Masters of Philosophy / In today's society, the misdiagnosis of school-age children with the neurological condition Child Absence Epilepsy (CAE) as having Attention-Deficit/Hyperactivity Disorder (ADHD) has a low profile. This may be because of the lack of popular awareness of CAE. The increasing social salience towards the neuropsychological condition of ADHD places these children at risk of experiencing high psychosocial effects. Many symptoms of CAE are also associated with ADHD. However if the condition is misdiagnosed as ADHD, the child with CAE is often mistreated, both medically and socially until the correct diagnosis is made. There is little research available on the psychosocial effects of the misdiagnosis of epilepsy as ADHD, and none available relating to CAE. This research study uses case study methodology to focus on how children with CAE are psychosocially affected at the time of the misdiagnosis of ADHD and subsequently. It also explores the experiences of their parents. An in-depth interview method was adopted to gather the personal recollections of these effects directly from the ten participants in this study. The participants were found with the assistance of Epilepsy Australia and constituted one adolescent from five different families who had experienced the sequence of events and effects under investigation, and a parent (guardian) who cared for these children during this period. The findings of this research indicate that as a result of labelling, these children were misjudged in their communities, leaving strong psychosocial effects on each of the child participants who had previously been misdiagnosed with ADHD. These effects include low self-esteem, insecurity and fear experienced most often in the company of peers. As a result, when reaching adulthood, most of these participants chose to isolate themselves from social contact whenever possible. The findings offer a basis for further research in the area.

Masters of Philosophy / In today's society, the misdiagnosis of school-age children with the neurological condition Child Absence Epilepsy (CAE) as having Attention-Deficit/Hyperactivity Disorder (ADHD) has a low profile. This may be because of the lack of popular awareness of CAE. The increasing social salience towards the neuropsychological condition of ADHD places these children at risk of experiencing high psychosocial effects. Many symptoms of CAE are also associated with ADHD. However if the condition is misdiagnosed as ADHD, the child with CAE is often mistreated, both medically and socially until the correct diagnosis is made. There is little research available on the psychosocial effects of the misdiagnosis of epilepsy as ADHD, and none available relating to CAE. This research study uses case study methodology to focus on how children with CAE are psychosocially affected at the time of the misdiagnosis of ADHD and subsequently. It also explores the experiences of their parents. An in-depth interview method was adopted to gather the personal recollections of these effects directly from the ten participants in this study. The participants were found with the assistance of Epilepsy Australia and constituted one adolescent from five different families who had experienced the sequence of events and effects under investigation, and a parent (guardian) who cared for these children during this period. The findings of this research indicate that as a result of labelling, these children were misjudged in their communities, leaving strong psychosocial effects on each of the child participants who had previously been misdiagnosed with ADHD. These effects include low self-esteem, insecurity and fear experienced most often in the company of peers. As a result, when reaching adulthood, most of these participants chose to isolate themselves from social contact whenever possible. The findings offer a basis for further research in the area.

Absence epilepsy is a neurological disorder that commonly occurs in children. Some studies have shown that absence seizures predominantly originate either in the thalamus or the cerebral cortex. Some cerebellar nuclei (CN) neurons project to these brain areas, as explained further in Fig. 2.6 in Chapter 2. Also, some CN neurons have been observed to show modulation during the absence seizures. This indicates that they somehow participate in the seizure and hence are referred to as "participating neurons" in this thesis. In this research, I demonstrate how machine learning techniques and computer simulations can be applied to investigate the properties and the input conditions present in these participating neurons. My investigation found a sub-group of CN neurons, with similar interictal spiking activity, spiking activity between the seizures, that are most likely to participate in seizures. To investigate the input conditions present in the CN neurons that produce this type of interictal activity, I used a morphologically realistic conductance based model of an excitatory CN projection neuron [66] and optimised the input parameters to this model using an Evolutionary Algorithm (EA). The results of the EA revealed that these participating CN neurons receive a synchronous and bursting input from Purkinje cells and bursting input with long intervals(approx. 500ms) from mossy fibre. The same interictal activity can also be produced when the Purkinje cell input to the CN neuron is asynchronous. The excitatory input in this case also had long interburst intervals but there is a decrease in excitatory and inhibitory synaptic weight. Surprisingly, a slight change in these input parameters can change the interictal spiking pattern to an ictal spiking pattern, the spiking pattern observed during absence seizures. I also discovered that it is possible to prevent a participating CN neuron from taking part in the seizures by blocking the Purkinje cell input.

Le cerveau est composé de réseaux de neurones interconnectés dont la mise en place au cours du développement cérébral est hautement régulée par des processus cellulaires, moléculaires et fonctionnels. Un dysfonctionnement de ces processus peut perturber l’établissement de ces réseaux et conduire à des pathologies neurologiques. L’épilepsie absence est une pathologie génétiquement déterminée qui apparait au cours de l’enfance. Les crises d’absences sont caractérisées par une altération de la conscience et par la présence de décharges de pointe-ondes (DPO) sur l’électroencéphalogramme initiées au sein d’un zone restreinte du cortex. Cependant, on sait peu de choses sur les mécanismes conduisant à la mise en place des décharges épileptiques récurrentes au cours de l’enfance (i.e. l’épileptogenèse). Nous avons fait l’hypothèse que des anomalies du processus de maturation cérébrale sont à l’origine de l’apparition des DPO.J’ai vérifié cette hypothèse chez un modèle génétique d’épilepsie absence, le rat GAERS. Dans un premier temps, j’ai étudié l’épileptogenèse du GAERS grâce à l’enregistrement in vivo du potentiel de champs local et de l’activité intracellulaire des neurones pyramidaux au niveau du site d’initiation des DPO, le cortex somatosensoriel (SoCX). Nous avons mis en évidence que les DPO se développent progressivement après la fin d’une période de maturation hautement sensible et malléable du SoCx (i.e. période critique). La maturation des décharges épileptiques consiste en une augmentation de leur fréquence, de leur durée et en l’évolution du motif de décharge jusqu’à l’âge adulte, période à laquelle ces paramètres atteignent une relative stabilité. De plus, ces changements sont associés à une altération graduelle des propriétés intrinsèques des neurones pyramidaux qui s’accompagne d’une augmentation progressive de la force de l’activité synaptique locale et d’une propension accrue des neurones du SoCx à générer des oscillations synchrones.Nous avons ensuite recherché les raisons de cette prédisposition anormale des neurones du SoCx à se synchroniser chez le GAERS. Dans ce but, nous avons cherché à mettre en évidence des anomalies de la maturation corticale au niveau de la structure et de l’organisation fonctionnelle du SoCx avant l’apparition des DPO. En combinant l’IRM, des marquages immunohistochimiques et le traçage rétrograde monosynaptique des connexions longue distance par le virus de la rage modifié, nous avons pu montrer qu’aucune anomalie globale du cerveau et du SoCx n’est présente chez le GAERS avant l’apparition des DPO. Afin de déterminer la présence d’anomalies fonctionnelles nous avons utilisé l’imagerie calcique biphoton et enregistré in vivo la dynamique de l’activité spontanée du réseau de neurones des couches 2-3 du SoCx. Chez le GAERS, nous avons mis en évidence que ces neurones sont plus actifs et dévoilent une organisation fonctionnelle différente de celle des animaux contrôles. Enfin, pour comprendre comment cette organisation fonctionnelle anormale est médiée, nous avons étudié la structure dendritique et synaptique du SoCx en combinant la microscopie électronique et la reconstruction morphologique de neurones. Nous avons mis en évidence un élargissement des épines dendritiques associé à un allongement de la densité post-synaptique au sein du SoCx chez le GAERS.L’ensemble de ces résultats démontrent la nature progressive du développement de l’épilepsie absence ainsi que l’existence d’anomalies de la maturation corticale qui affectent la structure et la fonction du réseau neuronal, avant l’apparition des crises épileptiques. Ces altérations constituent une prédisposition à l’établissement et l’évolution des DPO et sont une cible thérapeutique potentielle qui pourrait permettre de bloquer la mise en place des crises d’absences. / The brain is organized into several interconnected neuronal networks whose formation is highly regulated by cellular, molecular and functional processes. The dysfunction of these processes during brain development could disrupt neuronal circuit establishment and lead to neurological pathologies. Absence epilepsy is a genetically determined disease with a childhood onset. Absence seizures are characterized by an impairment of the consciousness associated on the electroencephalogram with spike and wave discharges (SWD). However, little is known about the mechanisms leading to the establishment of recurrent epileptic