La migration radiaire est un des processus clefs de la corticogenèse menant à l’établissement d’un cortex en six couches chez les mammifères. La compréhension de ce mécanisme complexe est nécessaire à une meilleure appréhension du développement cortical. Dans ce travail de thèse, j’ai étudié la migration des neurones pyramidaux du cortex sous deux angles distincts. La 1ère partie se place d’un point de vue développemental en appréciant comment le positionnement laminaire résultant d’une migration normale ou anormale affecte la maturation neuronale. La 2nde partie se concentre sur une pathologie migratoire, l’hétérotopie en bande sous-corticale, et les altérations cognitives parfois associées à cette malformation. Pour ces deux projets, la migration neuronale a été altérée chez le rat par knockdown (KD) in utero de la doublecortine (Dcx), un effecteur majeur de la migration. Les neurones positionnés anormalement présentent une orientation incorrecte, un arbre dendritique moins développé, une spinogenère réduite et une altération morpho-fonctionnelle de la synaptogenèse glutamatergique. De plus, notre étude a mis en évidence l’implication de Dcx dans la dendritogenèse et la régulation fine des synapses glutamatergiques in vivo. Enfin, nous avons utilisé les rats Dcx-KD comme modèle d’hétérotopie en bande afin d’étudier comment un déficit de migration neuronale impacte le fonctionnement du cortex. La caractérisation comportementale, réalisée à l’aide d’une large gamme de tests, n’a pas mis en évidence de déficits majeurs des capacités motrices, somatosensorielles ou cognitives chez ces animaux. / Radial migration is one of the key processes leading to the formation of a six-layered cortex in mammals. Understanding this mechanism is necessary to get a better grasp of cortical development. During my PhD, I studied neuronal migration of pyramidal neurons from two different points of views. The 1st part is related to fundamental biology and assesses how laminar misplacement resulting from migration failure influences neuronal maturation. The 2nd one focuses on pathology by investigating a migration disorder, subcortical band heterotopia, and associated cognitive deficits. For both projects, neuronal migration was impaired in rat through in utero knockdown (KD) of doublecortin (Dcx), a major effector of cortical migration. Misplaced neurons display an abnormal orientation, a simplified dendritic arbor, a decreased spinogenesis and morpho-functional alterations of glutamatergic synaptogenesis. Moreover, our study shows that Dcx plays a role in dendritogenesis, in shaping spine morphology and in fine-tuning glutamatergic synaptogenesis. Finally, we used Dcx-KD rats as an animal model of subcortical band heterotopia to assess how migration failure would impact cortical functions. The behavioral characterization carried out through a wide range of tests did not bring to light any major shortcoming regarding motor, somatosensory or cognitive abilities in these animals. Therefore, although Dcx-KD rats display a SBH and develop spontaneous seizures, it does not seem to recapitulate cognitive deficits found in patients.

Quantitative magnetic resonance imaging (MRI) was used to assess global and regional cerebral volumes in patients with a clinical diagnosis of subcortical vascular dementia (VD) and Alzheimer’s disease (AD). Whole brain volume, cerebrospinal fluid volume, volumes of the temporal, frontal and parietal lobes, the cerebellum and the amygdala-hippocampus complex were determined using a personal computer-based software. Seventeen patients with VD, 22 patients with AD and 13 healthy controls were included. Analysis of covariance using age as covariate demonstrated significant mean differences between controls and dementia groups with respect to all morphological parameters. However, apart from the volume of the cerebellum no significant volumetric differences were found between VD and AD. These results indicate that MRI-based volumetry allows differentiation between AD or VD from normal controls and that measurement of cerebellar volume may be of use to separate vascular and degenerative dementia. However, since the distribution of cerebral atrophy in both dementia groups is very similar, it is suggested that the atrophic changes are not specific to the underlying cause but rather reflect the selective vulnerability of neuronal structures. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21669号 / 医博第4475号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村井 俊哉, 教授 古川 壽亮, 教授 宮本 享 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

