Le stress chez les enfants avec convulsions fébriles : mécanismes et contribution au pronostic

Le stress est continuellement associé à la genèse, la fréquence et la sévérité des convulsions en épilepsie. De nombreux modèles animaux suggèrent qu’une relation entre le stress et les convulsions soit mise en place en début de vie, voire dès la période prénatale. Or, il existe peu de preuves de cette hypothèse chez l’humain. Ainsi, l’objectif général de cette thèse était d’examiner le lien entre le stress en début de vie, dès la conception, et les convulsions chez les humains. Pour ce faire, cette thèse avait comme intérêt principal les convulsions fébriles (CF). Il s’agit de convulsions pédiatriques communes et somme toute bénignes, bien qu’elles soient associées à de légères particularités neurologiques et cognitives. En ce sens, les CF représentent un syndrome de choix pour notre étude, considérant leur incidence fréquente en très bas âge et l’absence de conséquences majeures à long terme. Ainsi, elles permettent l’étude de la relation entre le stress en début de vie et les convulsions par l’entremise d’un relativement grand bassin populationnel, en réduisant l’impact de potentiels facteurs confondants. Dans ce contexte, notre objectif général a été étudié par l’entremise de cinq objectifs secondaires. D’abord, le premier objectif secondaire de cette thèse était de faire le point sur la littérature expliquant le lien entre les convulsions, le stress, ainsi que l’impact que pourrait avoir le stress sur le pronostic cognitif des syndromes convulsifs (article 1). Le second était d’examiner la relation entre les symptômes maternels auto-rapportés de stress, d’anxiété spécifique à la grossesse ou de dépression durant la grossesse et la période postpartum et les CF. Par le biais d’un devis longitudinal, les résultats de cette thèse suggèrent qu’une plus forte anxiété spécifique à la grossesse ainsi qu’une plus grande présence de symptômes dépressifs en période postnatale sont associées à une diminution du seuil convulsif des CF, caractérisée par un plus jeune âge lors du premier épisode convulsif (article 2). Étudié à travers ce même devis longitudinal, le troisième objectif secondaire de cette thèse était d’évaluer le lien entre des changements biologiques associés à l’exposition au stress prénatal et les CF. Or, nos résultats mettent plutôt en lumière des différences sur le plan du système sérotoninergique placentaire, sous-tendant une exposition ou une propension au stress. D’une part, ces changements seraient associés à une hausse de l’incidence des CF et, d’autre part, à une baisse du seuil convulsif (article 3). Par ailleurs, le quatrième sous-objectif couvert par cette thèse était d’étudier la réponse biologique de stress chez des enfants avec antécédents de CF afin de voir si elle se distingue de celle d’enfants sans antécédents convulsifs. Notre étude appariée suggère une plus forte sensibilité au stress chez les enfants avec antécédents de CF « simple » (article 4). Ainsi, ces résultats ne démontrent pas de changements systématiques à l’ensemble des enfants sur le plan de la réactivité au stress. Toutefois, des changements chez les enfants avec CF simples pourraient sous-tendre des anomalies prémorbides. Accessoirement, durant l’étude du quatrième sous-objectif, nous n’avons pas été en mesure d’identifier des anomalies cognitives dans les mois suivants un épisode de CF, ni d’associer le pronostic cognitif au profil de réactivité au stress. Dans ce contexte, le cinquième et dernier objectif secondaire visait à investiguer le pronostic électrophysiologique des CF et à en étudier l’association avec la réactivité au stress. Les résultats suggèrent la présence de particularités électrophysiologiques chez les enfants avec antécédents de CF « complexes », lesquelles pourraient être associées aux altérations cognitives vues chez cette population à long terme (article 5). Par-dessus tout, notons que ces particularités diffèrent en fonction du sous-type de CF complexes. Toutefois, les résultats obtenus dans le cadre de notre devis expérimental n’ont pas été en mesure d’identifier un rôle du stress sur ces atypies (addenda). Ensemble, ces résultats suggèrent l’existence d’un lien entre le stress en début de vie, dès la période prénatale, et les CF. Ils appuient l’importance d’investiguer le stress prénatal, postnatal et actuel en contexte de syndromes convulsifs en général, dont les CF. En raison de l’impact considérable du stress sur la qualité de vie des personnes vivant avec un syndrome convulsif, une meilleure caractérisation de la relation entre le stress précoce et les convulsions pourrait à long terme mener au développement d’interventions précoces et non invasives. Par ailleurs, même si ces résultats n’ont pas été en mesure d’identifier une relation entre la réactivité au stress et le pronostic cognitif ou électrophysiologique des CF, l’étude de ce lien est néanmoins suggérée par les études animales et devrait faire l’objet d’études futures.Stress is a phenomenon frequently associated with epileptogenesis and increased seizure frequency and severity. Animal studies suggest the relationship between stress and seizures may begin early in life, maybe even prenatally. Evidence showing a link between early programming through stress and seizure disorders has yet to be found in humans. Hence, the general objective of this thesis was to examine the relationship between early-life stress, including the prenatal period, and seizures in humans. For this purpose, the prime focus of this research was on febrile seizures (FS). FS are common and benign pediatric seizures, associated only with mild neurological and cognitive peculiarities. Due to their frequent incidence in early childhood and lack of severe consequences, they allow for the investigation of the relationship between early-life stress and seizures through a relatively large sample, while reducing the impact of potential confounding variables.In this context, our general objective was investigated through five sub-objectives. First, we aimed toreview the current knowledge on the link between seizures and stress, as well as the impact stress could have on the cognitive prognosis of seizure disorders (1starticle).The second sub-objective was to study the relationship between self-reported maternal emotion distress during both the pregnancy and postpartum period, on FS. Through a longitudinal cohort, this research supports increased prenatal pregnancy-specific anxiety and postpartum depressive symptoms are associated with a lowered FS threshold, as shown through a younger age at first FS occurrence (2ndarticle). Moreover, the third sub-objective, which was studied through the same longitudinal research, was to evaluate how biological changes associated with prenatal exposure to stress may be linked to FS. This study showed changes in the placental serotoninergic system are found in children with FS history. More precisely, these changes are associated with increased FS incidence, and lowered FS threshold (3rdarticle). On the other hand, the fourth sub-objective of this thesis was to study the biological stress response of children with past FS, compared to that of children without personal history of seizures. Our case-control study suggested only children with “simple” FS showed increased sensibility to stress (4tharticle). Hence, these results do not show systematic changes in the ivbiological stress reaction of all children with FS. Still, they do show changes in some children, which could be premorbid to the first FS episode.Incidentally, while studying the fourth sub-objective, we were unable to show changes in the developmental skills of children with FS, nor did we show an interaction with stress reactivity. Hence, the fifth and final subjective of this thesis was to investigate the electrophysiological prognosis of children with past FS, and its association with stress reactivity. Our results show differences in the electrophysiological profile of children with “complex” FS only, which could be linked to cognitive alterations in the long-term (5tharticle). Moreover, we showed these abnormalities differ depending on the type of complex FS. Still, we were unable to identify an additive or interactive link with stress reactivity (addendum). Taken together, these results highlight the existence of a link between stress, starting in the prenatal period, and FS. Hence, they highlight the importance of investigating prenatal, postnatal and current stress in the context of seizure disorders at large, including FS. Given the significant impact of stress on the quality of life of people living with epilepsy, increased knowledge on the link between early stress and seizures could lead to the development of early and non-invasive treatments targeting stress in the future. Moreover, although these results do not show stress to be associated with altered cognitive or electrophysiological prognosis in the context of FS, this link is nevertheless supported by animal research and should be the subject of future studie

