Neurochemical regulation of auditory information processing studied with EEG/MEG: application to schizophrenia

Cognitive impairments of attention, memory and executive functions are a fundamental feature of the pathophysiology of schizophrenia. The neurophysiological and neurochemical changes in the auditory cortex are shown to underlie cognitive impairmentsin schizophrenia patients. Functional state of the neural substrate of auditory information processing could be objectively and non-invasively probed with auditory event-related potentials (ERPs) and event- related fields (ERFs). In the current work, we explored the neurochemical effect on the neural origins of auditory information processing in relation to schizophrenia. By means of ERPs/ERFs we aimed to determine how neural substrates of auditory information processing are modulated by antipsychotic medication in schizophrenia spectrum patients (Studies I, II) and by neuropharmacological challenges in healthy human subjects (Studies III, IV). First, with auditory ERPs we investigated the effects of olanzapine (Study I) and risperidone (Study II) in a group of patients with schizophrenia spectrum disorders. After 2 and 4 weeks of treatment, olanzapine has no significant effects on mismatch negativity(MMN) and P300, which, as it has been suggested, respectively reflect preattentive and attention-dependent information processing. After 2 weeks of treatment, risperidone has no significant effect on P300, however risperidone reduces P200 amplitude. This latter effect of risperidone on neural resources responsible for P200 generation could be partly explained through the action of dopamine. Subsequently, we used simultaneous EEG/MEG to investigate the effects of memantine (Study III) and methylphenidate (Study IV) in healthy subjects. We found that memantine modulates MMN response without changing other ERP components. This could be interpreted as being due to the possible influence of memantine through the NMDA receptors on auditory change- detection mechanism, with processing of auditory stimuli remaining otherwise unchanged. Further, we found that methylphenidate does not modulate the MMN response. This finding could indicate no association between catecholaminergic activities and electrophysiological measures of preattentive auditory discrimination processes reflected in the MMN. However, methylphenidate decreases the P200 amplitudes. This could be interpreted as a modulation of auditory information processing reflected in P200 by dopaminergic and noradrenergic systems. Taken together, our set of studies indicates a complex pattern of neurochemical influences produced by the antipsychotic drugs in the neural substrate of auditory information processing in patients with schizophrenia spectrum disorders and by the pharmacological challenges in healthy subjects studied with ERPs and ERFs.

Lionhearts of the Playworld : An ethnographic case study of the development of agency in play pedagogy

This is an ethnographic case study of the creation and emergence of a playworld – a pedagogical approach aimed at promoting children’s development and learning in early education settings through the use of play and drama. The data was collected in a Finnish experimental mixed-age elementary school classroom in the school year 2003-2004. In the playworld students and teachers explore different social and cultural phenomena through taking on the roles of characters from a story or a piece of literature and acting inside the frames of an improvised plot. The thesis takes under scrutiny the notion of agency in education. It produces theoretically grounded empirical knowledge of the ways in which children struggle to become recognized and agentive actors in early education settings and how their agency develops in their interaction with adults. The study builds on the activity theoretical and sociocultural tradition and develops a methodological framework called video-based narrative interaction analysis for studying student agency as developing over time but manifesting through the situational material and discursive local interactions. The research questions are: 1. What are the children’s ways of enacting their agency in the playworld? 2. How do the children’s agentive actions change and develop over the spring? 3. What are the potentials and challenges of the playworld for promoting student agency? 4. How do the teachers and the children deal with the contradiction between control and agency in the playworld? The study consists of a summary part and four empirical articles which each have a particular viewpoint. Articles I and II deal with individual students’ paths to agency. In Article I the focus is on the role of resistance and questioning in enabling important spaces for agency. Article II takes a critical gender perspective and analyzes how two girls struggled towards recognition in the playworld. It also illuminates the role of imagination in developing a sense of agency. Article III examines how the open-ended and improvisational nature of the playworld interaction provided experiences and a sense of ‘shared agency’ for the students and teachers in the class. Article IV turns the focus on the teachers and analyzes how their role actions in the playworld helped the children to enact agency. It also discusses the challenges that the teachers faced in this work and asks what makes the playworld activity sustainable in the class. The summary part provides a critical literature review on the concept of agency and argues that the inherently contradictory nature of the phenomenon of agency has not been sufficiently theorized. The summary part also locates the playworld intervention in a historical frame by discussing the changing conceptions of adulthood and childhood in the West. By focusing on the changing role of play and art in both adults’ and children’s contemporary lives, the thesis opens up an important but often neglected perspective on the problem of promoting student agency in education. The results illustrate how engaging in a collectively imagined and dramatized pretend play space together with the children enabled the teachers to momentarily put aside their “knower” positions in the classroom. The fictive roles and the narrative plot helped them to create a necessary incompleteness and open-endedness in the activity that stimulated the children’s initiatives. This meant that the children too could momentarily step out of their traditional classroom positions as pupils and initiate action to further the collective play. Engaging in this kind of unconventional activity and taking up and enacting agency was, however, very challenging for the participating children and teachers. It often contradicted the need to sustain control and order in the classroom. The study concludes that play- and drama-based pedagogies offer a unique but undeveloped potential for developing educational spaces that help teachers and children deal with the often contradictory requirements of schooling.

