Phosphatidylserine enriched with polyunsaturated n-3 fatty acid supplementation for attention-deficit hyperactivity disorder in children and adolescents with epilepsy: A randomized placebo-controlled trial.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a frequent comorbidity in children with epilepsy, which management mostly relies on the usual treatments of ADHD, especially methylphenidate. Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed as an alternative therapeutic approach in ADHD without epilepsy but has never been evaluated in epilepsy-associated ADHD. METHODS: A multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA, in eicosapentaenoic- and docosahexaenoic-acid form, conjugated to a phospholipid vector (PS-Omega3) in children aged >6 and <16-years old, and suffering from any type of epilepsy and ADHD (inattentive or combined type) according to DSM-V. After a 4-week baseline period, patients were allocated (1:1) either to placebo group or to PS-Omega 3 group and entered a 12 week-double-blind treatment period which was followed by a 12 week-open-label treatment period. The primary outcome was the reduction of the ADHD-rating scale IV attention-deficit subscore after 12 weeks of treatment. RESULTS: The study was stopped early because of lack of eligible participants and the expected sample size was not reached. Seventy-four patients were randomized, 44 in PS-Omega3, and 30 in the placebo group. The reduction after 12 weeks of treatment in the inattention subscore of the ADHD-IV scale was -1.57 in the PS-Omega3 group, and -2.90 in the placebo group (p = 0.33, α = 5%). Results were similar after 24 weeks of treatment and for all other ADHD-related secondary outcomes, with no difference between placebo and PS-Omega3. CONCLUSION: Our study remaining underpowered, no formal conclusion about the effect of Ps-Omega3 could be drawn. However, our data strongly suggested that the PS-Omega 3 formulation used in the current study did not improve ADHD symptoms in children with epilepsy. PLAIN LANGUAGE SUMMARY: Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed in ADHD but has never been evaluated in patients with both epilepsy and ADHD. To address this issue, we conducted a multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA in children with epilepsy and ADHD. The study was stopped early because of lack of eligible participants, hampering formal conclusion. However, the evolution of the ADHD symptoms at 12 and 24 weeks did not differ between placebo and PUFA supplementation, strongly suggesting that PUFA did not improve ADHD symptoms in children with epilepsy.

Sleep Stage Transitions and Sleep-Dependent Memory Consolidation in Children with Narcolepsy-Cataplexy.

Electroencephalographic sleep stage transitions and altered first REM sleep period transitions have been identified as biomarkers of type 1 narcolepsy in adults, but not in children. Studies on memory complaints in narcolepsy have not yet investigated sleep-dependent memory consolidation. We aimed to explore stage transitions; more specifically altered REM sleep transition and its relationship with sleep-dependent memory consolidation in children with narcolepsy. Twenty-one children with narcolepsy-cataplexy and twenty-three healthy control children completed overnight polysomnography and sleep-dependent memory consolidation tests. Overnight transition rates (number of transitions per hour), global relative transition frequencies (number of transitions between a stage and all other stages/total number of transitions × 100), overnight transitions to REM sleep (transition from a given stage to REM/total REM transitions × 100), and altered first REM sleep period transitions (transitions from wake or N1 to the first REM period) were computed. Narcoleptic children had a significantly higher overnight transition rate with a higher global relative transition frequencies to wake. A lower sleep-dependent memory consolidation score found in children with narcolepsy was associated with a higher overnight transition frequency. As observed in narcoleptic adults, 90.48% of narcoleptic children exhibited an altered first REM sleep transition. As in adults, the altered sleep stage transition is also present in children with narcolepsy-cataplexy, and a higher transition rate could have an impact on sleep-dependent memory consolidation. These potential biomarkers could help diagnose type 1 narcolepsy in children more quickly; however, further studies with larger cohorts, including of those with type 2 narcolepsy and hypersomnia, are needed.

Interest of the BLAST paradigm and salivary markers for the evaluation of sleepiness in drivers.

