Febrile seizure incidence and age at first occurrence are associated with changes in placental normalized gene expression: the '3D' pregnancy cohort study.

Self-reported maternal prenatal stress (MPS) has been associated with earlier febrile seizure (FS) age of onset in offspring. Studies are needed to understand how the biological systems associated with exposure to psychological MPS are linked to seizure disorders in children. The present study aimed to investigate whether placental markers of MPS are linked to FS incidence and age at first occurrence. A subsample of children with FS (n = 28) and matched controls (n = 84), were drawn from the longitudinal 3D pregnancy cohort (N = 2366 mother-child dyads). Expression of placental genes associated with glucocorticoids, serotonin and fetal/placental growth were analysed from placental tissues, compared between groups and associated with age at first FS. Overall placental normalized gene expression was statistically different (p < .001). Children with FS showed overexpression of the serotonin transporter (mean difference = 0.61, 95% confidence interval [CI] = 0.9-1.13), connexin 43 (mean difference = 0.69, 95% CI = 0.30-1.09), zonula occludens-1 (mean difference = 0.84, 95% CI = 0.42-1.26) and underexpression of glucocorticoid receptor ß (mean difference = 0.84, 95% CI = -1.49 to 0.19) and serotonin receptor 2B (mean difference = 1.57, 95% CI = -2.35 to 0.78) compared to controls. Increased expression of the serotonin transporter predicted 37.2% in variation of age at first FS. The correlation matrix showed pregnancy-specific anxiety during the second trimester was moderately associated with age at first FS (r = -0.38) but was not a significant predictor in the regression model. Although our current results do not display a significant effect of self-reported MPS on FS, the present study is the first to show that placental gene biomarkers usually known to be associated with MPS display different expressions in children with FS. Specifically, our results suggest that placental genes associated with the glucocorticoid, serotonergic and fetal/placental growth systems may be candidate mechanisms leading to increased vulnerability offspring in FS. Because self-reported MPS was not found as a significant predictor in our statistical models, future studies are needed to investigate the mechanisms causing the observed changes in placental genes and their association with seizure disorders.

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.

Cognitive and behavioural development in children presenting with complex febrile seizures: at onset and school age.

OBJECTIVE: Our goal was to assess development, cognition and behaviour following an initial complex febrile seizure (FS), at onset and school age, in the context of known risk factors for cognitive development. METHODS: Two cohorts were recruited. Thirty-five infants with an initial complex FS were assessed within the first year post-seizure and compared to 30 controls (simple FS) based on measures of cognitive, motor and language development, behaviour and emotions. Additionally, 19 school-age children with previous complex FS (11 multiple, eight prolonged) were assessed and compared to 19 controls (simple FS) based on measures of intelligence, learning/memory, executive functioning, behaviour and emotions. RESULTS: Within the first year post-onset, infants with complex FS did not significantly differ from controls based on developmental measures. Seizure duration and age at seizure onset did not impact developmental outcome. School-age children with complex FS showed unaltered global intelligence, but lower executive functioning, compared to controls. Children with prolonged FS also showed evidence of a lower level of learning and memory abilities. Neuropsychological scores correlated with seizure duration. Children with complex FS showed more attentional problems and anxious/depressed symptomatology at onset and school age, and more hyperactivity at school age. SIGNIFICANCE: Infants with complex FS seemed to show normal development within the first year post-seizure onset. However, challenges in executive functioning, learning and memory at school age were found in children with a history of FS. Hence, at school age, cognitive challenges cannot be excluded based on undifferentiated early cognitive development, and may occur even in the absence of the most severe form of FS (i.e., FSE). Beyond the limits of this study (i.e., small sample size, use of parental questionnaires for emotional/behavioural outcome, absence of focal cases in the school-age cohort), our results suggest that a follow-up is necessary beyond the early preschool years in order to understand the long-term outcome.

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

OBJECTIVE: Studies have identified mild but 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 notably 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 mixed-analysis 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 150-600 ms 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.

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.

The relationship between acute stress and EEG repetition suppression in infants.

Over activation of the hypothalamo-pituitary-adrenal (HPA) axis in stress situations is known to influence learning and memory. In adults, an inverted-U shape relationship between acute stress, and learning and memory has been demonstrated. Whether this model fits learning performances in infants is unknown. In this study, we used EEG repetition suppression as physiological measure of learning and salivary cortisol in response to a stressor to investigate the relationship between acute stress and learning in infants. We hypothesized that EEG repetition suppression would be modulated by acute stress following an inverted-U shape relationship. Saliva samples were collected during an EEG experiment before, during and after EEG net installation in 37 healthy infants (18 males) aged between 6 and 26 months. The effect of variation in stress hormones on repetition suppression were modeled using a linear mixed model, with cortisol, age and sex as predictors. Results indicated that in healthy infants, elevations in stress hormones within the normal range are associated with a higher repetition suppression response and an increased response to the first presentation of the stimulus. The later increase could be related to vigilance. Considering that early childhood is a critical period of development, future studies should keep investigating the influence of stress on learning processes in infants.

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.

Electrophysiological correlates of emotional face processing after mild traumatic brain injury in preschool children.

Evidence suggests that social skills are affected by childhood mild traumatic brain injury (mTBI), but the neural and affective substrates of these difficulties are still underexplored. In particular, nothing is known about consequences on the perception of emotional facial expressions, despite its critical role in social interactions and the importance of the preschool period in the development of this ability. This study thus aimed to investigate the electrophysiological correlates of emotional facial expressions processing after early mTBI. To this end, 18 preschool children (mean age 53 ± 8 months) who sustained mTBI and 15 matched healthy controls (mean age 55 ± 11 months) were presented with pictures of faces expressing anger, happiness, or no emotion (neutral) while event-related potentials (ERP) were recorded. The main results revealed that P1 amplitude was higher for happy faces than for angry faces, and that N170 latency was shorter for emotional faces than for neutral faces in the control group only. These findings suggest that preschool children who sustain mTBI do not present the early emotional effects that are observed in healthy preschool children at visuospatial and visual expertise stages. This study provides new evidence regarding the consequences of childhood mTBI on socioemotional processing, by showing alterations of emotional facial expressions processing, an ability known to underlie social competence and appropriate social interactions.