Orientador: Maria Irma Hadler Coudry / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Estudos da Linguagem / Made available in DSpace on 2018-08-24T23:31:03Z (GMT). No. of bitstreams: 1 Silva_MichelliAlessandra_D.pdf: 3674772 bytes, checksum: 703b9250112516e655af328a4d05d3f1 (MD5) Previous issue date: 2014 / Resumo: Neste trabalho, apresento um conjunto de investigações sobre a linguagem na Síndrome do X-Frágil (abreviada como SXF). Descrevo como a SXF é caracterizada pela literatura médica, dando enfoque à maneira pela qual os portadores da síndrome são diagnosticados e como a sua entrada na linguagem (não) é considerada. Nota-se que os estudos realizados na área focalizam, sobretudo, as características clínicas dos portadores da síndrome, porém constata-se a falta de estudos mais aprofundados sobre seus desdobramentos no que diz respeito ao processo de aquisição e uso da fala, leitura e escrita; o que resulta, quase sempre, em uma concepção reduzida e equivocada de linguagem na qual são baseadas todas as condutas escolares e terapêuticas. Com base em Foucault (1994), Agamben (2009) e Bezerra (2013) analiso quais efeitos de poder/saber são produzidos por esse discurso e suas implicações. Tendo isso vista, acompanhei, de 2009 a 2012, o processo de aquisição e uso da fala, leitura e escrita de três sujeitos portadores da síndrome - PM, AS e RG - em sessões semanais individuais (1h de duração) e em grupo (2h de duração), no Centro de Convivência de Linguagens (CCazinho/IEL/UNICAMP). A metodologia adotada é de natureza heurística e tem por fundamento o conceito de dado-achado (COUDRY, 1996). Assumem-se, também, neste estudo, os pressupostos teóricos formulados pela Neurolinguística Discursiva (ND), em que são articulados a hipótese da historicidade e indeterminação da linguagem e os conceitos de trabalho e força criadora (FRANCHI, 1977). Benveniste (1972) e Jakobson (1972; 1975) são autores-âncora em relação aos conceitos de (inter)subjetividade e dos níveis de funcionamento da linguagem. Luria (1981) e Freud (1891) são incorporados por sua aproximação no que diz respeito ao funcionamento dinâmico e integrado de cérebro/mente, em que a linguagem está representada em todo o cérebro e não localizada em suas partes/centros. Com este estudo, foi possível identificar algumas das dificuldades linguísticas apresentadas pelos portadores da SXF em relação à aquisição e uso da fala/escrita/leitura, bem como levantar como discussão o quanto essas dificuldades são da ordem do patológico e o quanto fazem parte do processo normal de aquisição e uso da fala/escrita/leitura, ou da exposição dos sujeitos à leitura/escrita durante suas vidas. Apresento algumas análises de dados desse processo contrapondo-os ao discurso médico. A relevância desta pesquisa, portanto, recai sobre a importância de estudos longitudinais para se observar e compreender esses processos para, então, neles intervir. Ressalta-se a importância de olhar o sujeito para além da patologia, focalizando sua relação com a linguagem em sua história de vida e sua relação com o mundo e o tempo em que vive; uma forma de enfrentar os dispositivos que determinam o que é e o que não é doença / Abstract: On This paper, I present investigations on language in the Fragile X Syndrome (FXS). Describing how this pathology is characterized by the medical field, especially when it comes to the way the patients are diagnosed and how their entry in the language is (not) considered. It is noticed that the studies conducted by this field are most focused on the clinical characteristics of the patients, although lacking further studies on the process of speech, acquisition/use ¿ which results, almost always, in a reduced and misunderstood conception of language which all the therapeutic procedures are grounded. Based on Foucault (1994), Agamben (2009) and Bezerra (2013), It was analyzed the effects of power/knowledge produced by this discourse and its implications. Considering this, It was observed, from 2009 to 2012, the process of speech, reading and writing acquisition/use of three subjects with the syndrome - PM, AS and RG - in weekly individual sessions (1 hour) and group sessions (2 hours), at Social Center of Languages (CCazinho/IEL/UNICAMP). The methodology adopted is on heuristic nature and it is based on the concept of "dado-achado" (COUDRY, 1996). This study, also, assumes from the theoretical assumption made by the Discoursive Neurolinguistics (ND), where are articulated