Objectives: Sleepiness is associated with decreased cognitive abilities and remains one of the main causes of fatal road accidents. The tools currently available to assess sleepiness, such as questionnaires, are subject to intra- and inter-individual variability, while multiple sleep latency tests are only feasible in few sleep laboratories. The main objective of this study was to explore new potential markers (neurocognitive, biological) to objectively assess sleepiness in drivers. Methods: A total of 186 drivers (median age 44 years, range 20-74 years, 73% men, 14% obese) were included during a break at a highway service area, in the morning, while on the road for vacation. Questionnaires on sleepiness and sleep characteristics (habitual and on the night before travel), the Bron-Lyon Attention Stability Test (BLAST), and two salivary samples (α-amylase and oxalate) were collected. Associations between measures of sleepiness [Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS)], sleep characteristics, neurocognitive, and biological markers were tested using regression models adjusted for confounding factors. Results: The night before travel, 83% of the drivers reduced their sleep time and 30% slept 5 h or less. The higher the number of miles to be traveled, the higher the decrease, and the shorter the sleep time. The night before travel, 18 and 24% of the drivers complained of poor sleep quality and difficulty falling asleep. The sleep characteristics on the night before travel were associated with the habitual sleep characteristics. At the time of the test, 47% of the drivers scored pathologically on the SSS. Poor sleep quality and difficulty falling asleep the night before travel were associated with increased sleepiness as assessed by the SSS and decreased attentional ability as assessed by the BLAST. No association between salivary markers and acute sleepiness was observed. Conclusions: The sleep characteristics of the night before travel were associated with sleepiness and attentional performance. The SSS and the BLAST could be used by individual drivers in a self-evaluation context. Biological markers showed a high variability and limited association with sleep parameters across subjects, emphasizing the need for within-subject designs to assess their usefulness.

Sleep disorders and ADHD symptoms in children and adolescents with typical absence seizures: An observational study.

OBJECTIVE: To assess the occurrence of sleep disorders (SD) and attention deficit hyperactivity disorder (ADHD) symptoms in children with typical absence seizures (TAS) compared to control children and to evaluate the impact of epilepsy-related factors on sleep and attention in children with TAS. METHODS: The Sleep Disturbance Scale for Children (SDSC) and the ADHD rating scale were filled in by parents of a cohort composed by 82 children aged from 5 to 15.6 years, 49% of boys (41 with TAS with a syndromic diagnosis of childhood absence epilepsy and 41 controls). For children with TAS, the Pediatric Epilepsy Side Effects Questionnaire was completed. Statistical analyses were conducted in order to compare sleep and attention scores between groups. In children with TAS, a correlation was computed between these scores. Logistics regression models were conducted to identify predictors of excessive diurnal sleepiness and inattention in children with TAS. RESULTS: Compared to controls, children with TAS had higher total scores for subjective sleep (mean 42.9 vs 38.3, p = 0.05) and attention disorders (mean 16.8 vs 11.6, p = 0.01), especially for excessive diurnal sleepiness (mean 3.9 vs 3.2, p = 0.02) and inattention (mean 9.3 vs 5.6, p = 0.003) components. In children with TAS, sleep problems were significantly under-reported by parents. Sleep disorders symptoms as breathing-related sleep disturbance, excessive diurnal sleepiness or naps at or after 7 years of age were reported. Subjective sleep and attention disorders were significantly correlated (r = 0.43, p = 0.01). Subjective excessive diurnal sleepiness may be the result of a polytherapy (p = 0.05) or a side effect of anti-seizure medication (ASM) (p = 0.03) but children without medication side effects also reported subjective SD. In children with TAS, the risk of inattention symptoms was increased in boys (p = 0.02), with a high BMI (p = 0.05), or with ASM side effects (p = 0.03). CONCLUSIONS: This study demonstrates that children with TAS are at risk of sleep and attention disorder symptoms. If attention disorders in a context of epilepsy are now widely assessed and identified, sleep disorders are still under-estimated. An accurate identification and management of sleep disorders could improve academic performances, quality of life, and seizure management in children with TAS.

Screen exposure exacerbates ADHD symptoms indirectly through increased sleep disturbance.

