimotor gating, social exploration and working memory tests. Prepulse inhibition test was used to assess sensorimotor gating deficiency. Amphetamine provocation test investigated reaction to a psychostimulant. Open field considered exploratory behaviour and elevated plus maze assessed anxiety-related behaviour. Sucrose preference test and tail suspension test were employed to assess depression-related behaviour. Lastly, sociability/preference for social novelty (SPSN) test was used to assess autism-related behaviour in mice. Afterwards, 17 non-stressed mice were used for further testing, namely assessment of short-term enzyme replacement therapy via open field test, SPSN test and amphetamine provocation test. Moreover, another group of 32 alpha-mannosidosis mice and control mice were tested for the assessment of long-term enzyme replacement therapy via open field test and amphetamine provocation test. Test results were analysed using analysis of variance and Student's t-tests. Behaviour resembling the psychiatric symptoms in human patients was not found in present study. Gene x environmental stress interaction could not be confirmed, except in amphetamine provocation test, and enzyme replacement therapy did not reveal behavioural changes in alpha-mannosidosis mice either. Differences in symptoms between alpha-mannosidosis mice and human patients might be due to the younger age of mice. In addition, stress conditioning procedure might not have succeeded.

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Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties in social interaction and communication, and restricted interests and repetitive behaviors. Considering the increasing prevalence and high clinical, social and financial burden of ASD on society, there is a strong need for effective treatments. To date, therapeutic interventions mainly comprise behavioral social skills trainings, for which evidence is mixed. In addition, the only approved pharmacological therapies do not target the core characteristics of ASD. However, during the past 15 years, the neuropeptide oxytocin (OT) has gained increasing interest as a potential therapeutic approach for improving the core social impairments characteristic of ASD. OT is a neuropeptide with a dual function. As a hormone, OT is released into the bloodstream where it is known to affect bodily functions such as lactation and uterine contractions. Within the brain, OT acts as an important neuromodulator for modulating complex social behaviors such as interpersonal bonding, reciprocity and face processing, and the ability to establish trust and social attachment. The current doctoral project aimed to gain insight into the behavioral and neural effects of single-dose and multiple-dose administration of OT both in the neurotypical population and in individuals with ASD. Before initiating the clinical trial designed to assess the behavioral and neural effects of single-dose and multiple-dose intranasal OT administration in adult men with ASD (that forms the core of the current doctoral project), we first tested (parts of) the study procedure and outcome measures in a sample of typically developing adult men. In a first study, we assessed the immediate effects of single-dose OT treatment (compared to placebo (PL)) on emotion recognition from point-light biological motion and found that a single dose of intranasal OT had a significant, medium-sized effect on emotion recognition from point-light biological motion regardless of the emotional valence of the presented stimuli. Albeit moderate, these findings of OT-induced improvements in emotion recognition provided further support for a link between OT and the processing of social information. A complementary line of research has also highlighted the beneficial effects of intranasal OT administration on feelings of attachment, yet evidence on the effects of multiple-dose OT treatment in typically developing individuals was limited. Accordingly, in a subsequent study, we assessed the effects of two weeks of daily OT administration (compared to PL) on measures of attachment feelings, social responsiveness, quality of life and mood. Participants reported significant reductions in attachment avoidance and increases in reports of attachment toward peers after two weeks of OT treatment. In addition, treatment-induced changes were most pronounced for participants with less secure attachment towards their peers, indicating that normal variance at baseline modulated treatment response. OT treatment also improved participant's reports of mood with respect to tension and (tentatively) anger. Further, at the end of the two-week trial, both treatment groups (OT, PL) reported increased social responsiveness and quality of life, indicating that these effects were not treatment-specific. Again, the reported improvements in feelings of attachment after the multiple-dose treatment with OT provided further evidence in support of a pivotal role of OT in promoting social behavior and, in particular, the experience of attachment. After finding these beneficial effects of both single-dose and multiple-dose OT administration in typically developing adult men, we adopted the aforementioned outcome measures in a clinical trial with adult men with ASD. We investigated the immediate and long-term effects of multiple-dose OT treatment on a behavioral and neural level. To assess the behavioral effects of multiple-dose OT treatment, autism characteristics (social responsiveness, and restricted and repetitive behaviors (RRBs)), feelings of attachment and quality of life were assessed up to one month and