Yliopistokoulutuksen avoimuus ja refleksiivisyys : Suomalaisen yliopistoaikuiskoulutuksen rakenteistumisen analyysia

Openness and reflexivity of university education in the analysis of structuration of Finnish university adult education This research has been organised on three levels around a specific theoretical theme of the reflexivity of schooling. The argument developed has the same layered structure. At the first level, within the theoretical disposition of structuration, I develop methodological solutions, which allow the theme of reflexivity to be taken into account in the research concerning the organisational change of schooling. The conceptual work has been carried out in the research setting “morphogenesis vs. structuration”, which was initially formulated by Margaret Archer. Following this setting, structuration is taken to be a concern of the theoretical thinking of both Anthony Giddens and Pierre Bourdieu. The essential results achieved at this research level are presented as developing a synthesis of the theoretical thinking of Giddens and Bourdieu. I am arguing in favour of meta theoretical possibility and the empirical fertility of such a synthesis. The latter is especially the case, when the aim is to grasp the cultural dynamics in the processes of organising schooling. At the second level of empirical-historical theorising about schooling I confine the treatment of the theme of reflexivity to the topic of the openness of university education. While operating through the level of substantive theorising of schooling, I am constructing a cross disciplinary point of view on the phenomenon of openness and its empirical research. This is done in such manner that demonstrates how the structuration approach, understood as synthesising the meta theory of Giddens and Bourdieu, can take into account the theme of the reflexivity of schooling. In the actual empirical part of the study, the third level, I explore the genesis of the Finnish open university. This leads to narrowing down the topic of openness and to focussing on how adult education is organised. The analysis of structuration is supported by the ideal type -like notion of university adult education, since this allows the comparative and historical research strategy required for the task. I argue the importance of such a notion at the level of substantive theorising of schooling. The results of my historical analysis are presented through three articles and a commentary chapter.

Language in Acquisition : Early Lexical Development and Associations between Lexicon and Grammar Findings from Full-Term and Very-Low-Birth-Weight Finnish Children

The aim was to analyse the growth and compositional development of the receptive and expressive lexicons between the ages 0,9 and 2;0 in the full-term (FT) and the very-low-birth-weight (VLBW) children who are acquiring Finnish. The associations between the expressive lexicon and grammar at 1;6 and 2;0 in the FT children were also studied. In addition, the language skills of the VLBW children at 2;0 were analysed, as well as the predictive value of early lexicon to the later language performance. Four groups took part in the studies: the longitudinal (N = 35) and cross-sectional (N = 146) samples of the FT children, and the longitudinal (N = 32) and cross-sectional (N = 66) samples of VLBW children. The data was gathered by applying of the structured parental rating method (the Finnish version of the Communicative Development Inventory), through analysis of the children´s spontaneous speech and by administering a a formal test (Reynell Developmental Language Scales). The FT children acquired their receptive lexicons earlier, at a faster rate and with larger individual variation than their expressive lexicons. The acquisition rate of the expressive lexicon increased from slow to faster in most children (91%). Highly parallel developmental paths for lexical semantic categories were detected in the receptive and expressive lexicons of the Finnish children when they were analysed in relation to the growth of the lexicon size, as described in the literature for children acquiring other languages. The emergence of grammar was closely associated with expressive lexical growth. The VLBW children acquired their receptive lexicons at a slower rate and had weaker language skills at 2;0 than the full-term children. The compositional development of both lexicons happened at a slower rate in the VLBW children when compared to the FT controls. However, when the compositional development was analysed in relation to the growth of lexicon size, this development occurred qualitatively in a nearly parallel manner in the VLBW children as in the FT children. Early receptive and expressive lexicon sizes were significantly associated with later language skills in both groups. The effect of the background variables (gender, length of the mother s basic education, birth weight) on the language development in the FT and the VLBW children differed. The results provide new information of early language acquisition by the Finnish FT and VLBW children. The results support the view that the early acquisition of the semantic lexical categories is related to lexicon growth. The current findings also propose that the early grammatical acquisition is closely related to the growth of expressive vocabulary size. The language development of the VLBW children should be followed in clinical work.