OBJECTIVES: The aim of this study was twofold. First, to confirm the deleterious aspect of evening screen exposure in school-aged children, in particular the effect of screens in the bedroom. Second, to explore the three-way association between degree of screen exposure, sleep disturbance, and ADHD symptoms. Solid evidence exists on the link between sleep disturbance and ADHD symptoms, and screen exposure and sleep disturbance. However, no studies have formally assessed the impact of screen exposure on ADHD symptoms in children, as a function of sleep disturbance. METHODS: Parents of 374 French children (201 girls, 173 boys, mean age of 10.8 ± 2.8 years old) completed the Sleep Disturbance Scale for Children (SDSC), the Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale, and a questionnaire about their children's screen habits (total hours in the morning, afternoon, and evening per day). Correlational analyses between evening screen exposure, sleep quality and behavioral problems were conducted. Then, formal mediation analyses were run in order to quantify the relationship between variables. RESULTS: School-aged children with screens in their bedrooms demonstrated more sleep and behavioral problems. Evening TV exposure was associated with higher SDSC and ADHD scores. Furthermore, the Structural Equation Modelling approach confirmed that evening screen exposure is directly associated with more disrupted sleep, which in turn is directly associated with behavioral problems. CONCLUSIONS: These findings encourage families to avoid putting screens in their children's bedrooms, and limit evening screen exposure. They furthermore demonstrate the importance of taking into account screen exposure time (morning, afternoon, evening) and location (bedroom or elsewhere) in future studies.

Intellectual Abilities of Children with Narcolepsy.

High cognitive functioning could be a protective factor for school difficulties, behavioral and mood impairments in children with narcolepsy. To investigate this factor, we studied the intellectual abilities of 74 children with narcolepsy (43 boys, 11.7 years old at diagnosis, 91% of cataplexies, 64% obese, 100% HLA positive for DR-DQB1*06:02). All children underwent a one-night polysomnography followed by Multiple Sleep Latency Tests, an evaluation of intelligence quotient (IQ), and filled standardized questionnaires. Thirty-eight percent had high potentialities (HP defined by IQ > 130) and 48% had school difficulties. Using non-parametric tests, we found that HP children reported less difficulties at school and tended to have less impulsivity, conduct, and learning disorders than those without HP. They also tended to be less obese and had less desaturation. Using a multivariate regression analysis, we found an association between the REM sleep percentage and the IQ. REM sleep could be involved in the dynamic changes contributing to the equilibrium of intellectual functioning. This study highlights that despite their frequent school difficulties, narcolepsy per se is unlikely to be a cause of intellectual disability in children. Prompt diagnosis and management of comorbidities such as obesity and obstructive sleep apnea (OSA) could improve cognitive and school performances in these children.

Neural correlates of verbal working memory in children with epilepsy with centro-temporal spikes.

BACKGROUND: Previous functional magnetic resonance imaging (fMRI) studies have identified brain systems underlying different components of working memory (WM) in healthy subjects. The aim of this study was to compare the functional integrity of these neural networks in children with self-limited childhood epilepsy with centro-temporal spikes (ECTS) as compared to healthy controls, using a verbal working memory task (WMT). METHODS: Functional MRI of WM in seventeen 6-to-13 year-old children, diagnosed with ECTS, and 17 sex- and age-matched healthy controls were conducted at 3 T. To estimate BOLD responses during the maintenance of low, medium, and high WMT loads, we used a Sternberg verbal WMT. Neuropsychological testing prior to scanning and behavioral data during scanning were also acquired. RESULTS: Behavioral performances during WMT, in particular accuracy and response time, were poorer in children with ECTS than in controls. Increased WM load was associated with increased BOLD signal in all subjects, with significant clusters detected in frontal and parietal regions, predominantly in the left hemisphere. However, under the high load condition, patients showed reduced activation in the frontal, temporal and parietal regions as compared to controls. In brain regions where WM-triggered BOLD activation differed between groups, this activation correlated with neuropsychological performances in healthy controls but not in patients with ECTS, further suggesting WM network dysfunction in the latter. CONCLUSION: Children with ECTS differ from healthy controls in how they control WM processes during tasks with increasing difficulty level, notably for high WM load where patients demonstrate both reduced BOLD activation and behavioral performances.

Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF1 + ADHD) and ADHD Per Se.

Objective: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. Method: One group of children with NF1 + ADHD (N = 32), one group of children with ADHD (N = 31), and one group of healthy controls (N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Results: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. Conclusion: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1.

