Charline Urbain

Impact of focal interictal epileptiform discharges on behaviour and cognition in children

It is hypothesised that focal interictal epileptiform discharges (IED) may exert a deleterious effect on behaviour and cognition in children. This hypothesis is supported by the abnormally high prevalence of IED in several developmental disorders, like specific language impairment, and of cognitive and behavioural deficits in epileptic children after excluding confounding factors such as underlying structural brain lesions, drug effects, or the occurrence of frequent or prolonged epileptic seizures. Neurophysiological and functional neuroimaging evidence suggests that IED may impact cognition through either transient effects on brain processing mechanisms, or through more long-lasting effects leading to prolonged inhibition of brain areas distant from but connected with the epileptic focus (i.e. remote inhibition effect). Sustained IED may also impair sleep-related learning consolidation processes. Nowadays, the benefits of anti-epileptic treatment aimed at reducing IED are not established except in specific situations like epileptic encephalopathies with continuous spike and waves during slow-wave sleep. Well-designed pharmacological studies are still necessary to address this issue.

Is sleep-related consolidation impaired in focal idiopathic epilepsies of childhood? A pilot study.

We investigated sleep-related declarative memory consolidation in four children with focal idiopathic epilepsy. In a population of healthy control children, recall of learned pairs of words was increased after a night of sleep, but not after a daytime wakefulness period. In children with epilepsy (1 case of benign epilepsy with centro-temporal spikes, 1 case of benign childhood epilepsy with occipital paroxysms, and 2 cases of epileptic encephalopathy (EE) with continuous spike and waves during slow-wave sleep, CSWS), recall performance significantly decreased overnight, suggesting impairment in sleep-related declarative memory consolidation. Hydrocortisone treatment in one patient with EE with CSWS resulted in normalization of the sleep EEG together with normalization of overnight memory performance, which was not the case in the other EE/CSWS patient whose sleep EEG was only partially improved. These preliminary results suggest that interictal epileptiform discharges in idiopathic focal epilepsies may disrupt the brain processes underlying sleep-related memory consolidation.

Sleep spindle detection through amplitude-frequency normal modelling.

Manual scoring of sleep spindles can be very time-consuming, and achieving accurate manual scoring on a long-term recording requires high and sustained levels of vigilance, which makes it a highly demanding task with the associated risk of decreased diagnosis accuracy. Although automatic spindle detection would be attractive, most available algorithms are sensitive to variations in spindle amplitude and frequency that occur between both subjects and derivations, reducing their effectiveness. We propose here an algorithm that models the amplitude-frequency spindle distribution with a bivariate normal distribution (one normal model per derivation). Subsequently, spindles are detected when their amplitude-frequency characteristics are included within a given tolerance interval of the corresponding model. As a consequence, spindle detection is not directly based on amplitude and frequency thresholds, but instead on a spindle distribution model that is automatically adapted to each individual subject and derivation. The algorithm was first assessed against the scoring of one sleep scoring expert on EEG samples from seven healthy children. Afterward, a second study compared performance of two additional experts versus the algorithm on a dataset of six EEG samples from adult patients suffering from different pathologies, to submit the method to more challenging and clinically realistic conditions. Smaller and shorter spindles were more difficult to evaluate, as false positives and false negatives showed lower amplitude and smaller length than true positives. In both studies, normal modelling enhanced performance compared to fixed amplitude and frequency thresholds. Normal modelling is therefore attractive, as it enhances spindle detection quality.

Impaired sleep-related consolidation of declarative memories in idiopathic focal epilepsies of childhood