L'hétérotopie en bande sous-corticale (SBH) est une malformation caractérisée par la présence d'une bande de neurones ectopiques en regard du cortex normal ou normotopique. La plupart des patients ont une mutation d'un gène encodant une protéine indispensable à la migration des neurones. Les patients présentent une épilepsie pharmacorésistante. La chirurgie ne donne pas de résultats satisfaisants, le foyer épileptogène n'étant jamais clairement délimité. Un modèle de rat reproduisant les caractéristiques observées chez les patients à pu être généré. Même s'il est clair que le cortex normotopique et l'hétérotopie participent aux évènements épileptiformes, leur zone de genèse reste néanmoins inconnue. Le but de cette thèse a été de localiser l'origine de l'activité épileptiforme in vitro sur tranches de cerveau à l'aide d'une technique d'enregistrement multisite.Des activités épileptiformes (ILEs) ont été enregistrées à l'aide d'une technique d'enregistrement extracellulaire multisite à 60 canaux. Un outil d'analyse développé sous Matlab a ensuite permis de caractériser les ILEs et notamment leur origine et étendues spatiales. Après avoir identifié l'importance du cortex normotopique dans la genèse des ILEs, nous en avons supprimé l'excitabilité in vivo. Nous montrons que la surexpression de ces canaux dans les neurones ectopiques n'altère pas la susceptibilité aux crises des animaux concernés alors que la surexpression de ces canaux dans l'hétérotopie et dans le cortex normotopique améliore le phénotype épileptique. Nos résultats suggèrent ainsi un rôle majeur du cortex normotopique dans la genèse des activités épileptiques dans le syndrome du double cortex. / Subcortical Band Heterotopia (SBH) is a cortical malformation formed when neocortical neurons prematurely stop their migration in the white matter, forming a heterotopic band below the normotopic cortex, and is generally associated with intractable epilepsy. Although it is clear that the band heterotopia and the overlying cortex both contribute to creating an abnormal circuit prone to generate epileptic discharges, it is less understood which part of this circuitry is the most critical. Here, we sought to identify the origin of epileptiform activity in a targeted genetic model of SBH in rats.Rats with SBH were generated by knocking‐down the Dcx gene into neocortical progenitors of rat embryos. Origin, spatial extent and laminar profile of bicuculline‐induced interictal‐like activity on neocortical slices were analyzed by using extracellular recordings from 60‐channels microelectrode arrays. Susceptibility to pentylenetetrazole‐induced seizures was assessed by electrocorticography in head‐restrained nonanaesthetized rats. We show that the band heterotopia does not constitute a primary origin for interictal‐like epileptiform activity in vitro and is dispensable for generating induced seizures in vivo. Further, we report that most interictal‐like discharges originating in the overlying cortex secondarily propagates to the band heterotopia. Importantly, we found that in vivo suppression of neuronal excitability in SBH does not alter the higher propensity of Dcx‐KD rats to display seizures. These results suggest a major role of the normotopic cortex over the band heterotopia in generating interictal epileptiform activity and seizures in brains with SBH.

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.

Low-grade gliomas (LGGs) constitute a major challenge for health care because of their location and nature. LGGs are often found in eloquent areas, and their infiltrative growth cause neurological reorganization, which complicates the mapping of important functions. Awake surgery in combination with direct electrical stimulation (DES) and intraoperative tests is a relatively new method for mapping the brain's functional limits, thus eliminating as much of the tumor as possible while maintaining important functions. At present there is no available intraoperative test for semantic processing in Swedish. Tests of specific linguistic abilities improves the specificity of mapping which reduces post-operative linguistic impairments. Intraoperative tests can thus contribute to increased quality of life in the patient group. This study was based on the Dutch Lingusistic Intraoperative Protocol (DuLIP) test battery to create a Swedish version of the subtest semantic odd word out (SOWO). SOWO tests semantic processing via lexical reading. The adjusted and extended version of SOWO was tested during a pilot trial on 26 standard-language people. The study has resulted in a new semantic intraoperative test in Swedish that will be clinically examined at University Hospital in Uppsala. Hopefully, the new test contributes to better treatment options for patients with LGG. / Lågmaligna tumörer (LGG) utgör en stor utmaning för vården på grund av deras lokalisation och karaktär. LGG återfinns ofta i elokventa områden och deras infiltrativa växtsätt orsakar neurologisk omorganisering, vilket komplicerar kartläggning av viktiga funktioner. Vakenkirurgi i kombination med direkt elektrisk stimulering (DES) och intraoperativa tester är en relativt ny metod för att kartlägga hjärnans funktionella gränser och därmed kunna avlägsna så stor del av tumören som möjligt samtidigt som viktiga funktioner kan bevaras. I dagsläget finns det inget tillgängligt intraoperativt test för semantisk bearbetning på svenska. Tester av specifika lingvistiska förmågor förbättrar specificiteten av kartläggningen vilket minskar postoperativa språkliga nedsättningar. Intraoperativa tester kan därmed bidra till ökad livskvalitet hos patientgruppen. Denna studie har utgått från det nederländska testbatteriet Dutch Lingusistic Intraoperative Protocol (DuLIP) för att skapa en svensk version av deltestet semantic odd word out (SOWO). SOWO testar semantisk bearbetning via lexikal läsning. Den anpassade och utökade versionen av SOWO pilottestades på 26 normalspråkiga personer. Studien har resulterat i ett nytt semantiskt intraoperativt test på svenska som ska prövas kliniskt på Akademiska sjukhuset i Uppsala. Förhoppningsvis bidrar det nya testet till bättre behandlingsmöjligheter för patienter med LGG.

