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Agnese Suppiej,1 Elisa Cainelli1,2 1Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Italy; 2Lifespan Cognitive Neuroscience Laboratory (LCNL), Department of General Psychology, University of Padua, Italy Abstract: Cognitive and neuropsychological impairments are well documented in adult ­multiple sclerosis (MS). Research has only recently focused on cognitive disabilities in pediatric cases, highlighting some differences between pediatric and adult cases. Impairments in several functions have been reported in children, particularly in relation to attention, processing speed, visual–motor skills, and language. Language seems to be particularly vulnerable in pediatric MS, unlike in adults in whom it is usually preserved. Deficits in executive functions, which are considered MS-specific in adults, have been inconsistently reported in children. In children, as compared to adults, the relationship between cognitive dysfunctions and the two other main symptoms of MS, fatigue and psychiatric disorders, was poorly explored. Furthermore, data on the correlations of cognitive impairments with clinical and neuroimaging features are scarce in children, and the results are often incongruent; interestingly, involvement of corpus callosum and reduced thalamic volume differentiated patients identified as having a cognitive impairment from those without a cognitive impairment. Further studies about pediatric MS are needed in order to better understand the impact of the disease on brain development and the resulting effect on cognitive functions, particularly with respect to different therapeutic strategies. Keywords: central nervous system, child, deficit, IQ, inflammatory demyelination, neuropsychological

The mechanisms of perinatal stroke are poorly understood but preclinical studies point to the crucial role of perinatal inflammation. Carotid artery occlusion represents a very rare and severe cause of perinatal stroke. We describe two cases diagnosed with extensive ischemic stroke due to carotid artery occlusion. In both cases, we demonstrated placental vasculopathy. High levels of C-reactive protein in mother and/or neonates suggested inflammatory mechanism as a potential trigger. Both cases underwent hypothermic treatment without complications because of initial diagnosis of perinatal asphyxia. The prognosis at the time of the last follow up was severe including cerebral palsy, epilepsy and cognitive impairment. Our cases contribute to the actual debate on pathogenic mechanisms and treatment options for this rare condition. [ABSTRACT FROM AUTHOR]

From the start of pregnancy, mother and child induce reciprocal neurobiological changes in the brain that will prove critical for neurodevelopment and survival of both. Molecular communication between mother and fetus is constantly active and persists even after the fetus starts to synthesize its hormones in late gestation. Intriguingly, some mother and fetus exchange cells remain in the other's brain and body with long-lasting effects and memories that do not follow the laws of classical genetics but involve complex epigenetic mechanisms. After childbirth, mother and child go through a transitional phase, a sort of limbo in which both will have a peculiar functioning profile, which is adaptive for contingencies but also renders them vulnerable. The interplay between these two "limbo" states allows for an easier transition to the subsequent phases of development. In this review, we will trace mother's and child's path from pregnancy to the months following birth and, in particular, unravel i) the key features of pregnancy and brain development and the reciprocal influences; ii) how a transitory pattern of functioning characterize mother and child, moving them toward more flexible and evolved forms; and iii) how mother and fetus act during childbirth to promote neuroprotection, pain reduction, and neurophysiological changes. Therefore, this review covers a wide range of topics, integrating neuroanatomical, neurological, biochemical, neurophysiological, and psychological studies in a meaningful way, trying to integrate them in a holistic view of the mother-child interface that is usually neglected., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Listening to heartbeat sounds have been found to affect cardiac activity and behavior. However, less is known about the effects of these stimuli on brain activity and cognition. Alpha oscillations (8-13 Hz) are considered markers of cortical activation. Frontal alpha Asymmetry (FαA) reflects the valence attributed to the stimulus and the tendency to approach/avoid it., Aim: This study investigates the effects of sounds mimicking heart pulsations at different rhythms on reaction times and neurophysiological activity., Method: EEG data were collected during a resting-state condition and two Simple Reaction Time tasks (SRT), during which artificially generated heartbeat sounds at fast (120 bpm, FastBeat condition) or slow (60 bpm, SlowBeat condition) rhythms were administered. Alpha power was compared across the three conditions. Differences in the SRT and FαA values were examined between the FastBeat and SlowBeat conditions., Results: Compared to the resting-state condition, decreased alpha activity over bilateral frontocentral regions was observed in both tasks. The comparison between the FastBeat and the SlowBeat conditions revealed faster response times, a pattern of alpha suppression over right frontal regions, and lower FαA values in the former., Conclusions: The similarity of alpha reductions elicited in the comparison between the resting-state and the two task conditions suggests that these patterns were ascribable to processes common to both conditions (SRT task, auditory stimulation). In contrast, the differences between the two conditions suggest that fast heartbeat sounds are perceived as more adverse and stressful stimuli, inducing cortical activation over regions associated with negative states and avoidant tendencies., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Children who experience adversities in the pre-perinatal period are at increased risk of developing impairment later in life, despite the absence of overt brain and neurological abnormalities. However, many of these children exhibit sequelae several years after a period of normal appearance. As a result, the need for reliable developmental assessments for the early detection of infants at high risk of adverse neurodevelopmental outcomes has emerged. The Griffiths Mental Developmental Scales have a promising but poorly explored prognostic ability. This longitudinal study evaluated the predictive power of the Griffiths Mental Developmental Scales at 12 and 24 months on the cognitive and neuropsychological profile at 6 years of age in a sample of 70 children with a history of prematurity or perinatal asphyxia but without brain and neurological abnormalities. We found that the Griffiths Mental Developmental Scales at 24 months had good predictive ability on the intelligence quotient at 6 years and the capacity to predict some neuropsychological performances. On the other hand, the Griffiths Mental Developmental Scale at 12 months was not associated with the performance at 6 years or 24 months.   Conclusion: Data on brain development converge to indicate that the first two years of age represent a critical stage of development, particularly for children experiencing mild pre-perinatal adversities who are thought to exhibit white matter dysmaturity. For this reason, this age is crucial for identifying which children are at major risk, leaving enough time to intervene before overt deficits become apparent. Brain development in the first 2 years could explain the limited reliability of early neurodevelopmental testing. What is Known: • Pre-perinatal adversities increase the risk of developing neurodevelopmental disorders. • The predictive ability of the Griffith scale is poorly explored in low-grade conditions. What is New: • The predictive ability of the Griffith scale has been investigated in low-risk children. • A complete neuropsychological profile could offer a more accurate prediction than the intellectual quotient., (© 2023. The Author(s).)