Kadonneet pojat : Monitapaustutkimus ESY-poikien kompleksisesta koulu-urasta ja elämänkulusta

Lost boys. A multiple case study of the complex school career and life-course of male students who have attended special classes for the emotionally and behaviourally maladjusted The purpose of this thesis is to describe the school career and the life-course of eight former special-class students from the comprehensive school to their further education and into adulthood. The members of the target group have been students of special classes for pupils with emotional and behavioural difficulties in southern Finland. The interviews were made 1994-1997 at school and for follow-up interviews 2002-2003, when the participants were already adults. Six mothers were also interviewed. The qualitative data was gathered using individual interviews and Adult Attachment Interview. The aim was to explore the life-histories of subjects from early childhood to early adulthood. Information was gathered also from the documents concerning the students´ school attendance. Every single life-history is illustrated as a life-course graphic. The data has been analysed using different frames of reference and combining different theories. In addition to theories considering developmental risk factors and protective factors, the data is considered using theories of control over life, attribution, self-efficacy and identity and attitudes towards education. The experiential living mode of the students has been studied, as well. The results of this study show that the frames of references which are used complement each other. The target students clustered identically in spite of the frames of reference. As a result, the study has illustrated the same phenomenon from different points of view. The results of the study consist of three types of school careers: The winding career, the vicious circle career and the straight career. The three careers differ from each other in developmental risk and protective factors and post-school life-courses of the students. The type of childhood families and especially the fathers´ attention to the school education as well as the free time of their sons was important. Keywords: Pupils with emotional and behavioural difficulties, maladjustment to school, life-course, identity

Vammaisen lapsen äidin vanhemmuuden kokemus sekä lähiympäristön ja kasvatuskumppanuuden merkitys

The parenthood experience of a mother with a disabled child and the meaning of the social environment and parent-professional partnerships The importance of parental guidance when a family has a child with a disability or autism has been pointed out by several studies. The present research was based on the premise that by supporting the mother we can help the whole family to cope better and the professionals in day care or at school are able to support parents. The starting point was the subjective experience, which is also the central focus of the phenomenological method. The purpose of this study was firstly to describe the experience of the mother and the dialogue between mother and educational professionals. Secondly it was the task of this research to discover what kind of support and information the mother obtains from her social environment. At the background of this study there was the ecological theory of Bronfenbrenner, the ecocultural approach by Gallimore and the interactive examination of family that take into consideration the whole environment and personal situation. The research data was collected by interviewing the mothers, the day care personnel and the teachers at school. In this research there were a total of 32 interviews and 24 informants: 10 mothers who have a child with a disability and/or autism, 8 professionals in day care and 6 teachers at school. This study was longitudinal because the same mothers were interviewed twice, first in 1998 and then after five years in 2003. It was thus possible to get information on whether their life situation had changed and the nature of those changes. The data of this study was analysed by the method of phenomenological psychology that was applied for this study. The findings indicated that all mothers had experienced many complicated emotional feelings such as: anger, mourning, fear and sadness as well as love and bonding. It can be said that several human feelings existed at the same time. Mothers experienced that the support of the social environment, for example, relatives, families in the same situation and persons taking care of the child had significant meaning for their coping. However the life situation among the mothers varied. Mostly mothers received valuable support for their parenthood and they have adopted a strong emotion for manage ring. Mothers with an autistic child were more stressed than mothers with a mentally retarded child. A few mothers had numerous problems with taking care of their child and they did not get enough help. Same mothers were very exhausted too and the situation was quite the same after five years, when their child was teenager. All mothers said that after starting school the support for the family had significally diminished. Mothers said that dialogue with teacher got on without problems, but there were meetings seldom, so it wasn´t possible to get enough support for their parenthood. Keywords: parenthood, motherhood, disability, early special education, family-centred.