one year post-treatment. To assess the neural effects of multiple-dose OT treatment, we performed functional magnetic resonance imaging (fMRI) in order to study the changes in task-related brain activity of the posterior superior temporal sulcus (pSTS) and amygdala up to one month and one year post-treatment. To do so, we adopted a double-blind, randomized, placebo-controlled, parallel design (clinical trial) during which we tested participants (i) at baseline, (ii) after a single dose of OT, (iii) immediately after four weeks of continual OT treatment, and at two follow-up sessions, (iv) one month (four weeks) and (v) one year post-treatment. A key question was to evaluate whether any beneficial effects of continual OT treatment would outlast the period of actual administration until one month or even one year post-treatment. On a behavioral level, results revealed that the four-week, multiple-dose OT treatment did not improve social responsiveness, but did induce medium- to large-sized improvements in RRBs, reduced feelings of avoidance towards others and increased feelings of vigor, which outlasted the period of actual administration until one month and even one year post-treatment. On a neural level, results revealed that the four-week, multiple-dose treatment attenuated activity in bilateral amygdala and induced sustained higher levels of task-related activity within (right) pSTS. Anew, these treatment-induced neural changes were shown to outlast the intervention until one month and even one year post-treatment, indicating that continual OT treatment induced long-lasting neural changes in core regions of the social brain circuit. Importantly, we also showed that the extent of amygdala attenuation was associated with the extent of (long-term) improvements in self-reports of social functioning (social responsiveness). This dissertation provides evidence that intranasal administration of OT, albeit in single-dose or multiple-dose form, is effective for inducing behavioral and neural changes in typically developing adult men and adult men with ASD. In particular, for the first time, we show that these changes outlast the administration period until one year post-treatment. These findings provide first indications for the anxiolytic role and social salience boosting effect of OT in adult men with ASD. However, in order to generalize these findings, more research replicating these findings in larger and more diverse samples is necessary.

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Populaire samenvatting Autisme spectrum stoornissen (ASS), worden gedefinieerd als pervasieve ontwikkelingsstoornissen die gekenmerkt worden door afwijkingen in het sociale gedrag, beperkte interesse en repetitief gedrag. De symptomen zijn reeds merkbaar op jonge leeftijd en kunnen tot uiting komen door verminderd oogcontact, atypische reacties tijdens een conversatie of – op andermans emoties en moeilijkheden bij het opbouwen en onderhouden van sociale relaties. Niettegenstaande de hoge globale prevalentie (1-2%) van de aandoening en de impact die deze aandoening heeft op het alledaags functioneren, is er tot op de dag van vandaag nog steeds geen farmaceutische interventie gevonden die gericht is op het behandelen van de kernsymptomen van ASS. In de zoektocht naar een potentiele farmaceutische behandeling voor ASS is er sinds het laatste decennium echter toenemende interesse in het neuropeptide ‘oxytocine’ (OT). In het bijzonder zijn neuromodulerende kenmerken op het complexe menselijk sociaal gedrag en zijn rol als promotor van pro-sociale attitudes hebben hiertoe bijgedragen. Om de werkelijke farmaceutische capaciteiten van OT op de kernsymptomen van ASS na te gaan, is er echter onderzoek nodig dat de effecten van langdurige OT toediening nauwgezet opvolgt. In deze studie werden daarom de onmiddellijke - en retentie (na stopzetting van de therapie) effecten, op het gedrag (meer specifiek het herkennen van emoties uit lichaamstaal) van mensen met ASS, na meervoudige OT toediening nagegaan. De proefpersonen werden willekeurig, en zonder weten van de onderzoeker of de deelnemer zelf, toegewezen aan een oxytocine - of placebo groep. Vervolgens werd aan de proefpersonen gevraagd om aan de hand van een neusspray, gedurende vier opeenvolgende weken, elke ochtend de dagelijkse dosis van 24 internationale eenheden (6 puffs van de aan hen toegewezen neusspray) intra-nasaal toe te dienen. Op vijf afgesproken meetmomenten (baseline, na de eerste OT toediening, na vier weken van dagelijkse OT toediening, vier weken na stopzetting van de behandeling en ongeveer een jaar na stopzetting van de behandeling) werd daarna de experimentele taak ondergaan. Tijdens deze taak kregen de deelnemers video clips voorgeschoteld waarop een menselijk silhouet, aan de hand van witte stippen ter hoogte van de grote gewrichten op een zwarte achtergrond, werd afgebeeld. In de getoonde video clips werden door een acteur drie mogelijke acties uitgevoerd (stappen, springen, trappen) in twee mogelijke emotionele toestanden (blij, boos). Vervolgens was het doel van de taak dat de deelnemers aan gaven in welke emotionele toestand de actie in de videoclip werd uitgevoerd. Na analyse van de resultaten kunnen we besluiten dat op vlak van emotieherkenning uit lichaamstaal significante verbeteringen over tijd werden gedetecteerd in deze studie. Helaas werden deze gedetecteerde verbeteringen over tijd zowel terug gevonden in onze oxytocine - als placebo groep. Hieruit kunnen we vervolgens concluderen dat enig interventie-specifiek effect – indien aanwezig – gemaskeerd kan zijn door een meer algemeen leer effect.