Background: Psychopathology has not yet been studied beyond pediatric age for all degrees of prematurity, including late-preterm, particularly in those who grew up with no apparent neurodevelopmental sequelae. This study aimed to examine psychopathological outcome following preterm birth and admission to neonatal intensive care in young adults without major neurodevelopmental and psychopathological problems that emerged during childhood., Methods: An Italian single-center prospective cohort study. Eighty-nine young adults (40 admitted to neonatal intensive care unit with less than 37 weeks of gestation and no medical history of other neurological or psychiatric conditions in childhood and 49 healthy peers born at term, matched by age, sex, and education) underwent neuropsychiatric interviews at the age of 20 ± 1 years; MINI International Neuropsychiatric Interview, Beck Depression Inventory and Barratt Impulsive Scale, results were correlated to individual neonatal data and cognitive measures., Results: We found a significantly higher prevalence of psychopathology at MINI score (22.5% vs. 4.2%; χ2 = 6.7; p = 0,010) and prevalence of previous stressful life events in the preterm compared to at-term group. B.D.I. (testing depression) and BIS-11(testing impulsivity) did not highlight a statistically significant difference between the groups. All patients had average I.Q., a statistically significant difference (p < 0.001) was observed between groups with a better performance in controls than cases., Conclusions: Preterm infants attaining young adult age with otherwise typical development during childhood are at risk of psychopathology and lower resilience to stressful life events. The MINI interview could be a useful tool to highlight the psychopathology of preterm infants attaining adult age., Competing Interests: Declaration of competing interest None declared., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Dyslexia is one of the most studied learning disorders. Despite this, its biological basis and main causes are still not fully understood. Electroencephalography (EEG) could be a powerful tool in identifying the underlying mechanisms, but knowledge of the EEG correlates of developmental dyslexia (DD) remains elusive. We aimed to systematically review the evidence on EEG correlates of DD and establish their quality. In July 2021, we carried out an online search of the PubMed and Scopus databases to identify published articles on EEG correlates in children with dyslexia aged 6 to 12 years without comorbidities. We follow the PRISMA guidelines and assess the quality using the Appraisal Tool questionnaire. Our final analysis included 49 studies (14% high quality, 63% medium, 20% low, and 2% very low). Studies differed greatly in methodology, making a summary of their results challenging. However, some points came to light. Even at rest, children with dyslexia and children in the control group exhibited differences in several EEG measures, particularly in theta and alpha frequencies; these frequencies appear to be associated with learning performance. During reading-related tasks, the differences between dyslexic and control children seem more localized in the left temporoparietal sites. The EEG activity of children with dyslexia and children in the control group differed in many aspects, both at rest and during reading-related tasks. Our data are compatible with neuroimaging studies in the same diagnostic group and expand the literature by offering new insights into functional significance., (© 2022. The Author(s).)