the historicity and indeterminacy of language and concepts of work and creative force (FRANCHI, 1977). Benveniste (1972) and Jakobson (1972, 1975) are references on the concepts of the (inter)subjectivity and levels of language operation. Luria (1981) and Freud (1891) are incorporated by their approach on respect to the dynamic performance and integrated brain/mind, as well as the assumption that language is represented in the whole brain and not located in parts/centers. Through this study, it was possible to identify some linguistic difficulties presented by patients with FXS in relation to the use and acquisition of speech/writing/reading, in order to discuss what may be pathological, what is part of a normal speech reading and writing acquisition/use and how may be related to other factors, or the exposure of the subjects to read/write during their lives. Finally some data analyses are presented to oppose the data presented by the deterministic medical discourse. The relevance of this research, therefore, is on the importance of longitudinal studies to observe and understand these processes, to then, act on them. It is emphasized the importance of looking beyond the subject¿s pathology , focusing on his relationship with language, his life history and his relation to the world and the time in which he lives, a way of confronting the apparatus that determine what is and what is not a disease / Doutorado / Linguistica / Doutora em Linguística

Le syndrome du X fragile (SXF) est la première cause héréditaire de déficience intellectuelle et également la première cause monogénique d’autisme. Le SXF est causé par l'expansion de la répétition du nucléotide CGG sur le gène FMR1, ce qui empêche l’expression de la protéine FMRP. L’absence du FMRP mène à une altération du développement structurel et fonctionnel de la synapse, ce qui empêche la maturation des synapses induite par l’activité et l’élagage synaptique, qui sont essentiels pour le développement cérébral et cognitif. Nous avons investigué les potentiels reliés aux événements (PRE) évoqués par des stimulations fondamentales auditives et visuelles dans douze adolescents et jeunes adultes (10-22) atteints du SXF, ainsi que des participants contrôles appariés en âge chronologique et développemental. Les résultats indiquent un profil des PRE altéré, notamment l’augmentation de l’amplitude de N1 auditive, par rapport aux deux groupes contrôle, ainsi que l’augmentation des amplitudes de P2 et N2 auditifs et de la latence de N2 auditif. Chez les patients SXF, le traitement sensoriel semble être davantage perturbé qu’immature. En outre, la modalité auditive semble être plus perturbée que la modalité visuelle. En combinaison avec des résultats anatomique du cerveau, des mécanismes biochimiques et du comportement, nos résultats suggèrent une hyperexcitabilité du système nerveux dans le SXF. / We investigated early auditory and visual information processing in Fragile X Syndrome (FXS), the most common form of X-linked Intellectual Disability (ID) and the only known monogenetic cause of autism. FXS is caused by a trinucleotide repeat expansion in the FMR1 (‘Fragile X mental retardation 1’) gene, which prevents expression of the ‘fragile X mental retardation protein’ (FMRP). FMRP absence leads to altered structural and functional development of the synapse, while also preventing activity-based synapse maturation and synaptic pruning, which are essential for cerebral and cognitive development. We review the contribution of electrophysiological signal studies for the understanding of information processing in FXS and compare event-related potential (ERP) findings to those concerning other clinical populations that share symptoms with FXS. In our research project, we investigated ERPs evoked by basic auditory and visual stimulation in twelve adolescents and young adults (10-22) with FXS, as well as healthy chronological- and developmental- age matched controls. We found an altered ERP profile in FXS, including increased auditory N1 amplitude, relative to both control groups, as well as increased auditory P2 and N2 amplitudes and increased auditory N2 latencies. Rather than being immature, sensory processing appears to be specifically disrupted in FXS. Furthermore, the auditory modality seems to be more affected than the visual modality. In combination with brain anatomical, biochemical and behavioural findings, our results suggest a hyperexcitable nervous system in FXS.