La dyslexie développementale est un trouble neuro-développemental qui affecte spécifiquement l’apprentissage du langage écrit d’environ 10% des enfants en âge scolaire. Ces dernières années, plusieurs études ont montré la présence des anomalies oculomotrices chez les enfants dyslexiques. Toutefois, plusieurs questions sur la performance oculomotrice des enfants dyslexiques sont encore sans réponse ou restent peu étudiées.Dans cette thèse, nous avons réalisé trois études afin d’examiner l’oculomotricité des enfants dyslexiques comparativement à celle des enfants non-dyslexiques. Pour la première fois, nous avons enregistré les saccades verticales chez les enfants dyslexiques (étude 1). Les résultats ont montré que, comparés aux enfants non-dyslexiques de même âge chronologique, les enfants dyslexiques avaient des latences plus longues, de faibles précisions et des vitesses saccadiques ayant une asymétrie haut/bas. Les études 2 et 3 nous ont permis d’élargir les investigations, respectivement, sur la fixation visuelle et sur la reconnaissance visuo-auditive phonologique chez les enfants dyslexiques. Nous avons reporté une fixation visuelle et une reconnaissance visuo-auditive phonologique de faible qualité chez les enfants dyslexiques par rapport aux groupes d’enfants-non dyslexiques de même âge chronologique et de même âge de lecture.Nous avons suggéré que le développement atypique du système visuel magnocellulaire, de même que celui des structures cortico-sous-corticales et des difficultés attentionnelles expliqueraient les perturbations oculomotrices des enfants dyslexiques. Ainsi, nous avons proposé des voies de rééducation oculomotrice en vue de contribuer à l’amélioration des capacités de lecture des enfants dyslexiques.Mots-clés: Mouvements oculaires, saccades, fixations, système visuel, cortex visuel, structures cortico-sous-corticales, attention, dyslexie développementale. / ABSTRACTDevelopmental dyslexia is a neurodevelopmental disorder that affects written language learning of about 10% of school-age children. During the last years, several studies have shown the presence of oculomotor abnormalities in dyslexia. However, several questions about the oculomotor performance of dyslexic children are still unanswered.We conducted three studies to examine eye movements of dyslexic children with respect to non-dyslexic age-matched children. In the first of our study, we investigated vertical saccades performance in dyslexic children. The results showed that, dyslexic children had longer latencies, poor precision and slow saccadic speed with up / down asymmetry. Studies 2 and 3 respectively allowed us to enlarge the investigation of visual fixation as well as visual-auditory phonological capabilities in dyslexic children. We reported a low quality of visual fixation and visual-auditory phonological recognition in children with dyslexia compared with the non-dyslexic children.Taken together, all these findings suggested, in dyslexic children, an immaturity of the magnocellular visual system, as well as of the cortico-subcortical structures responsible for oculomotor performances. Attentional capabilities, that are poor in dyslexic children, would be also explained their oculomotor deficiencies reported. Thus, we proposed oculomotor rehabilitation that could be able to improve reading skills in dyslexia.Key words: Eye movements, saccades, fixations, visual system, visual cortex, cortical and sub-cortical structures, attention, developmental dyslexia.

Background The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures. Methods T1-weighted MRI scans were subsegmented and multi-stage quality controlled using FreeSurfer. Left/right hemispheric amygdala nuclei volumes were cross-sectionally compared between females with AN (n = 168, 12–29 years) and age-matched healthy females (n = 168) applying general linear models. Associations with plasma leptin, body mass index (BMI), illness duration, and psychiatric symptoms were analyzed via robust linear regression. Results Globally, most amygdala nuclei volumes in both hemispheres were reduced in AN v. healthy control participants. Importantly, four specific nuclei (accessory basal, cortical, medial nuclei, corticoamygdaloid transition in the rostral-medial amygdala) showed greater volumetric reduction even relative to reductions of whole amygdala and total subcortical gray matter volumes, whereas basal, lateral, and paralaminar nuclei were less reduced. All rostral-medially clustered nuclei were positively associated with leptin in AN independent of BMI. Amygdala nuclei volumes were not associated with illness duration or psychiatric symptom severity in AN. Conclusions In AN, amygdala nuclei are altered to different degrees. Severe volume loss in rostral-medially clustered nuclei, collectively involved in olfactory/food-related reward processing, may represent a structural correlate of AN-related symptoms. Hypoleptinemia might be linked to rostral-medial amygdala alterations.

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