BLAST: A short computerized test to measure the ability to stay on task. Normative behavioral data and detailed cortical dynamics.

This article provides an exhaustive description of a new short computerized test to assess on a second-to-second basis the ability of individuals to «â€¯stay on task ¼, that is, to apply selectively and repeatedly task-relevant cognitive processes. The task (Bron/Lyon Attention Stability Test, or BLAST) lasts around 1 min, and measures repeatedly the time to find a target letter in a two-by-two letter array, with an update of all letters every new trial across thirty trials. Several innovative psychometric measures of attention stability are proposed based on the instantaneous fluctuations of reaction times throughout the task, and normative data stratified over a wide range of age are provided by a large (>6000) dataset of participants aged 8 to 70. We also detail the large-scale brain dynamics supporting the task from an in-depth study of 32 participants with direct electrophysiological cortical recordings (intracranial EEG) to prove that BLAST involves critically large-scale executive attention networks, with a marked activation of the dorsal attention network and a deactivation of the default-mode network. Accordingly, we show that BLAST performance correlates with scores established by ADHD-questionnaires.

BLAST paradigm: A new test to assess brief attentional fluctuations in children with epilepsy, ADHD, and normally developing children.

BACKGROUND: Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations. OBJECTIVE/METHODS: The recently developed Bron-Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition. RESULTS: In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores. CONCLUSIONS: This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron-Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.

Mind-wandering, or the allocation of attentional resources, is sleep-driven across childhood.

Mind-wandering or the spontaneous, uncontrolled changes in the allocation of attention resources (lapses) may cause variability in performance. In childhood, the relationship between the activation state of the brain, such as in attentional performance, and sleep has not been explored in detail. We investigated the role of sleep in attentional performance, and explored the most important parameters of their relationship. We objectively measured momentary lapses of attention of 522 children and correlated them with sleep schedules. In the subgroup of young children (age 7.1 ± 0.6 years; 60.8% girls), increasing age, long sleep duration and assessment closer to the previous night's sleep period was associated with impaired performance speed and consistency. From pre-adolescence (age 9.4 ± 0.8 years; 50.5% girls) onwards somno-typologies may develop. As a result, in adolescence (age 13.4 ± 1.2 years; 51.3% girls) not only sleep duration but also sleep midpoint and sleep regularity influence the individual speed and stability of attention. Across development, regularity of sleep, individual sleep midpoint and bedtime become increasingly important for optimal performance throughout the day. Attentional performance and sleep shared almost half of their variance, and performance was sleep-driven across childhood. Future studies should focus on intra- and inter-individual differences in sleep-wake behavior to improve performance or decrease mind-wandering in youth by targeting sleep habits.

Don't speak too fast! Processing of fast rate speech in children with specific language impairment.

BACKGROUND: Perception of speech rhythm requires the auditory system to track temporal envelope fluctuations, which carry syllabic and stress information. Reduced sensitivity to rhythmic acoustic cues has been evidenced in children with Specific Language Impairment (SLI), impeding syllabic parsing and speech decoding. Our study investigated whether these children experience specific difficulties processing fast rate speech as compared with typically developing (TD) children. METHOD: Sixteen French children with SLI (8-13 years old) with mainly expressive phonological disorders and with preserved comprehension and 16 age-matched TD children performed a judgment task on sentences produced 1) at normal rate, 2) at fast rate or 3) time-compressed. Sensitivity index (d') to semantically incongruent sentence-final words was measured. RESULTS: Overall children with SLI perform significantly worse than TD children. Importantly, as revealed by the significant Group × Speech Rate interaction, children with SLI find it more challenging than TD children to process both naturally or artificially accelerated speech. The two groups do not significantly differ in normal rate speech processing. CONCLUSION: In agreement with rhythm-processing deficits in atypical language development, our results suggest that children with SLI face difficulties adjusting to rapid speech rate. These findings are interpreted in light of temporal sampling and prosodic phrasing frameworks and of oscillatory mechanisms underlying speech perception.

Behavioral and fMRI responses to fearful faces are altered in benign childhood epilepsy with centrotemporal spikes (BCECTS).