We aimed to assess the glucose and lactate kinetics during therapeutic hypothermia (TH) in infants with hypoxic-ischemic encephalopathy and its relationship with longitudinal neurodevelopment. We measured glucose and lactate concentrations before TH and on days 2 and 3 in infants with mild, moderate, and severe hypoxic-ischemic encephalopathy (HIE). Neurodevelopment was assessed at 2 years. Participants were grouped according to the neurodevelopmental outcome into favorable (FO) or unfavorable (UFO). Eighty-eight infants were evaluated at follow-up, 34 for the FO and 54 for the UFO group. Severe hypo- (< 2.6 mmol/L) and hyperglycemia (> 10 mmol/L) occurred in 18% and 36% from the FO and UFO groups, respectively. Glucose-to-lactate ratio on day 1 was the strongest predictor of unfavorable metabolic outcome (OR 3.27 [Formula: see text] 1.81, p = 0.032) when adjusted for other clinical and metabolic variables, including Sarnat score., Conclusion: Glucose-to-lactate ratio on day 1 may represent a new risk marker for infants with HIE undergoing TH., What Is Known: • Glucose and lactate are key metabolic fuels during neonatal hypoglycemia. This suggests that their concentrations may influence the neurodevelopmental outcome of neonates experiencing hypoxic-hischemic encephalopathy (HIE)., What Is New: • We describe the relative availbility of glucose and lactate before and during theraputic hypothermia in neonates with HIE., (© 2022. The Author(s).)

Recent decades have seen a dramatic increase in neurodevelopmental disorders and the attention paid to them. Since their emergence in the not-so-distant past, some neurodevelopmental disorders have undergone considerable redefinition and, beginning in the 21st century, there has been a massive increase in research. In this paper, we briefly review the history of some of them, address some of the issues that characterize their current management and relationship with neurological pathologies, and share some insights for the future.

Objectives: Intra-amniotic inflammation is a subclinical condition frequently caused by either microbial invasion of the amniotic cavity or sterile inflammatory stimuli, e.g., alarmins. An accumulating body of evidence supports a role for maternal immune activation in the genesis of fetal neuroinflammation and the occurrence of neurodevelopmental disorders such as cerebral palsy, schizophrenia, and autism. The objective of this study was to determine whether fetal exposure to mid-trimester intra-amniotic inflammation is associated with neurodevelopmental disorders in children eight to 12 years of age., Methods: This is a retrospective case-control study comprising 20 children with evidence of prenatal exposure to intra-amniotic inflammation in the mid-trimester and 20 controls matched for gestational age at amniocentesis and at delivery. Amniotic fluid samples were tested for concentrations of interleukin-6 and C-X-C motif chemokine ligand 10, for bacteria by culture and molecular microbiologic methods as well as by polymerase chain reaction for eight viruses. Neuropsychological testing of children, performed by two experienced psychologists, assessed cognitive and behavioral domains. Neuropsychological dysfunction was defined as the presence of an abnormal score (<2 standard deviations) on at least two cognitive tasks., Results: Neuropsychological dysfunction was present in 45% (9/20) of children exposed to intra-amniotic inflammation but in only 10% (2/20) of those in the control group (p=0.03). The relative risk (RR) of neuropsychological dysfunction conferred by amniotic fluid inflammation remained significant after adjusting for gestational age at delivery [aRR=4.5 (1.07-16.7)]. Of the 11 children diagnosed with neuropsychological dysfunction, nine were delivered at term and eight of them had mothers with intra-amniotic inflammation. Children exposed to intra-amniotic inflammation were found to have abnormalities in neuropsychological tasks evaluating complex skills, e.g., auditory attention, executive functions, and social skills, whereas the domains of reasoning, language, and memory were not affected in the cases and controls., Conclusions: Asymptomatic sterile intra-amniotic inflammation in the mid-trimester of pregnancy, followed by a term birth, can still confer to the offspring a substantial risk for neurodevelopmental disorders in childhood. Early recognition and treatment of maternal immune activation in pregnancy may be a strategy for the prevention of subsequent neurodevelopmental disorders in offspring., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The most common adverse pre/perinatal events have a great impact on neurodevelopment, with avalanche effects on academic performance, occupational status, and quality of life. Although the injury process starts early, the effects may become evident much later, when life starts to pose more challenging demands. In the present work, we want to address the impact of early insults from an evolutionary perspective by performing unsupervised cluster analysis. We fed all available data, but not the group identification, into the algorithm for 114 children aged 5-10 years, with different adverse medical conditions: healthy (n = 30), premature (n = 28), neonatal hypoxic-ischemic encephalopathy (n = 28), and congenital heart disease (n = 28). We measured general intelligence and many neuropsychological domains (language, attention, memory, executive functions, and social skills). We found three emerging groups that identify children with multiple impairments (cluster 3), children with variable neuropsychological profiles but in the normal range (cluster 2), and children with adequate profiles and good performance in IQ and executive functions (cluster 1). Our analysis divided our patients by severity levels rather than by identifying specific neuropsychological phenotypes, suggesting different developmental trajectories that are characterized by good resilience to early stressful events with adequate development or by pervasive vulnerability to neurodevelopmental disorders.