Prolonged and unprolonged complex febrile seizures differently affect frontal theta brain activity

Objective: Studies have identified persistent cognitive and functional deficits, which could be linked to each other, in children with complex febrile seizures (FS). Our aim was to investigate differences in brain activity in children with a history of complex FS, through a study paradigm associated with the development of learning capacities and using electroencephalographic (EEG) signal. To further increase our understanding of these differences, complex FS were studied separately depending on their type. Method: EEG was recorded in 43 children with past FS. Brain activity associated with auditory learning was investigated using a habituation paradigm, in which repetition suppression (RS) is typically found following stimulus repetition. Auditory stimuli were repeated three times, and each presentation were analysed separately in the time-frequency (TF) domain. A mixedanalysis of variance was used to assess differences in spectral power between stimulus repetition and FS type (simple vs complex prolonged; CP vs complex unprolonged; CUP). Results: Repetition effects were found in the 3-6 Hz during 150-600ms time window after stimulus onset at frontal sites (F(2, 40)=5.645, p=0.007, η2p=0.220). Moreover, an interaction effect between stimulus repetition and FS type (F(4, 80)=2.607, p=0.042, η2p=0.115) was found. Children with CP FS showed greater increase in spectral power in response to the first stimulus presentation, while children with CUP FS failed to show a RS pattern. Significance: Our results show distinct abnormalities in brain activity to a habituation paradigm. We argue that these changes suggest children with CP FS may be hyperexcitable, while children with CUP FS show impaired habituation processes. Still, these differences may be associated with other clinical features linked to complex FS as well. Hence, the role of these differences in complex FS incidence and prognosis should be the subject of future studies

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Développement cognitif des enfants épileptiques : contribution du stress