Collaborative Design in a Virtual Learning Environment : Three Design Experiments in Textile Teacher Education

The aim of the study was to analyze and facilitate collaborative design in a virtual learning environment (VLE). Discussions of virtual design in design education have typically focused on technological or communication issues, not on pedagogical issues. Yet in order to facilitate collaborative design, it is also necessary to address the pedagogical issues related to the virtual design process. In this study, the progressive inquiry model of collaborative designing was used to give a structural level of facilitation to students working in the VLE. According to this model, all aspects of inquiry, such as creating the design context, constructing a design idea, evaluating the idea, and searching for new information, can be shared in a design community. The study consists of three design projects: 1) designing clothes for premature babies, 2) designing conference bags for an international conference, and 3) designing tactile books for visually impaired children. These design projects constituted a continuum of design experiments, each of which highlighted certain perspectives on collaborative designing. The design experiments were organized so that the participants worked in design teams, both face-to-face and virtually. The first design experiment focused on peer collaboration among textile teacher students in the VLE. The second design experiment took into consideration end-users needs by using a participatory design approach. The third design experiment intensified computer-supported collaboration between students and domain experts. The virtual learning environments, in these design experiments, were designed to support knowledge-building pedagogy and progressive inquiry learning. These environments enabled a detailed recording of all computer-mediated interactions and data related to virtual designing. The data analysis was based on qualitative content analysis of design statements in the VLE. This study indicated four crucial issues concerning collaborative design in the VLE in craft and design education. Firstly, using the collaborative design process in craft and design education gives rise to special challenges of building learning communities, creating appropriate design tasks for them, and providing tools for collaborative activities. Secondly, the progressive inquiry model of collaborative designing can be used as a scaffold support for design thinking and for reflection on the design process. Thirdly, participation and distributed expertise can be facilitated by considering the key stakeholders who are related to the design task or design context, and getting them to participate in virtual designing. Fourthly, in the collaborative design process, it is important that team members create and improve visual and technical ideas together, not just agree or disagree about proposed ideas. Therefore, viewing the VLE as a medium for collaborative construction of the design objects appears crucial in order to understand and facilitate the complex processes in collaborative designing.

Nuorten hyvinvointi, opiskelu ja opinto-ohjaus erityisen koulutustehtävän saaneessa lukiossa

This is a case-study of students well-being studying in Sibelius Upper Secondary School which has got a special educational task in dance and music. The first purpose of this study is to analyse the students well-being, motivation, studying satisfaction and try to find out what kind of problems the students meet when studying in Upper Secondary School. The second purpose of this study is to try find means in counselling to help students in their Upper Secondary School Studies. The data were gathered in three parts. The first questioning was based on Allardt s (1976; 1998) well-being theory. In this questioning (N = 187) the students described their satisfaction in having (material things), loving (social relationships) and being (free time). The second data was collected by interviews (N = 19). The third data is a follow-up questioning (N = 10) for graduated students. The whole data was analysed with qualitative methods. The gathered qualitative data were compared with the quantitative data gathered by the National Institute for Health and Welfare. Results of this study indicate that the students in this case-study are mainly satisfied with their well-being, social and material things in their studying environment including counselling and teaching. The research results show that some of the students are exhausted due too muchtime spent in studying. This was verified also in the quantitative data gathered by the National Institute for Health and Welfare. These students suffer for the lack of free time and rest. Students who are motivated and have reached the autonomous way of studying do better in their Upper Secondary School Studies than those who study in unautonomous way.A quite wide range of students tend to make individual studying programmes and spend four or more years in Upper Secondary School instead of the three year programme. The individual programme gives them more time for practicing their special skills in the field of the school s special educational task and to give themselves more time for studying the basic subjects of the Upper Secondary School. Some of the students who tend to take extra years in Upper Secondary School have difficulties in their studying skills and are unsure of their studying motivation. The competition among students in Upper Secondary School with the special educational task causes stress and exhaustion for some of the studied students. These students have difficulties with integrating themselves into the social environment. For the other students the school s social environment works as a motivator for their studies and increases their well-being in their studies. According to the results of the follow-up questioning in this study the students value most the network with the other students they made while studying at the Sibelius Upper Secondary School. According to this study the students would need more counselling in all stages of their Upper Secondary School Studies. The autonomous students do quite well in their studies despite of the small amount of given counselling. They would also need more counselling in planning their further studies after Upper Secondary School. The biggest challenges to student counselling in Sibelius Upper Secondary School are helping the students to find their individual ways of studying and helping them to learn the ways of autonomous studying skills. Keywords: Upper Secondary School with a special educational task, well-being, talent, Upper Secondary School, Young person in Upper Secondary School, motivation, counselling, studying

Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease

Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease Stem cells provide the self-renewing cell pool for developing or regenerating organs. The mechanisms underlying the decisions of a stem or progenitor cell to either self-renew and maintain multipotentiality or alternatively to differentiate are incompletely understood. In this thesis work, I have approached this question by investigating the role of the proto-oncogene Myc in the regulatory functions of neural progenitor cell (NPC) self-renewal, proliferation and differentiation. By using a retroviral transduction technique to create overexpression models in embryonic NPCs cultured as neurospheres, I show that activated levels of Myc increase NPC self-renewal. Furthermore, several mechanisms that regulate the activity of Myc were identified. Myc induced self-renewal is signalled through binding to the transcription factor Miz-1 as shown by the inhibited capacity of a Myc mutant (MycV394D), deficient in binding to Miz-1, to increase self-renewal in NPCs. Furthermore, overexpression of the newly identified proto-oncogene CIP2A recapitulates the effects of Myc overexpression in NPCs. Also the expression levels and in vivo expression patterns of Myc and CIP2A were linked together. CIP2A stabilizes Myc protein levels in several cancer types by inhibiting its degradation and our results suggest the same function for CIP2A in NPCs. Our results also support the conception of self-renewal and proliferation being two separately regulated cellular functions. Finally, I suggest that Myc regulates NPC self-renewal by influencing the way stem and progenitor cells react to the environmental cues that normally dictate the cellular identity of tissues containing self-renewing cells. Neurosphere cultures were also utilised in order to characterise functional defects in a human disease. Neural stem cell cultures obtained post-mortem from foetuses of lethal congenital contracture syndrome (LCCS) were used to reveal possible cell autonomous differentiation defects of patient NPCs. However, LCCS derived NPCs were able to differentiate normally in vitro although several transcriptional differences were identified by using microarray analysis. Proliferation rate of the patient NPCs was also increased as compared to NPCs of age-matched control foetuses.

Cathepsin D Deficiency - Molecular and Cellular Mechanisms of Neurodegeneration

Cathepsin D (CTSD) is a lysosomal protease, the deficiency of which is fatal and associated with neurodegeneration. CTSD knock-out mice, which die at the age of four weeks, show intestinal necrosis, loss of lymphoid cells and moderate pathological changes in the brain. An active-site mutation in the CTSD gene underlies a neurodegenerative disease in newborn sheep, characterized by brain atrophy without any changes to visceral tissues. The CTSD deficiences belong to the group of neuronal ceroid-lipofuscinoses (NCLs), severe neurodegenerative lysosomal storage disorders. The aim of this thesis was to examine the molecular and cellular mechanisms behind neurodegeneration in CTSD deficiency. We found the developmental expression pattern of CTSD to resemble that of synaptophysin and the increasing expression of CTSD to coincide with the active period of myelination in the rat brain, suggesting a role for CTSD in early rat brain development. An active-site mutation underlying the congenital ovine NCL not only affected enzymatic activity, but also changed the stability, processing and transport of the mutant protein, possibly contributing to the disease pathogenesis. We also provide CTSD deficiency as a first molecular explanation for human congenital NCL, a lysosomal storage disorder, characterized by neuronal loss and demyelination in the central nervous system. Finally, we show the first evidence for synaptic abnormalities and thalamocortical changes in CTSD-deficient mice at the molecular and ultrastructural levels. Keywords: cathepsin D, congenital, cortex, lysosomal storage disorder, lysosome, mutation, neurodegeneration, neuronal ceroid-lipofuscinosis, overexpression, synapse, thalamus