discharges (i.e. epileptogenesis). We hypothesized that SWD onset originates from an abnormal brain maturation.During my PhD, I examined this hypothesis in a recognized genetic model of absence epilepsy, the GAERS rat. First, I studied the epileptogenic process by recording in vivo the local field potential and the intracellular activities of pyramidal neurons in the initiating area of SWD, the somatosensory cortex (SoCx), at different post natal days in GAERS. We showed that SWD progressively developed after the end of a highly sensitive and plastic maturation period of the SoCx (i.e critical period). Afterward, epileptic discharges maturation consists in an increase of their duration, their number and in an evolution of the pattern reaching a relative stability at adulthood. Moreover, these changes are associated with a gradual abnormal alteration of the intrinsic properties of pyramidal neurons which is accompanied with a progressive increase in the strength of the local synaptic activity and a growing propensity of SoCx neurons to generate synchronized oscillations.Then, we explored the reasons for this abnormal susceptibility of SoCx neurons to be more synchronized in GAERS. We sought to bring to light anomalies of SoCx maturation at the structural and functional organization level prior to SWD onset in GAERS. Combining MRI, immunohistochemistry labeling and rabies-mediated retrograde monosynaptic tracing to reveal long-range connectivity, we showed that, prior to SWD onset, no brain and SoCx architecture abnormalities could be observed in GAERS. Then, using two photon calcium imaging we recorded in vivo the spontaneous activity of SoCx layers 2-3 neurons to evidence their functional organization. We found that these neurons were more active and unveiled a different functional organization in GAERS compared to control animals. Finally, to understand how is mediated this abnormal functional organization, we studied the dendritic and synaptic fine structure of SoCx neurons by combining electron microscopy and morphological neuron reconstruction. We highlighted an enlargement of the dendritic spines as well as an increase of the post-synaptic density length in the GAERS SoCx.Taken together, these findings showed the progressive nature of absence epilepsy development and the presence of abnormalities in the cortical maturation which affect the structure and the functional of the neuronal network the prior to SWD. These alterations constitute a breeding ground for the establishment and evolution of SWD. Future studies will aim at interfering with the epileptogenesis process should target these early alterations to stop seizure development.

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Le fonctionnement cérébral est régit par deux grandes forces : un système excitateur, principalement supporté par la transmission gluue,tamatergiq qui s'oppose à un système inhibiteur, principalement supporté par la transmission GABAergique. L'influence mutuelle et équilibrée de ces deux forces est déterminante pour établir et maintenir une activité neuronale physiologique au sein des réseaux neuronaux. Le récepteur métabotropique du glutamate de type 7, mGlu7, est capable de moduler à la fois la transmission glutamatergique et GABAergique, mais sa localisation et son rôle synaptique précis restent largement méconnus à l'heure actuelle. Il semble important pour contrôler le fonctionnement d'une circuiterie particulière supportant notamment la perception sensorielle lors de l'éveil ou la perte de conscience lors de l'endormissement, mais aussi les crises épileptiques d'absence lors d'un dysfonctionnement : le circuit thalamo-cortical. Cette thèse porte sur l'étude des fonctions physiologiques médiées par le récepteur mGlu7a au sein du réseau thalamo-cortical chez la souris. Pour cela, j'ai décortiqué la localisation et les processus électrophysiologiques engendrés par le récepteur dans les synapses thalamiques constituant la circuiterie thalamo-corticale. Le récepteur mGlu7a s'estavéré essentiel dans le contrôle des rythmes oscillatoires au sein du thalamus, associés à la fois au sommeil (les fuseaux de sommeil) et aux épilepsies de type absence.Ce récepteur était présumé ne fonctionner que lors d'activités neuronales intenses. Cette étude complète ce tableau. Elle met en évidence une activité constitutive du récepteur mGlu7a au sein des synapses excitatrices et inhibitrices. Il