Le syndrome du X fragile (SXF) est la première cause héréditaire de déficience intellectuelle et également la première cause monogénique d’autisme. Le SXF est causé par l'expansion de la répétition du nucléotide CGG sur le gène FMR1, ce qui empêche l’expression de la protéine FMRP. L’absence du FMRP mène à une altération du développement structurel et fonctionnel de la synapse, ce qui empêche la maturation des synapses induite par l’activité et l’élagage synaptique, qui sont essentiels pour le développement cérébral et cognitif. Nous avons investigué les potentiels reliés aux événements (PRE) évoqués par des stimulations fondamentales auditives et visuelles dans douze adolescents et jeunes adultes (10-22) atteints du SXF, ainsi que des participants contrôles appariés en âge chronologique et développemental. Les résultats indiquent un profil des PRE altéré, notamment l’augmentation de l’amplitude de N1 auditive, par rapport aux deux groupes contrôle, ainsi que l’augmentation des amplitudes de P2 et N2 auditifs et de la latence de N2 auditif. Chez les patients SXF, le traitement sensoriel semble être davantage perturbé qu’immature. En outre, la modalité auditive semble être plus perturbée que la modalité visuelle. En combinaison avec des résultats anatomique du cerveau, des mécanismes biochimiques et du comportement, nos résultats suggèrent une hyperexcitabilité du système nerveux dans le SXF. / We investigated early auditory and visual information processing in Fragile X Syndrome (FXS), the most common form of X-linked Intellectual Disability (ID) and the only known monogenetic cause of autism. FXS is caused by a trinucleotide repeat expansion in the FMR1 (‘Fragile X mental retardation 1’) gene, which prevents expression of the ‘fragile X mental retardation protein’ (FMRP). FMRP absence leads to altered structural and functional development of the synapse, while also preventing activity-based synapse maturation and synaptic pruning, which are essential for cerebral and cognitive development. We review the contribution of electrophysiological signal studies for the understanding of information processing in FXS and compare event-related potential (ERP) findings to those concerning other clinical populations that share symptoms with FXS. In our research project, we investigated ERPs evoked by basic auditory and visual stimulation in twelve adolescents and young adults (10-22) with FXS, as well as healthy chronological- and developmental- age matched controls. We found an altered ERP profile in FXS, including increased auditory N1 amplitude, relative to both control groups, as well as increased auditory P2 and N2 amplitudes and increased auditory N2 latencies. Rather than being immature, sensory processing appears to be specifically disrupted in FXS. Furthermore, the auditory modality seems to be more affected than the visual modality. In combination with brain anatomical, biochemical and behavioural findings, our results suggest a hyperexcitable nervous system in FXS.

La trisomie 21 (T21), le Syndrome X Fragile (SXF), la Sclérose tubéreuse de Bourneville (STB) et les mutations SYNGAP1 sont causés par des dysfonctionnements des voies moléculaires qui entraînent notamment un déséquilibre dans l’excitation et l’inhibition de l’activité neuronale qui aurait des impacts sur le développement et le fonctionnement du cerveau. Toutefois, il est difficile de faire le pont entre les déséquilibres moléculaires observés dans les modèles animaux et les particularités structurelles, fonctionnelles et cognitives observées dans ces syndromes chez l’humain. À notre connaissance, peu d’études ont comparé différents syndromes génétiques sur les processus sensoriels, l’apprentissage de base ou encore leurs caractéristiques comportementales en utilisant des paradigmes similaires et translationnels, permettant de mieux comprendre leurs particularités. Le premier volet de cette thèse vise à identifier si l’activité électroencéphalographique serait un biomarqueur adéquat représentant les altérations neurobiologiques tant des processus sensoriels que d’apprentissage chez les humains présentant ces syndromes. L’étude #1 avait comme objectif de décrire le traitement sensoriel auditif, comme il s’agit d’un processus élémentaire, et ce, chez les mutations SYNGAP1 qui représentent une condition génétique encore peu étudiée chez l’humain. Les résultats ont d’ailleurs permis d’identifier une diminution de la synchronisation de phase et une augmentation de la puissance dans la bande gamma qui distinguent cette condition génétique tant des participants sans DI que de la T21. Toujours dans l’esprit d’identifier des biomarqueurs électroencéphalographiques, mais cette fois au niveau