L’épilepsie est un désordre neurologique souvent infantile associé à des comorbidités qui impliquent des troubles cognitifs. Depuis quelques années, les études des chercheurs suggèrent que la qualité de vie des personnes atteintes d’épilepsie est plus sévèrement impactée par les comorbidités associées à la maladie que par les crises. Il importe donc de diminuer la sévérité des troubles cognitifs chez les personnes épileptiques. Dans cet article, nous relevons les hypothèses de la littérature actuelle qui stipulent que le stress pourrait être un facteur affectant négativement le développement cognitif des enfants épileptiques. Ainsi, nous décrivons les atteintes neuropsychologiques inhérentes aux syndromes convulsifs, la relation biologique du stress et la relation entre le stress et les syndromes convulsifs. Deux modes d’action, évoqués par les chercheurs, par lesquels le stress serait un facteur aggravant les comorbidités des personnes qui présentent un syndrome convulsif seront aussi décrits.Epilepsy is a neurodevelopmental disorder with an onset mainly during childhood, and is linked to life-long cognitive deficits. In this article, we suggest that stress could negatively influence the cognitive development in children suffering from epilepsy. The object of this article is to present two explanations that are complementary and cumulative regarding the link between stress and cognitive development in epileptic children and to review the current knowledge regarding them. First, stress influences seizures’ frequency and severity, which influences cognitive development. Secondly, stress causes cognitive deficits which might be added to the cognitive deficits caused by seizures

Age at first febrile seizure correlates with perinatal maternal emotional symptoms

Objective: Prenatal exposure to stress and fever are factors lowering seizure threshold in animal models. The fever effect on seizure threshold is well documented in human infants, however the associations between maternal perinatal stress and infants’ susceptibility to seizures is unknown. This is the first study in humans to investigate longitudinally, whether in humans, the effect of maternal perinatal emotional symptoms such as stress, anxiety and depression that may trigger a biological stress response on age at first seizure occurrence. Method: The study sample is a subgroup drawn from a longitudinal follow up cohort (3D cohort study: Design, Develop, Discover, N= 2366 mother-infant dyads). Twenty-nine otherwise healthy infants who had a febrile seizure (FS) episode before the last follow-up visit (around 24 months of age) were studied. Mothers completed questionnaires regarding their emotional health at each pregnancy trimester and at three months postpartum. The link between maternal emotional symptoms and infant age at first FS was assessed through correlations and multiple regressions. Results: We found that maternal anxiety symptoms during the second trimester of pregnancy are linked to the age at first FS (r(23) =−0.459, p =0.021) and explain 21.1% of its variance. Postnatal maternal depression symptoms at 3 months postpartum were also associated with the age at first FS (r(23) =−0.587, p= 0.002) and explained an additional 17.6% of variance. Together, the variables explained 38.7% of the variance in age at first FS. Maternal perceived stress symptoms at 3 months postpartum were also linked to the age at first FS (r (23) =−0.418, p=0.038), however, stress did not significantly contribute to the variance of age at first FS.. Significance: Our results suggest a link between increased perinatal maternal emotional symptoms and the age at first FS. An earlier age at first FS may be the manifestation of a lower seizure threshold. Early first seizure occurrence is a risk factor for compromised neurological and cognitive development. Further studies should address the mechanisms by which perinatal maternal emotional symptoms may have an impact on seizure threshold in humans

Febrile seizures and increased stress sensitivity in children : how it relates to seizure characteristics

BACKGROUND: Studies suggest that the relationship between seizures and stress starts early in life. However, evidence of long-term altered stress reactivity following early-life seizures is lacking. Our objectives were to assess alterations in stress hormone reactivity in children with past febrile seizures (FS) and investigate how these alterations relate to clinical characteristics. METHOD: This case-control study compared a convenience sample of children with simple FS (n = 24), complex FS (n = 18), and matched healthy controls (n = 42). Stress was induced by electrode placement for an electroencephalography (EEG) exam. Salivary cortisol to stress, using three samples collected before and after the stressor, was compared between groups and sex. The relationship between stress reactivity and clinical characteristics (i.e., FS duration, age at first FS, time since the last FS) was investigated. RESULTS: Cortisol reactivity to stress was significantly different depending on study groups, F(1, 78) = 6.415, p = 0.003, η2p = 0.141, but not sex nor was there a significant interaction between group and sex (p ≥ 0.581). Participants with simple FS showed higher cortisol reactivity to stress (M = 14.936, Standard deviation (SD) = 26.852) compared with those with complex FS (M = -4.663, SD = 18.649, p = 0.015) and controls (M = -3.817, SD = 18.907, p = 0.003). There was no significant difference between participants with complex FS and controls (p > 0.999). Stress reactivity was not linked to clinical characteristics. CONCLUSIONS: Children with past simple FS showed greater changes in salivary cortisol following stress, suggesting enhanced stress sensitivity. As similar results were not found in a population with complex FS, our study shows that stress alterations are not caused by seizure severity. Future studies are needed to investigate whether stress sensitivity may be premorbid to simple FS and may contribute to simple FS incidence

Effects of eight neuropsychiatric copy number variants on human brain structure.

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen's d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions