Distinct attentional and executive profiles in neurofibromatosis type 1: Is there difference with primary attention deficit-hyperactivity disorder?

PURPOSE: Attentional and executive dysfunctions are the most frequent cognitive disorders in neurofibromatosis type 1 (NF1), with a high prevalence of attention deficit-hyperactivity disorder (ADHD). We (i) compared attentional profiles between NF1 children with and without ADHD and children with primary ADHD criteria and (ii) investigated the possible relationship between attentional disorders and "unidentified bright objects" (UBOs) in NF1. METHODS: This retrospective study included 47 NF1 children, 25 with ADHD criteria (NF1+adhd group), matched for age, sex, and cognitive level with 47 children with primary ADHD (ADHD group). We collected computer task (sustained-attention, visuomotor-decision, inhibition, and cognitive-flexibility tasks) scores normalized for age and sex, and brain magnetic resonance imaging data. RESULTS: (i) Working memory was impaired in all groups. (ii) Omissions (p < 0.002) and response-time variability (p < 0.05) in sustained-attention and visuomotor-decision tasks and errors (p < 0.02) in the cognitive-flexibility task were lower for the NFI+adhd and ADHD groups than for the NF1-no-adhd group. (iii) The NF1+adhd group had slower response times (p ≤ 0.02) for inhibition and visuomotor-decision tasks than the other groups. (iv) We found no relevant association between cognitive performance and UBOs. CONCLUSIONS: NF1 children with ADHD have an attentional and executive functions deficit profile similar to that of children with primary ADHD, but with a slower response-time, increasing learning difficulties. The atypical connectivity of fronto-striatal pathways, poorer dopamine homeostasis, and increased GABA inhibition observed in NF1 renders vulnerable the development of the widely distributed neural networks that support attentional, working-memory, and executive functions.

Negative central activity in extremely preterm newborns: EEG characterization and relationship with brain injuries and neurodevelopmental outcome.

OBJECTIVE: To characterize Negative Central Activity (NCA), an overlooked electroencephalographic activity of preterm newborns and investigate its relationship with brain injuries, dysfunction, and neurodevelopmental outcome. METHODS: 109 preterm infants (23-28 weeks) were retrospectively included. NCA were selected at the negative peak on EEG. Individual averaged NCA were automatically characterized. Brain structural data were collected from cranial ultrasounds (cUS). The neurodevelopmental outcome at two years of age was assessed by the Denver Developmental Screening Test-II. RESULTS: Thirty-six (33%) children showed NCA: 6,721 NCA were selected, a median of 75 (interquartile range, 25/157.3) per EEG. NCA showed a triphasic morphology, with a mean amplitude and duration of the negative component of 24.6-40.0 µV and 222.7-257.3 ms. The presence of NCA on EEG was associated with higher intraventricular haemorrhage (IVH) grade on the first (P = 0.016) and worst neonatal cUS (P < 0.001) and poorer neurodevelopmental outcome (P < 0.001). CONCLUSIONS: NCA is an abnormal EEG feature of extremely preterm newborns that may correspond to the functional neural impact of a vascular pathology. SIGNIFICANCE: The NCA relationships with an adverse outcome and the presence/severity of IVH argue for considering NCA in the assessment of pathological processes in the developing brain network and for early outcome prediction.

Tri-axial rubidium and helium optically pumped magnetometers for on-scalp magnetoencephalography recording of interictal epileptiform discharges: a case study.

Cryogenic magnetoencephalography (MEG) enhances the presurgical assessment of refractory focal epilepsy (RFE). Optically pumped magnetometers (OPMs) are cryogen-free sensors that enable on-scalp MEG recordings. Here, we investigate the application of tri-axial OPMs [87Rb (Rb-OPM) and 4He gas (He-OPM)] for the detection of interictal epileptiform discharges (IEDs). IEDs were recorded simultaneously with 4 tri-axial Rb- and 4 tri-axial He-OPMs in a child with RFE. IEDs were identified visually, isolated from magnetic background noise using independent component analysis (ICA) and were studied following their optimal magnetic field orientation thanks to virtual sensors. Most IEDs (>1,000) were detectable by both He- and Rb-OPM recordings. IEDs were isolated by ICA and the resulting magnetic field oriented mostly tangential to the scalp in Rb-OPMs and radial in He-OPMs. Likely due to differences in sensor locations, the IED amplitude was higher with Rb-OPMs. This case study shows comparable ability of Rb-OPMs and He-OPMs to detect IEDs and the substantial benefits of triaxial OPMs to detect IEDs from different sensor locations. Tri-axial OPMs allow to maximize spatial brain sampling for IEDs detection with a limited number of sensors.

Predicting the Neurodevelopmental Outcome in Extremely Preterm Newborns Using a Multimodal Prognostic Model Including Brain Function Information.

Importance: Early assessment of the prognosis of preterm newborns is crucial for accurately informing parents and making treatment decisions. The currently available prognostic models rarely incorporate functional brain information from conventional electroencephalography (cEEG). Objective: To examine the performance of a multimodal model combining (1) brain function information with (2) brain structure information (cranial ultrasonography), and (3) perinatal and (4) postnatal risk factors for the prediction of death or neurodevelopmental impairment (NDI) in extremely preterm infants. Design, Setting, and Participants: Preterm newborns (23-28 weeks' gestational age) admitted to the neonatal intensive care unit at Amiens-Picardie University Hospital were retrospectively included (January 1, 2013, to January 1, 2018). Risk factors from the 4 categories were collected during the first 2 weeks post delivery. Neurodevelopmental impairment was assessed at age 2 years with the Denver Developmental Screening Test II. No or moderate NDI was considered a favorable outcome. Death or severe NDI was considered an adverse outcome. Data analysis was performed from August 26, 2021, to March 31, 2022. Main Outcomes and Measures: After the selection of variables significantly associated with outcome, 4 unimodal prognostic models (considering each category of variable independently) and 1 multimodal model (considering all variables simultaneously) were developed. After a multivariate analysis for models built with several variables, decision-tree algorithms were run on each model. The areas under the curve for decision-tree classifications of adverse vs favorable outcomes were determined for each model, compared using bootstrap tests, and corrected for type I errors. Results: A total of 109 newborns (58 [53.2% male]) born at a mean (SD) gestational age of 26.3 (1.1) weeks were included. Among them, 52 (47.7%) had a favorable outcome at age 2 years. The multimodal model area under the curve (91.7%; 95% CI, 86.4%-97.0%) was significantly higher than those of the unimodal models (P < .003): perinatal model (80.6%; 95% CI, 72.5%-88.7%), postnatal model (81.0%; 95% CI, 72.6%-89.4%), brain structure model (cranial ultrasonography) (76.6%; 95% CI, 67.8%-85.3%), and brain function model (cEEG) (78.8%; 95% CI, 69.9%-87.7%). Conclusions and Relevance: In this prognostic study of preterm newborns, the inclusion of brain information in a multimodal model was associated with significant improvement in the outcome prediction, which may have resulted from the complementarity of the risk factors and reflected the complexity of the mechanisms that interfered with brain maturation and led to death or NDI.

The frontal sharp transient in newborns: An endogenous neurobiomarker concomitant to the physiological and critical transitional period around delivery?

The frontal sharp transient (FST) consists of transient electrical activity recorded around the transitional period from the in to ex utero environment. Although its positive predictive value is assumed, nothing is known about its functionality or origin. The objectives were (i) to define its characteristics and (ii) to develop functional hypothesis. The 128-channels high-resolution electroencephalograms of 20 healthy newborns (37.1-41.6 weeks) were studied. The morphological and time-frequency characteristics of 418 FSTs were analyzed. The source localization of the FSTs was obtained using a finite element head model (5 layers and fontanels) and various source localization methods (distributed and dipolar). The characteristics (duration, slopes, and amplitude) and the localization of FSTs were not modulated by the huge developmental neuronal processes that occur during the very last period of gestation. The sources were located beneath the ventral median part of the frontal lobe around the interhemispheric fissure, suggesting that the olfactory bulbs and orbitofrontal cortex, essential in olfaction and the mother-infant attachment relationship, are likely candidates for the generation of FSTs. FSTs may contribute to the implementation of the functionalities of brain structures involved in the higher-order processing necessary for survival ahead of delivery, with a genetic fingerprint.

Evolution of cross-frequency coupling between endogenous oscillations over the temporal cortex in very premature neonates.

Temporal theta activity in coalescence with slow-wave (TTA-SW) is one of the first neurobiomarkers of the neurodevelopment of perisylvian networks in the electroencephalography (EEG). Dynamic changes in the microstructure and activity within neural networks are reflected in the EEG. Slow oscillation slope can reflect synaptic strength, and cross-frequency coupling (CFC), associated with several putative functions in adults, can reflect neural communication. Here, we investigated the evolution of CFC, in terms of SW theta phase-amplitude coupling (PAC), during the course of very early development between 25 and 32 weeks of gestational age in 23 premature neonates. We used high-resolution EEG and dipole models as spatial filters to extract the source waveforms corresponding to TTA-SW. We also carried out nonlinear phase-dependent correlation measurements to examine whether the characteristics of the SW slopes are associated with TTA-SW coupling. We show that neurodevelopment leads to temporal accumulation of the SW theta PAC toward the trough of SW. Steepness of the negative going slope of SW determined the degree of this coupling. Systematic modulation of SW-TTA CFC during development is a signature of the complex development of local cortico-cortical perisylvian networks and distant thalamo-cortical neural circuits driving this nested activity over the perisylvian networks.

Back to basics: the neuronal substrates and mechanisms that underlie the electroencephalogram in premature neonates.

Electroencephalography is the only clinically available technique that can address the premature neonate normal and pathological functional development week after week. The changes in the electroencephalogram (EEG) result from gradual structural and functional modifications that arise during the last trimester of pregnancy. Here, we review the structural changes over time that underlie the establishment of functional immature neural networks, the impact of certain anatomical specificities (fontanelles, connectivity, etc.) on the EEG, limitations in EEG interpretation, and the utility of high-resolution EEG (HR-EEG) in premature newborns (a promising technique with a high degree of spatiotemporal resolution). In particular, we classify EEG features according to whether they are manifestations of endogenous generators (i.e. theta activities that coalesce with a slow wave or delta brushes) or come from a broader network. Furthermore, we review publications on EEG in premature animals because the data provide a better understanding of what is happening in premature newborns. We then discuss the results and limitations of functional connectivity analyses in premature newborns. Lastly, we report on the magnetoelectroencephalographic studies of brain activity in the fetus. A better understanding of complex interactions at various structural and functional levels during normal neurodevelopment (as assessed using electroencephalography as a benchmark method) might lead to better clinical care and monitoring for premature neonates.

Stretch syncope or epileptic seizure? A pathologic hypothesis for self-induced stretch syncope.

We report on a 7-year-old female who presented paroxysmal episodes of loss of consciousness with clonic movements. The electroencephalogram (EEG) evidenced diffuse slow wave activations, with no symptoms. Epilepsy was suspected but antiepileptic drugs were ineffective. Video-EEG monitoring revealed that the syncope was triggered by stretching with a tachycardia that started during the stretch maneuver and diffuse slow waves on the EEG 2s before the symptoms. Stretch syncope can result in striking manifestations with subcortically driven clonic movements that can be mistaken for signs of epilepsy. Stretching might lead to transient hypoxia of the brainstem; in turn, this might activate the thalamocortical loop and thus generate cardiovascular changes, EEG slow waves, and physical manifestations.

Impact of prematurity on neurodevelopment.

The consequences of prematurity on brain functional development are numerous and diverse, and impact all brain functions at different levels. Prematurity occurs between 22 and 36 weeks of gestation. This period is marked by extreme dynamics in the physiologic maturation, structural, and functional processes. These different processes appear sequentially or simultaneously. They are dependent on genetic and/or environmental factors. Disturbance of these processes or of the fine-tuning between them, when caring for premature children, is likely to induce disturbances in the structural and functional development of the immature neural networks. These will appear as impairments in learning skills progress and are likely to have a lasting impact on the development of children born prematurely. The level of severity depends on the initial alteration, whether structural or functional. In this chapter, after having briefly reviewed the neurodevelopmental, structural, and functional processes, we describe, in a nonexhaustive manner, the impact of prematurity on the different brain, motor, sensory, and cognitive functions.

