Somatosensory-evoked delta brush activity in very pre-term infants

INTRODUCTION: Delta brushes - slow waves with over-riding alpha-beta oscillations - are a hallmark of the pre-term EEG, and can be evoked by somatosensory stimulation (Whitehead et al., 2017). As such, they may be a biomarker of early sensory processing, with their attenuation indicating maturation of somatosensory circuits. In animal models, the somatosensory system is known to mature in a rostro-caudal progression, with hindlimb somatosensation last to develop, but little is known about the development of somatosensory processing in the human infant brain. Here we investigated the attenuation of delta brush activity following tactile stimulation of hands and feet over the pre-term period. METHODS: We recorded 16-channels EEG and evaluated the somatosensory evoked response following tactile mechanical stimulation of hands and feet in 38 pre-term infants at low-risk of adverse neurodevelopment (exclusion: (i) intra-ventricular haemorrhage ⩾ grade III; (ii) severe growth restriction (defined as <2nd birth weight centile)). We then looked at changes in the amplitude of the slow delta wave and of the over-riding alpha-beta oscillations in the evoked response between very pre-term (28 + 2 − 31 + 2 weeks + days, n = 13) and moderately pre-term (32 + 2 − 35 + 4 weeks + days, n = 25) infants using point-by-point t-tests (statistical significance set at p < 0.01 to account for multiple comparisons). RESULTS: Tactile stimulation of hands and feet evoked a long-lasting diffuse negative delta slow wave, with onset latency at ∼100 ms, peak latency at ∼500 ms, and peak amplitude of ∼100 μV and ∼50 μV for hand and foot stimulation respectively, and an increase in alpha-beta oscillations concurrent with the peak latency of this slow wave. We first looked at changes in the amplitude of the slow delta wave. This delta wave attenuated in amplitude in the older age group most prominently over the contralateral parietal-temporal region for hand stimulation, and most prominently over the midline parietal and bilateral temporal regions for foot stimulation. Next, we looked at changes in the amplitude of the alpha-beta oscillations which co-occurred with the peak latency of this slow delta wave. Alpha-beta oscillations attenuated in amplitude in the older age group over bilateral parietal regions for hand stimulation, while there was no difference between the age groups for foot stimulation. CONCLUSION: This is the first developmental study of delta brushes evoked by stimulation of the upper and lower limbs. Our results indicate that in very pre-term infants tactile stimulation evokes diffuse delta brush activity, which attenuates across development most markedly over the parietal-temporal regions. Interestingly, delta brush alpha-beta oscillations only decrease with development for hand stimulation, but not foot stimulation, suggesting that somatosensory maturation may occur earlier for the hands in line with studies of older infants (Whitehead et al., submitted for publication), and animal models

Electroencephalographic characteristics of epileptic seizures in preterm neonates

OBJECTIVE: Although seizures are more common in the neonatal period than in any other stage of childhood, those in preterm neonates are still poorly described. The aim of this study was to assess electro-clinical characteristics of seizures occurring before a corrected age of 40 weeks in neonates born prematurely. METHOD: Retrospective analysis of EEG-documented seizures in neonates born prematurely. Seizures in a group of term neonates served as controls. RESULTS: Fifty-six prematurely born and 46 term born neonates were included. Median duration of seizures was 52 s in preterm and 96 s in term neonates. Seizures were focal or multifocal. In least mature neonates, they involved smaller regions of onset and remained localised. With increasing corrected age, propagation became more frequent. The electrographic pattern – maximal frequency of oscillation and the onset pattern also evolved with age. Electro-clinical seizures were observed in 25% of preterm versus 50% of term neonates; almost all electro-clinical seizures involved the central (motor) regions. CONCLUSION: Ictal EEG features undergo changes depending on corrected age. Most seizures are subclinical, thus EEG is essential for diagnosis. SIGNIFICANCE: Relating ictal EEG pattern to corrected age can improve diagnosis and ultimately management

Does sleep benefit memory consolidation in children with focal epilepsy?

OBJECTIVE: Children with epilepsy have high rates of both cognitive impairment and sleep disruption. It is thus assumed that sleep-dependent memory consolidation is vulnerable to ongoing epileptic activity, but direct evidence of this is limited. METHODS: We performed a within-subject comparison of memory retention across intervals of wake or overnight sleep. Healthy children (n = 21, 6-16 years, 12 female) and children with focal epilepsy (n = 22, 6-16 years, 9 female) performed verbal and visuospatial memory tasks under each condition. Sleep was assessed with electroencephalography (EEG) polysomnography during the overnight interval. Interictal discharges were quantified manually. RESULTS: Memory retention was greater in the sleep condition in both the verbal (F1,39 = 10.8, p = 0.002, Cohen's d = 0.67) and the visuospatial (F1,36 = 4.23, p = 0.05, Cohen's d = 0.40) tasks, with no significant interaction of group by condition in either task. Across the total sample, gain in memory retention with sleep in the verbal task correlated with duration of slow wave sleep (r = 0.4, p = 0.01). In patients, sleep-dependent memory consolidation was negatively correlated with interictal discharge rate in both the verbal (ρ = -0.49, p = 0.04) and visuospatial (ρ = -0.45, p = 0.08) tasks. On post hoc analysis, a longer history of epilepsy (r = 0.53, p = 0.01) and a temporal (t10 = 1.8, p = 0.1, Cohen's d = 0.86) rather than an extratemporal seizure focus (t10 = 0.8, p = 0.4, Cohen's d = 0.30) was associated with greater contribution of sleep to verbal memory retention. SIGNIFICANCE: We have demonstrated that memory consolidation in children with focal epilepsy benefits from sleep, showing the same correlation with slow wave sleep as in healthy children, but an inverse relationship with the interictal discharge load during sleep. This mechanism appears to be increasingly recruited with longer duration of illness, indicating a resilient homeostatic function which may be harnessed to aid learning

Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines

The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMAPaediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private–public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of offpatent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes

Double jeopardy: the influence of excessive daytime sleepiness and impaired cognition on health‐related quality of life in adults with heart failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106066/1/ejhfhfs054.pd

Parent-led massage and sleep EEG for term-born infants: A randomized controlled parallel-group study

AIM: To examine the impact of parent-led massage on the sleep electroencephalogram (EEG) features of typically developing term-born infants at 4 months. METHOD: Infants recruited at birth were randomized to intervention (routine parent-led massage) and control groups. Infants had a daytime sleep EEG at 4 months and were assessed using the Griffiths Scales of Child Development, Third Edition at 4 and 18 months. Comparative analysis between groups and subgroup analysis between regularly massaged and never-massaged infants were performed. Groups were compared for sleep stage, sleep spindles, quantitative EEG (primary analysis), and Griffiths using the Mann-Whitney U test. RESULTS: In total, 179 out of 182 infants (intervention: 83 out of 84; control: 96 out of 98) had a normal sleep EEG. Median (interquartile range) sleep duration was 49.8 minutes (39.1-71.4) (n = 156). A complete first sleep cycle was seen in 67 out of 83 (81%) and 72 out of 96 (75%) in the intervention and control groups respectively. Groups did not differ in sleep stage durations, latencies to sleep and to rapid eye movement sleep. Sleep spindle spectral power was greater in the intervention group in main and subgroup analyses. The intervention group showed greater EEG magnitudes, and lower interhemispherical coherence on subgroup analyses. Griffiths assessments at 4 months (n = 179) and 18 months (n = 173) showed no group differences in the main and subgroup analyses. INTERPRETATION: Routine massage is associated with distinct functional brain changes at 4 months

An introduction to neonatal EEG

Electroencephalography (EEG) is used in neonatal care to assess encephalopathy, seizure recognition and classification, to make epilepsy syndrome diagnoses and to assess the maturity of neonatal brain activity. A basic understanding of the EEG is very helpful in ensuring that clinicians gain as much information as possible from this helpful, non-invasive investigation. The neonatal EEG is complex and accurate reporting requires detailed clinical information to be provided on request forms. Even when this is provided EEG reports are frequently returned to the neonatal unit loaded with technical details, making it difficult for neonatal staff to fully understand them. This article reviews the basics of EEG, the changes seen with increasing gestational age, and changes seen in common pathologies. We also provide a structured approach to the interpretation of the neonatal EEG report, and discuss its role in prognostication. Amplitude integrated EEG is reviewed in our companion paper

Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior

The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1+/− mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1