In recent years, the increase of psychopathological disorders in the population has become a health emergency, leading to a great effort to understand psychological vulnerability mechanisms. In this scenario, the role of the autonomic nervous system (ANS) has become increasingly important. This study investigated the association between ANS, social skills, and psychopathological functioning in children. As an ANS status proxy, we measured heart rate variability (HRV). Infants admitted to the neonatal intensive care unit of the University Hospital of Padova because of preterm birth or neonatal hypoxic-ischemic encephalopathy were sequentially recruited from January 2011 to June 2013 and followed long-term up to school age in this cross-sectional observational study. We recorded 5 minutes of HRV immediately before measuring performance in social abilities tasks (affect recognition and theory of mind, NEPSY-II) in 50 children (mean age 7.4 ± 1.4 years) with and without risk factors for developing neuropsychiatric disorders due to pre-/perinatal insults without major sequelae. Children also completed extensive cognitive, neuropsychological, and psychosocial assessment. Parents were assessed with psychopathological interviews and a questionnaire (CBCL 6-18). Analysis in a robust Bayesian framework was used to unearth dependencies between HRV, social skills, and psychopathological functioning. Social task scores were associated with HRV components, with high frequency the most consistent. HRV bands were also associated with the psychopathological questionnaire. Only normalized HRV high frequency was able to distinguish impaired children in the affect recognition task. Our data suggest that ANS may be implicated in social cognition both in typical and atypical developmental conditions and that HRV has cross-disease sensitivity. We suggest that HRV parameters may reflect a neurobiological vulnerability to psychopathology. The study was approved by the Ethics Committee of the University Hospital of Padova (Comitato Etico per la Sperimentazione, Azienda Opedaliera di Padova, approval No. 1693P)., Competing Interests: None

Asymmetry characterizes the brain in both structure and function. Anatomical asymmetries explain only a fraction of functional variability in lateralization, with structural and functional asymmetries developing at different periods of life and in different ways. In this work, we perform a scoping review of the cerebral asymmetries in the first brain development phases. We included all English-written studies providing direct evidence of hemispheric asymmetries in full-term neonates, foetuses, and premature infants, both at term post-conception and before. The final analysis included 57 studies. The reviewed literature shows large variability in the used techniques and methodological procedures. Most structural studies investigated the temporal lobe, showing a temporal planum more pronounced on the left than on the right (although not all data agree), a morphological asymmetry already present from the 29th week of gestation. Other brain structures have been poorly investigated, and the results are even more discordant. Unlike data on structural asymmetries, functional data agree with each other, identifying a leftward dominance for speech stimuli and an overall dominance of the right hemisphere in all other functional conditions. This generalized dominance of the right hemisphere for all conditions (except linguistic stimuli) is in line with theories stating that the right hemisphere develops earlier and that its development is less subject to external influences because it sustains functions necessary to survive., (© 2021. The Author(s).)

In the first days after birth, a major focus of research is to identify infants with hypoxic-ischemic encephalopathy at higher risk of death or severe neurological impairment, despite therapeutic hypothermia (TH). This is especially crucial to consider redirection of care, according to neonatal outcome severity. We aimed to seek associations between some neonatal routine parameters, usually recorded in Neonatal Intensive Care Units, and the development of severe outcomes. All consecutive patients prospectively recruited for TH for perinatal asphyxia, born between February 2009 and July 2016, were eligible for this study. Severe outcome was defined as death or major neurological sequelae at one year of age. Among all eligible neonates, the final analysis included 83 patients. Severe outcome was significantly associated with pH and base excess measured in the first hour of life, mode of delivery, Apgar score, Sarnat and Sarnat score, electroencephalogram-confirmed neonatal epileptic seizures, and antiepileptic therapy. Studying univariate analysis by raw relative risk (RR) and 95% confidence intervals (CI), severe outcome was significantly associated with pH ( p = 0.011), Apgar score ( p = 0.003), Sarnat score ( p < 0.001), and Caesarian section ( p = 0.015). Conclusions. In addition to clinical examination, we suggest a clinical-electroencephalographic protocol useful to identify neonates at high neurological risk, available before rewarming from TH.