OBJECTIVE: We hypothesized that children with benign childhood epilepsy with centrotemporal spikes (BCECTS) might have altered social cognitive skills and underlying neural networks. METHODS: We studied 13 patients with BCECTS and 11 age-matched controls using event-related functional magnetic resonance imaging (fMRI) with an emotional discrimination task consisting of viewing happy, fearful, scrambled, and neutral faces. Behavioral performance measured during the task was correlated with clinical variables and behavioral ratings. RESULTS: In comparison with age-matched controls, children with BCECTS performing a fearful faces detection task showed significantly reduced bilateral fMRI activation in the insular cortex, caudate, and lentiform nuclei, as well as increased response time. The percentage of errors made by children with BCECTS correlated negatively with age, a finding not observed in controls. In patients, accuracy positively correlated with time since the last seizure. The above abnormalities were not observed during happy faces detection task, except for a slower response in children with BCECTS as compared to controls. SIGNIFICANCE: Our study suggests that BCECTS is associated with altered social cognition network and function, particularly for the identification of fearful faces. The age dependency of some of these findings supports the view that a delayed maturation of spiking cortical regions might underlie the cognitive dysfunction observed in BCECTS.

The French Sleep Disturbance Scale for Children.

OBJECTIVE: The psychometric properties of the Sleep Disturbance Scale for Children (SDSC) have been shown to be accurate, even when translated into several languages. The aim of the present study was to translate, adapt, and validate the SDSC for a French-speaking population. METHODS: After forward- and back-translation, the tool was further translated and adapted into the French language. It was then pretested in terms of clarity on 33 French-speaking parents. Pretesting demonstrated that the questionnaire was well understood, indicating good clarity. During the validation phase, a total of 447 French-speaking parents of children aged between 4 and 16  years completed the SDSC. Among these, 66 children were diagnosed with sleep disorders by a pediatric specialist after a sleep consultation and polysomnographic recordings. RESULTS: The factor analysis revealed five factors: difficulty in initiating and maintaining sleep (DIMS), sleep breathing disorders (SBD), disorders of excessive somnolence (DOES), parasomnias (PARA) and non-restorative sleep (NRS). This psychometric structure is reliable and logical in comparison with the experts' diagnoses. Convergent validity, divergent and internal reliability are very good. Inter-parental concordance in scoring the child's sleep problem does show differences in the ways in which parents report their children's sleep patterns. Cut-off was calculated for the total score (45). CONCLUSION: This study validated a 25-item French version of the questionnaire. The French SDSC could therefore be used to aid screening of sleep disorders in the general population.

ADHD in childhood epilepsy: Clinical determinants of severity and of the response to methylphenidate.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is commonly observed in children with epilepsy. However, factors associated with the development of ADHD and which might help to guide its therapeutic management, remain an issue of debate. METHODS: We conducted a multicenter prospective observational study that included children, aged 6-16 years, with both epilepsy and ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After inclusion, patients entered a 12-16 week follow-up period during which they were either treated with methylphenidate or they did not receive specific ADHD treatment. ADHD was evaluated with the ADHD Rating Scale-IV. RESULTS: One hundred sixty-seven patients were included, of which 91 were seizure-free during the preinclusion baseline period. At inclusion, the ADHD Rating Scale-IV total score was 30.4 ± (standard deviation) 9.2, the inattentive subscore was 17.3 ± 4.4, and the hyperactive subscore was 13.2 ± 6.6. We did not detect any difference of ADHD Rating Scale-IV scores across patients' age or gender, age at epilepsy onset, epilepsy syndrome, seizure frequency, or number of ongoing antiepileptic drugs. Methylphenidate was initiated in 61 patients, including 55 in whom a follow-up evaluation was available. At the last follow-up, 41 patients (75%) treated with methylphenidate and 39 (42%) of those who did not received ADHD therapy demonstrated ≥25% decrease of ADHD Rating Scale-IV total score (p < 0.001). Response to methylphenidate was greater in girls but was not influenced by any epilepsy-related variables. SIGNIFICANCE: We did not detect any epilepsy-related factor associated with the severity of ADHD. Twenty-five percent of patients did not respond to methylphenidate. A better understanding of the pathologic process that underlies ADHD development in childhood epilepsy might be required to improve therapeutic strategies.

Partial validation of a French version of the ADHD-rating scale IV on a French population of children with ADHD and epilepsy. Factorial structure, reliability, and responsiveness.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a well-known comorbidity in children with epilepsy. In English-speaking countries, the scores of the original ADHD-rating scale IV are currently used as main outcomes in various clinical trials in children with epilepsy. In French-speaking countries, several French versions are in use though none has been fully validated yet. We sought here for a partial validation of a French version of the ADHD-RS IV regarding construct validity, internal consistency (i.e., scale reliability), item reliability, and responsiveness in a group of French children with ADHD and epilepsy. METHOD: The study involved 167 children aged 6-15years in 10 French neuropediatric units. The factorial structure and item reliability were assessed with a confirmatory factorial analysis for ordered categorical variables. The dimensions' internal consistency was assessed with Guttman's lambda 6 coefficient. The responsiveness was assessed by the change in score under methylphenidate and in comparison with a control group. RESULTS: The results confirmed the original two-dimensional factorial structure (inattention, hyperactivity/impulsivity) and showed a satisfactory reliability of most items, a good dimension internal consistency, and a good responsiveness of the total score and the two subscores. CONCLUSION: The studied French version of the ADHD-RS IV is thus validated regarding construct validity, reliability, and responsiveness. It can now be used in French-speaking countries in clinical trials of treatments involving children with ADHD and epilepsy. The full validation requires further investigations.

The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of about 1/3000, independent of ethnicity, race, or gender. Attention Deficit Hyperactivity like Disorder (ADHD)-like characteristics are often reported in patients with NF1. We hypothesised that learning disabilities in NF1 children were related to ADHD symptoms. Treatment with methylphenidate (MPD) has improved learning disabilities in ADHD by acting on neurotransmitters. Our objective was to evaluate its efficacy on ADHD-like symptoms in neurofibromatosis type 1 children (7-12 years). METHODS: This was a randomised, double blind, placebo controlled, and crossover trial comparing 0.5 to 0.8 mg/kg/d of MPD as it is indicated for ADHD to placebo in NF1 children with ADHD-like symptoms. Children aged 7 to 12 years were eligible when their IQ was between 80 and 120. The total follow-up was 9 weeks including 4 weeks for each period and 1 week wash out. Fifty subjects (25 for each period) were required for testing the primary study hypothesis. The main outcome was an improvement in scores on the simplified Conners' Parent Rating Scale. RESULTS: Thirty-nine patients were included between April 2004 and December 2010. Twenty participants received MPD and 19 placebo during the first period. They all completed the trial. MPD decreased the simplified Conners by 3.9 points (±1.1, p = 0. 0003). CONCLUSIONS: This is the first randomised controlled trial showing the short-term benefit of MPD on simplified Conners scores in NF1 children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00169611.

White matter development in children with benign childhood epilepsy with centro-temporal spikes.