OBJECTIVE Declarative memory is consolidated during sleep in healthy children. We tested the hypothesis that consolidation processes are impaired in idiopathic focal epilepsies (IFE) of childhood in association with frequent interictal epileptiform discharges (IEDs) during sleep. METHODS A verbal (word-pair association) and a nonverbal (2D object location) declarative memory task were administrated to 15 children with IFEs and 8 control children 6-12 years of age. Patients had either centrotemporal (11 patients) or occipital (4 patients) IEDs. All but 3 patients had a history of unprovoked seizures, and 6 of them were treated with valproate (VPA). The learning procedure (location of object pairs presented on a grid; association of word pairs) was executed in the evening. Retrieval was tested immediately after learning and on the next morning after a night of sleep. Participants were tested twice, once in natural home conditions and one month later in the unfamiliar conditions of the sleep unit under EEG monitoring. RESULTS Overnight recall performance was lower in children with IFE than in control children on both tasks (ps<0.05). Performance in home conditions was similar to that in hospital conditions. Higher spike-wave index (SWI) during nonrapid eye movement (NREM) sleep was associated with poorer performance in the nonverbal task (p<0.05). Valproate treatment was not associated with overnight recall performance for both tasks (ps>0.05). CONCLUSION Memory consolidation is impaired in IFE of childhood. The association between higher SWI during NREM sleep and poorer nonverbal declarative memory consolidation supports the hypothesis that interictal epileptic activity could disrupt sleep memory consolidation.

Pathophysiology of sleep-dependent memory consolidation processes in children.

Cognitive impairments are often associated with abnormal sleep activity in developmental disorders and pathologies of childhood. Besides, accumulated evidence indicates that post-training sleep benefits to the consolidation of recently learned information in healthy adults and children. Although sleep-dependent consolidation effects in children are clearly established for declarative memories, they remain more debated in the procedural memory domain. Nowadays, recent experimental data suggest close interactions between the development of sleep-dependent plasticity markers, cortical maturation and cognition in children. In the present review, we propose that studying sleep and memory consolidation processes in developmental disorders and acquired childhood pathologies can provide novel, enlightening clues to understand the pathophysiological mechanisms subtending the disruption of long-term cerebral plasticity processes eventually leading to cognitive and learning deficits in children.

Selective modulations of attentional asymmetries after sleep deprivation

Pseudoneglect is a slight but consistent misplacement of attention toward the left visual field, commonly observed in young healthy subjects. This leftward attentional bias is thought to result from a right hemispheric dominance in visuospatial processing. Changes in endogenous levels of alertness may modulate attentional asymmetries and pseudoneglect in particular. In line with this hypothesis, it has been shown that sleep deprived shift-workers present a reversal of their attentional bias in a landmark (LDM) task (Manly, T., Dobler, V. B., Dodds, C. M., & George, M. A. (2005). Rightward shift in spatial awareness with declining alertness. Neuropsychologia, 43(12), 1721-1728). However, circadian disturbances and fatigue effects at the end of a shift work may have contributed to this reversal effect. In a first experiment, we show that sleep deprivation (SD) under controlled conditions does not markedly change the leftward bias, observable both at 21:00 and at 07:00 after SD. In a second experiment, we tested the hypothesis that a drastic reduction or inversion in the attentional bias would be present only when both the circadian drive for sleep propensity is maximal (i.e. around 05:00) and homeostatic sleep pressure is high. Thus participants were tested at 21:00 and under SD conditions at 05:00 and 09:00. Additionally, we used the greyscales (GS) task well-known to evidence a leftward bias in luminance judgments. Although results evidenced a consistent leftward bias both in the LDM and GS, we found a suppression of the leftward bias at the circadian nadir of alertness (05:00) after SD only for the GS, but not for the LDM. Noticeably, the leftward bias in the GS vanished at 05:00 after SD but reappeared at 09:00 despite continued SD, suggesting a predominant circadian influence on attentional asymmetries in the GS. Additionally, inter-sessions correlations evidenced a reproducible, consistent bias both in the LDM and GS, with no consistent relationship between the two tasks, suggesting independence of the neural networks subtending performance in LDM and GS. Overall, our results suggest that SD per se does not impede the leftward bias both in LDM and GS, whereas circadian-related variations in vigilance may impact attentional asymmetries in luminance judgments.