The intimate relationship between coalescent generators in very premature human newborn brains: Quantifying the coupling of nested endogenous oscillations.

Temporal theta slow-wave activity (TTA-SW) in premature infants is a specific neurobiomarker of the early neurodevelopment of perisylvian networks observed as early as 24 weeks of gestational age (wGA). It is present at the turning point between non-sensory driven spontaneous networks and cortical network functioning. Despite its clinical importance, the underlying mechanisms responsible for this spontaneous nested activity and its functional role have not yet been determined. The coupling between neural oscillations at different timescales is a key feature of ongoing neural activity, the characteristics of which are determined by the network structure and dynamics. The underlying mechanisms of cross-frequency coupling (CFC) are associated with several putative functions in adults. In order to show that this generic mechanism is already in place early in the course of development, we analyzed electroencephalography recordings from sleeping preterm newborns (24-27 wGA). Employing cross-frequency phase-amplitude coupling analyses, we found that TTAs were orchestrated by the SWs defined by a precise temporal relationship. Notably, TTAs were synchronized to the SW trough, and were suppressed during the SW peak. Spontaneous endogenous TTA-SWs constitute one of the very early signatures of the developing temporal neural networks with key functions, such as language and communication. The presence of a fine-tuned relationship between the slow activity and the TTA in premature neonates emphasizes the complexity and relative maturity of the intimate mechanisms that shape the CFC, the disruption of which can have severe neurodevelopmental consequences.

Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: Is there a major genetic factor?

Myoclonic-atonic epilepsy (MAE) is thought to have a genetic etiology. Mutations in CHD2, SLC2A1 and SLC6A1 genes have been reported in few patients showing often intellectual disability prior to MAE onset. We aimed to explore putative causal genetic factors in MAE. We performed array-CGH and whole-exome sequencing in 27 patients. We considered non-synonymous variants, splice acceptor, donor site mutations, and coding insertions/deletions. A gene was causal when its mutations have been already linked to epilepsy or other brain diseases or when it has a putative function in neuronal excitability or brain development. We identified candidate disease-causing variants in 11 patients (41%). Single variants were found in some known epilepsy-associated genes (namely CHD2, KCNT1, KCNA2 and STXBP1) but not in others (SLC2A1 and SLC6A1). One new candidate gene SUN1 requires further validation. MAE shows underlying genetic heterogeneity with only few cases linked to mutations in genes reported in developmental and epileptic encephalopathies.

Preterm Modulation of Connectivity by Endogenous Generators: The Theta Temporal Activities in Coalescence with Slow Waves.

The neuronal activity of the preterm brain is characterized by various endogenous activities whose roles in neurodevelopmental maturation processes have not been fully elucidated. The preterm EEG is characterized by discontinuities composed of short bursts of activity with dominant low frequencies. One of the earliest endogenous activities is the theta temporal activity in coalescence with slow waves (TTA-SW), which appears at 24 to 32 weeks of gestational age (wGA). The present study investigated the influence of TTA-SW on the spatial organization of the early preterm brain network. To achieve this objective, High-Density EEG data were recorded from preterm infants (29-32 wGA) and functional connectivity (FC) was estimated from the scalp EEG. TTA-SW, particularly in the theta band, induced increased FC between left temporal and left frontal areas and between left temporal and parietal areas with TTA-SW at the left temporal region, while FC was limited to the right temporal regions in the case of TTA-SW at the right temporal region. Regardless of the lateralization of TTA-SW, long-range FCs were observed between left frontal to left parietal areas, suggesting that these regions, together with the temporal region, provide a basis for coherent neuronal activation across distal cortical regions. TTA-SW dynamic features showed that brief phases of TTA-SW had an impact on both local and whole brain network organization, supporting the importance of TTA-SW as a biomarker of brain development.