Benign childhood epilepsy with centro-temporal spikes (BCECTS) is a unique form of non-lesional age-dependent epilepsy with rare seizures, focal electroencepalographic abnormalities affecting the same well delineated cortical region in most patients, and frequent mild to moderate cognitive dysfunctions. In this condition, it is hypothesized that interictal electroencepalographic discharges might interfere with local brain maturation, resulting in altered cognition. Diffusion tensor imaging allows testing of this hypothesis by investigating the white matter microstructure, and has previously proved sensitive to epilepsy-related alterations of fractional anisotropy and diffusivity. However, no diffusion tensor imaging study has yet been performed with a focus on BCECTS. We investigated 25 children suffering from BCECTS and 25 age-matched control subjects using diffusion tensor imaging, 3D-T1 magnetic resonance imaging, and a battery of neuropsychological tests including Conner's scale and Wechsler Intelligence Scale for Children (fourth revision). Electroencephalography was also performed in all patients within 2 months of the magnetic resonance imaging assessment. Parametric maps of fractional anisotropy, mean-, radial-, and axial diffusivity were extracted from diffusion tensor imaging data. Patients were compared with control subjects using voxel-based statistics and family-wise error correction for multiple comparisons. Each patient was also compared to control subjects. Fractional anisotropy and diffusivity images were correlated to neuropsychological and clinical variables. Group analysis showed significantly reduced fractional anisotropy and increased diffusivity in patients compared with control subjects, predominantly over the left pre- and postcentral gyri and ipsilateral to the electroencephalographic focus. At the individual level, regions of significant differences were observed in 10 patients (40%) for anisotropy (eight reduced fractional anisotropy, one increased fractional anisotropy, one both), and 17 (56%) for diffusivity (13 increased, one reduced, three both). There were significant negative correlations between fractional anisotropy maps and duration of epilepsy in the precentral gyri, bilaterally, and in the left postcentral gyrus. Accordingly, 9 of 12 patients (75%) with duration of epilepsy>12 months showed significantly reduced fractional anisotropy versus none of the 13 patients with duration of epilepsy≤12 months. Diffusivity maps positively correlated with duration of epilepsy in the cuneus. Children with BCECTS demonstrate alterations in the microstructure of the white matter, undetectable with conventional magnetic resonance imaging, predominating over the regions displaying chronic interictal epileptiform discharges. The association observed between diffusion tensor imaging changes, duration of epilepsy and cognitive performance appears compatible with the hypothesis that interictal epileptic activity alters brain maturation, which could in turn lead to cognitive dysfunction. However, such cross-sectional association does not demonstrate causality, and other hitherto unidentified factors could represent the common cause to part or all of the observed findings.

Reactivity to visual signals in neurofibromatosis type 1: is everything ok?

OBJECTIVE: Deficits in multiple aspects of attention are a hallmark of the cognitive impairments found with neurofibromatosis type I (NF1). Given, however, that some attention components are hierarchically organized, it is possible that sustained attention, flexibility, and resistance to interference deficits observed in NF1 may be because of weakened lower order attention components. This study investigated the state of these low-level components in NF1. METHOD: Twenty participants with NF1 (ages 7-13) and 20 matched controls participated in a visual task. They were required to locate a target as quickly and as accurately as possible and to ignore a potential distractor that could appear either before, at the same time, or after the target. Response times (RTs) were collected, and indices of alerting (i.e., reactivity to warning signals), distraction, and interruption (i.e., reactivity to signals appearing during attentive processing) were computed. RESULTS: The amplitude of the indices differed between the groups, F(2, 76) = 3.1, p < .05. No difference was found with alerting (p > .85) or distraction (p > .84), but the interruption index was higher in the NF1 group than the controls (p < .043). CONCLUSIONS: Elementary components on which more complex attention processes are based are not all ok in NF1. It is suggested that overreactivity to and longer inspection of visual signals occurring outside the current focus of attention characterizes NF1 and that this might be partially responsible for focus of attention instability and lower interference resistance in NF1.

Rhythmic auditory stimulation influences syntactic processing in children with developmental language disorders.

OBJECTIVE: Children with developmental language disorders have been shown to be impaired not only in language processing (including syntax), but also in rhythm and meter perception. Our study tested the influence of external rhythmic auditory stimulation (i.e., musical rhythm) on syntax processing in children with specific language impairment (SLI; Experiment 1A) and dyslexia (Experiment 1B). METHOD: Children listened to either regular or irregular musical prime sequences followed by blocks of grammatically correct and incorrect sentences. They were required to perform grammaticality judgments for each auditorily presented sentence. RESULTS: Performance of all children (SLI, dyslexia, and controls) in the grammaticality judgments was better after regular prime sequences than after irregular prime sequences, as shown by d' data. The benefit of the regular prime was stronger for SLI children (partial η2 = .34) than for dyslexic children (partial η2 = .14), who reached higher performance levels. CONCLUSION: Together with previous findings on deficits in temporal processing and sequencing, as well as with the recent proposition of a temporal sampling (oscillatory) framework for developmental language disorders (U. A. Goswami, 2011, Temporal sampling framework for developmental dyslexia, Trends in Cognitive Sciences, Vol. 15, pp. 3-10), our results point to potential avenues in using rhythmic structures (even in nonverbal materials) to boost linguistic structure processing.