exerce donc un frein permanent sur l’entrée de Ca2+ dans les présynapses, un acteur crucial pour le développement du système nerveux, la transmission synaptique, l'excitabilité et la plasticité neuronales. Je montre que cette activitémodule la libération de glutamate et de GABA, mais aussi la plasticité à court terme dans certaines synapses du circuit. De plus, le récepteur mGlu7a limite le tonus inhibiteur au sein du thalamus et ainsi l'excitabilité globale thalamique.De façon surprenante pour un récepteur du glutamate, l'ensemble de ces résultats suggère une action physiologique du récepteur mGlu7a particulièrement impliquée dans le contrôle de l'état d'excitabilité des neurones GABAergiques thalamiques et corticaux. En limitant l'apparition d'activités synchrones au sein de la circuiterie, son action abouti in fine au maintien d'un état conscient de l'individu, nécessaire aux traitements des informations sensorielles, mais aussi à l'apprentissage et la mémoire. / Brain functionning is gouverned by two master forces : excitation, mainly supported by glutamatergic transmission, and inhibition, mainly supported by GABAergic transmission. The mutual and balanced influence of these two forces is instrumental to establish and maintain a physiological neuronal activity, particulary in neuronal networks involving several interconnected brain area and neuron types. The metabotropic glutamate receptor type 7, mGlu7, modulates both glutamatergic and GABAergic transmission, but its precise localization andsynaptic role are still widly unknown. Recently, a genetic mouse model has highlighted mGlu7a receptor's involvement into the functionning of a particular network supporting somatosensory perception during arousal and loss of consciousness during sleep, as well as absence epileptic seizures : the thalamo-cortical network. This thesis aims at understanding physiological functions mediated by the mGlu7a receptor in the thalamo-cortical circuit. I have dissected localization and electrophysiologicalprocesses triggered by the receptor in thalamic synapses. The mGlu7a receptor was proved as essential to control oscillatory rythmes in the thalamus, associated with both sleep-related waves (spindles) and absence epileptic seizures.This receptor was supposed to function only during high neuronal activities. In addition, our study highlights a constitutive activity of mGlu7a receptor in excitatory and inhibitory synapses. It thus exerts a permanent brake on Ca2+ presynaptic entry, which is crucial for neuronal developpement, synaptic transmission, excitability and plasticity. I found that this mechanism modulates glutamate and GABA release, but also short term plasticity in thestudied network. Moreover, mGlu7a receptor slows down the inhibitory tonus in the thalamus and thalamic excitability.Surprisingly for a glutamate receptor, these data suggest that the physiological action of mGlu7a receptor is highly involved in the control of the excitability of inhibitory thalamic and cortical neurons. By decreasing synchronous activities of the network, its action leads in fine to the maintenance of a conscious, awake state of a subject, that is necessary for sensorial informations processing, learning and memory.

After the dispensation of the White Paper 6 in schools, there were no detailed guidelines to accommodate the learners with invisible impairments like absence epilepsy, especially those who live in underprivileged communities. Affected learners are still struggling and not receiving proper instruction in ordinary schools because of the nature of absence epilepsy. It seems like it is unknown that they are suffering, because the symptoms are absent. These learners are performing poorly; they are having learning and behavioural problems. At home parents are ignorant of their plight, teachers are oblivious of their problems and at schools they are being discriminated against by other children. As a result, they repeat grades and some end up leaving school to join the unemployed. They have a low self-esteem and remain unsociable. This is because they suffer from absence epilepsy which is a medical problem. Absence epilepsy is unknown to both parents and teachers in these communities. Cultural beliefs and ignorance prevent parents from taking these children to clinics for identification, which results in them not being supported in schools. / Inclusive Education / M. Ed. (Inclusive Education)