Background: Data on long-term outcomes in the era before therapeutic hypothermia (TH) showed a higher incidence of cognitive problems. Since the introduction of TH, data on its results are limited., Methods: Our sample population consisted of 40 children with a history of hypoxic-ischemic encephalopathy (HIE) treated with TH, with an average age of 6.25 years (range 5.5, 7.33), 24 (60%) males; and 33 peers with an average age of 8.8 years (6.08, 9.41), 17 (51%) males. Long-term follow-up data belong to two centers in Padova and Torino. We measured general intelligence (WPPSI-III or WISC-IV) and neuropsychological functioning (language, attention, memory, executive functions, social skills, visual motor abilities). We also administered questionnaires to their parents on the children's psychopathological profiles and parental stress., Results: We found differences between groups in several cognitive and neuropsychological domains: intelligence, visuomotor skills, executive functions, and attention. Interestingly, IQ test results effectively differentiated between the groups (HIE vs. controls). Furthermore, the incidence of psychopathology appears to be significantly higher in children with HIE (35%) than in control peers (12%)., Conclusions: Our study supports previous findings on a higher incidence of neuropsychological, cognitive, and psychopathological sequelae after HIE treated with TH. As hypothesized, TH does not appear to ameliorate the outcome after neonatal HIE in those children who survive without major sequelae.

Competing Interests: None

Objective: Patients with epilepsy are at risk for several lifetime problems, in which neuropsychological impairments may represent an impacting factor. We evaluated the neuropsychological functions in children suffering from three main epilepsy categories. Further, we analyzed the longitudinal evolution of the neuropsychological profile over time., Methods: Patients undergoing neuropsychological evaluation at our Department from 2012 to 2018 were identified retrospectively. We selected patients aged 6-16 years and with at least two evaluations. Three epilepsy categories were considered: focal/structural, focal self-limited, and idiopathic generalized. Each evaluation included the same structured assessment of main neuropsychological domains. The effect of the epilepsy category, illness duration, seizure status, and medication was computed in multilevel models., Results: We identified 103 patients (focal self-limited = 27; focal/structural = 51; and idiopathic generalized = 25), for 233 evaluations. The majority of deficits were reported in attention and executive functions (>30% of patients); the results were dichotomized to obtain global indexes. Multilevel models showed a trend toward statistical significance of category of epilepsy on the global executive index and of illness duration on global attention index. Illness duration predicted the scores of executive and attention tasks, while category and medication predicted executive task performance. Focal/structural epilepsies mostly affected the executive domain, with deficits persisting over time. By contrast, an ameliorative effect of illness duration for attention was documented in all epilepsies., Conclusions: This study offers lacking information about the evolution of deficits in time, the role of epilepsy category, and possible psychological implications for high-order cognitive skills, central in several social and academic problems.

Background: Brain injury, impaired brain maturation, and long-term neurodevelopmental disorders are common in infants with congenital heart diseases (CHD). We aimed to assess whether plasma glial fibrillary acidic protein (GFAP) can predict neurodevelopmental anomalies in CHD infants operated on cardiopulmonary bypass (CPB)., Methods: We measured plasma GFAP in 38 infants at multiple CPB phases. Cognitive, neuropsychological, and psychopathological functioning were assessed 5.7 ± 2.2 years after surgery. We identified an impaired global neurodevelopmental index (NDI) when at least two domains were abnormal. The relationships between NDI, GFAP, and clinical variables were explored with non-supervised feature selection methods and modeled with a nested non-linear logistic regression., Results: Intelligence quotient scores were within the normal range in 84% of children, whereas 58% showed an abnormal NDI, with the greatest impairments in the psychopathological area. The plasma GFAP peak was 0.95 (0.44-1.57) ng/mL, and it was correlated with age, weight, duration of surgery phases, and CPB minimum temperature. In the regression model, the GFAP peak was associated with an impaired NDI with a possible flexible point toward NDI impairment at 0.49 ng/mL, keeping constant ICU stay, CPB duration, CHD anatomy, weight, and CPB minimum temperature., Conclusion: GFAP is a promising early marker of abnormal long-term neuropsychological development.