Sleep-dependent Neurophysiological Processes in Implicit Sequence Learning

Behavioral studies have cast doubts about the role that posttraining sleep may play in the consolidation of implicit sequence learning. Here, we used event-related fMRI to test the hypothesis that sleep-dependent functional reorganization would take place in the underlying neural circuits even in the possible absence of obvious behavioral changes. Twenty-four healthy human adults were scanned at Day 1 and then at Day 4 during an implicit probabilistic serial RT task. They either slept normally (RS) or were sleep-deprived (SD) on the first posttraining night. Unknown to them, the sequential structure of the material was based on a probabilistic finite-state grammar, with 15% chance on each trial of replacing the rules-based grammatical (G) stimulus with a nongrammatical (NG) one. Results indicated a gradual differentiation across sessions between RTs (faster RTs for G than NG), together with NG-related BOLD responses reflecting sequence learning. Similar behavioral patterns were observed in RS and SD participants at Day 4, indicating time- but not sleep-dependent consolidation of performance. Notwithstanding, we observed at Day 4 in the RS group a diminished differentiation between G- and NG-related neurophysiological responses in a set of cortical and subcortical areas previously identified as being part of the network involved in implicit sequence learning and its offline processing during sleep, indicating a sleep-dependent processing of both regular and deviant stimuli. Our results suggest the sleep-dependent development of distinct neurophysiological processes subtending consolidation of implicit motor sequence learning, even in the absence of overt behavioral differences.

Desynchronization of fronto-temporal networks during working memory processing in autism.

Mounting evidence suggests that autism is a network disorder, characterized by atypical brain connectivity, especially in the context of high level cognitive processes such as working memory (WM). Accordingly, atypical WM processes have been related to the social and cognitive deficits observed in children with autism spectrum disorder (ASD).

Sleep and memory consolidation: Motor performance and proactive interference effects in sequence learning

That post-training sleep supports the consolidation of sequential motor skills remains debated. Performance improvement and sensitivity to proactive interference are both putative measures of long-term memory consolidation. We tested sleep-dependent memory consolidation for visuo-motor sequence learning using a proactive interference paradigm. Thirty-three young adults were trained on sequence A on Day 1, then had Regular Sleep (RS) or were Sleep Deprived (SD) on the night after learning. After two recovery nights, they were tested on the same sequence A, then had to learn a novel, potentially competing sequence B. We hypothesized that proactive interference effects on sequence B due to the prior learning of sequence A would be higher in the RS condition, considering that proactive interference is an indirect marker of the robustness of sequence A, which should be better consolidated over post-training sleep. Results highlighted sleep-dependent improvement for sequence A, with faster RTs overnight for RS participants only. Moreover, the beneficial impact of sleep was specific to the consolidation of motor but not sequential skills. Proactive interference effects on learning a new material at Day 4 were similar between RS and SD participants. These results suggest that post-training sleep contributes to optimizing motor but not sequential components of performance in visuo-motor sequence learning.

Atypical spatiotemporal signatures of working memory brain processes in autism

Working memory (WM) impairments may contribute to the profound behavioural manifestations in children with autism spectrum disorder (ASD). However, previous behavioural results are discrepant as are the few functional magnetic resonance imaging (fMRI) results collected in adults and adolescents with ASD. Here we investigate the precise temporal dynamics of WM-related brain activity using magnetoencephalography (MEG) in 20 children with ASD and matched controls during an n-back WM task across different load levels (1-back vs 2-back). Although behavioural results were similar between ASD and typically developing (TD) children, the between-group comparison performed on functional brain activity showed atypical WM-related brain processes in children with ASD compared with TD children. These atypical responses were observed in the ASD group from 200 to 600 ms post stimulus in both the low- (1-back) and high- (2-back) memory load conditions. During the 1-back condition, children with ASD showed reduced WM-related activations in the right hippocampus and the cingulate gyrus compared with TD children who showed more activation in the left dorso-lateral prefrontal cortex and the insulae. In the 2-back condition, children with ASD showed less activity in the left insula and midcingulate gyrus and more activity in the left precuneus than TD children. In addition, reduced activity in the anterior cingulate cortex was correlated with symptom severity in children with ASD. Thus, this MEG study identified the precise timing and sources of atypical WM-related activity in frontal, temporal and parietal regions in children with ASD. The potential impacts of such atypicalities on social deficits of autism are discussed.