d’un processus cognitif de base, l’étude #2 avait pour objectif de comparer tous ces syndromes dans un paradigme de suppression neuronale (SN) afin de vérifier la présence de SN et de comparer l’apprentissage de base chez ces populations. Les résultats ont identifiés que la T21 et le SXF présentaient tous les deux un patron de SN et que le SXF présentait relativement une plus forte habituation indiquant des particularités spécifiques selon les syndromes. Le deuxième volet, davantage clinique, permet de comparer les profils comportementaux associés au fonctionnement adaptatif entre les syndromes et à décrire les pistes d’intervention existantes. L’étude #3 a notamment mis en évidence que le QI et les symptômes de TDAH sont associés au fonctionnement adaptatif auprès de ces différents syndromes dont le SXF et la STB. Cet article a aussi permis de décrire les profils comportementaux de ces mêmes conditions en révélant davantage de difficultés rapportées chez les individus présentant un SXF, alors que la T21 présentait moins de particularités cliniques au niveau comportemental. Enfin, l’article #4 a mis en lumière diverses interventions utilisées auprès de la population présentant une DI notamment des stratégies cognitivo-comportementales et compensatoires. Cette thèse permet donc de dresser un portrait spécifique de ces syndromes génétiques concernant leur signature électrophysiologique lors du traitement sensoriel et de l’apprentissage ainsi que sur le plan des comorbidités comportementales et de leur relation avec le fonctionnement adaptatif, pour ensuite aborder les interventions actuelles en DI. Les diverses particularités identifiées à plusieurs niveaux ont permis de générer des suggestions pouvant guider certaines interventions futures. / Down syndrome (DS), Fragile X syndrome (FXS), Tuberous sclerosis complex (TSC) and SYNGAP1 mutations are caused by dysfunctions of the molecular pathways which lead among others to an imbalance in excitation and inhibition of the neuronal activity that would impact the brain development and its functioning. However, it is difficult to directly bridge the gap between the molecular imbalances observed in animal models with the structural, functional and cognitive characteristics observed in human with these syndromes. To our knowledge, few studies have compared those different genetic syndromes on sensory processing, basic learning or on their behavioural issues using similar and translational paradigms then allowing a better understanding of their specificities. The first part of this thesis aims to identify whether electroencephalographic activity would be an adequate biomarker representing neurobiological alterations both in sensory processing and learning in humans with these syndromes. The goal of study #1 was to describe auditory sensory processing, as a very first basic process, in SYNGAP1 mutations being a genetic condition still little studied in humans. Results showed a decrease in phase synchronization and an increase in the power of gamma band which distinguish this genetic condition both from participants without ID and from DS. Still in order to identify electroencephalographic biomarkers, but this time at a basic cognitive level, study #2 aimed to compare all these syndromes in a repetition suppression (RS) paradigm in order to observe the presence of RS and compare basic learning in these populations. The results identified a RS pattern in both DS and FXS. FXS also exhibited relatively higher habituation then indicating specific features according to the syndrome. The second part, addressing clinical aspects, permits to compare the behavioural profiles associated with adaptive functioning between syndromes and to describe existing interventions on ID population. Study #3 notably highlighted that IQ and ADHD symptoms are associated with adaptive functioning especially in FXS and TSC. This article also made it possible to describe the behavioural profiles of these syndromes, revealing more difficulties reported in individuals with FXS, while DS presented fewer behavioural issues. Finally, article #4 highlighted various interventions used with ID population, notably cognitive-behavioural and compensatory strategies. This thesis therefore makes it possible to gain a better understanding of these genetic syndromes concerning their electrophysiological signature during sensory processing and learning as well as in terms of behavioural comorbidities and their relationship with adaptive functioning, to then address current ID interventions. These different syndromic particularities identified at several levels made it possible to generate suggestions that could guide future interventions in this field.