Cholesterol Disturbances in Inherited Neurodegenerative Diseases : Studies on Npc1, Ppt1 and Ctsd deficient mice

The central nervous system (CNS) is the most cholesterol-rich organ in the body. Cholesterol is essential to CNS functions such as synaptogenesis and formation of myelin. Significant differences exist in cholesterol metabolism between the CNS and the peripheral organs. However, the regulation of cholesterol metabolism in the CNS is poorly understood compared to our knowledge of the regulation of cholesterol homeostasis in organs reached by cholesterol-carrying lipoprotein particles in the circulation. Defects in CNS cholesterol homeostasis have been linked to a variety of neurodegenerative diseases, including common diseases with complex pathogenetic mechanisms such as Alzheimer s disease. In spite of intense effort, the mechanisms which link disturbed cholesterol homeostasis to these diseases remain elusive. We used three inherited recessive neurodegenerative disorders as models in the studies included in this thesis: Niemann-Pick type C (NPC), infantile neuronal ceroid lipofuscinosis and cathepsin D deficiency. Of these three, NPC has previously been linked to disturbed intracellular cholesterol metabolism. Elucidating the mechanisms with which disturbances of cholesterol homeostasis link to neurodegeneration in recessive inherited disorders with known genetic lesions should shed light on how cholesterol is handled in the healthy CNS and help to understand how these and more complex diseases develop. In the first study we analyzed the synthesis of sterols and the assembly and secretion of lipoprotein particles in Npc1 deficient primary astrocytes. We found that both wild type and Npc1 deficient astrocytes retain significant amounts of desmosterol and other cholesterol precursor sterols as membrane constituents. No difference was observed in the synthesis of sterols and the secretion of newly synthesized sterols between Npc1 wild type, heterozygote or knockout astrocytes. We found that the incorporation of newly synthesized sterols into secreted lipoprotein particles was not inhibited by Npc1 mutation, and the lipoprotein particles were similar to those excreted by wild type astrocytes in shape and size. The bulk of cholesterol was found to be secreted independently of secreted NPC2. These observations demonstrate the ability of Npc1 deficient astrocytes to handle de novo sterols, and highlight the unique sterol composition in the developing brain. Infantile neuronal ceroid lipofuscinosis is caused by the deficiency of a functional Ppt1 enzyme in the cells. In the second study, global gene expression studies of approximately 14000 mouse genes showed significant changes in the expression of 135 genes in Ppt1 deficient neurons compared to wild type. Several genes encoding for enzymes of the mevalonate pathway of cholesterol biosynthesis showed increased expression. As predicted by the expression data, sterol biosynthesis was found to be upregulated in the knockout neurons. These data link Ppt1 deficiency to disturbed cholesterol metabolism in CNS neurons. In the third study we investigated the effect of cathepsin D deficiency on the structure of myelin and lipid homeostasis in the brain. Our proteomics data, immunohistochemistry and western blotting data showed altered levels of the myelin protein components myelin basic protein, proteolipid protein and 2 , 3 -cyclic nucleotide 3 phosphodiesterase in the brains of cathepsin D deficient mice. Electron microscopy revealed altered myelin structure in cathepsin D deficient brains. Additionally, plasmalogen-derived alkenyl chains and 20- and 24-carbon saturated and monounsaturated fatty acids typical for glycosphingolipids were found to be significantly reduced, but polyunsaturated species were significantly increased in the knockout brains, pointing to a decrease in white matter. The levels of ApoE and ABCA1 proteins linked to cholesterol efflux in the CNS were found to be altered in the brains of cathepsin D deficient mice, along with an accumulation of cholesteryl esters and a decrease in triglycerols. Together these data demonstrate altered myelin architecture in cathepsin D deficient mice and link cathepsin D deficiency to aberrant cholesterol metabolism and trafficking. Basic research into rare monogenic diseases sheds light on the underlying biological processes which are perturbed in these conditions and contributes to our understanding of the physiological function of healthy cells. Eventually, understanding gained from the study of disease models may contribute towards establishing treatment for these disorders and further our understanding of the pathogenesis of other, more complex and common diseases.