Neurological Maturation Research Articles

A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. Hundreds of pathogenic variants have been described, associated with a significant phenotypic heterogeneity observed among patients. To date, different knockout mouse models have been generated. Here we present a new knockin CDKL5 mouse model carrying a humanized, well-characterized nonsense variant (c.1090G > T; p.E364X) described in the C-terminal domain of the CDKL5 protein in a female patient with a milder phenotype. Both male and female Cdkl5E364X mice were analyzed. The novel Cdkl5E364X mouse showed altered neurological and motor neuron maturation, hyperactivity, defective coordination and impaired memory and cognition. Gene expression analysis highlighted an unexpected reduction of Cdkl5 expression in Cdkl5E364X mice brain tissues, with a significant increase in overall neuron-specific gene expression and an area-dependent alteration of astrocyte- and oligodendrocyte-specific transcripts. Moreover, our results showed that the loss of CDKL5 protein had the most significant impact on the cerebellum and hippocampus, compared to other analyzed tissues. A targeted analysis to study synaptic plasticity in cerebellum and hippocampus showed reduced Gabra1 and Gabra5 expression levels in females, whereas Gabra1 expression was increased in males, suggesting an opposite, sex-dependent regulation of the GABA receptor expression already described in humans. In conclusion, the novel Cdkl5E364X mouse model is characterized by robust neurological and neurobehavioral alterations, associated with a molecular profile related to synaptic function indicative of a cerebellar GABAergic hypofunction, pointing to Gabra1 and Gabra5 as novel druggable target candidates for CDD.

Toward Process-Oriented, Dimensional Approaches for Diagnosis and Treatment of Speech Sound Disorders in Children: Position Statement and Future Perspectives.

Children with speech sound disorders (SSD) form a heterogeneous group, with respect to severity, etiology, proximal causes, speech error characteristics, and response to treatment. Infants develop speech and language in interaction with neurological maturation and general perceptual, motoric, and cognitive skills in a social-emotional context. After a brief introduction into psycholinguistic models of speech production and levels of causation, in this review article, we present an in-depth overview of mechanisms and processes, and the dynamics thereof, which are crucial in typical speech development. These basic mechanisms and processes are: (a) neurophysiological motor refinement, that is, the maturational articulatory mechanisms that drive babbling and the more differentiated production of larger speech patterns; (b) sensorimotor integration, which forms the steering function from phonetics to phonology; and (c) motor hierarchy and articulatory phonology describing the gestural organization of syllables, which underlie fluent speech production. These dynamics have consequences for the diagnosis and further analysis of SSD in children. We argue that current diagnostic classification systems do not do justice to the multilevel, multifactorial, and interactive character of the underlying mechanisms and processes. This is illustrated by a recent Dutch study yielding distinct performance profiles among children with SSD, which allows for a dimensional interpretation of underlying processing deficits. Analyses of mainstream treatments with respect to the treatment goals and the speech mechanisms addressed show that treatment programs are quite transparent in their aims and approach and how they contribute to remediating specific deficits or mechanisms. Recent studies into clinical reasoning reveal that the clinical challenge for speech-language pathologists is how to select the most appropriate treatment at the most appropriate time for each individual child with SSD. We argue that a process-oriented approach has merits as compared to categorical diagnostics as a toolbox to aid in the interpretation of the speech profile in terms of underlying deficits and to connect these to a specific intervention approach and treatment target.

Historical Perspectives and Clinical Updates on Preterm Bottle Feeding With Noninvasive Ventilation.

The controversial topic of oral feeding while on noninvasive ventilation remains at the forefront of preterm intensive care management. The intersection of pulmonary, neurologic, and gastrointestinal maturation coalesces at a postmenstrual age that requires changes in practices compared with those used in older infants. Various animal models in the past decades aimed to gain physiological knowledge of noninvasive ventilation effects on the suck-swallow-breathe coordination sequence. However, the preterm infant poses nuanced anatomic challenges. Although concerns for oral feeding while on noninvasive ventilation include aspiration risks and potential inpatient obstacles, there is evidence to support the feasibility, initiation, and progression of oral feedings while an infant is supported on high-flow nasal cannula and continuous positive airway pressure. There is evidence to support that this may accelerate attainment of oral feeding milestones and, thus, eventual hospital discharge. More recent multidisciplinary institutional protocols may provide cautious guidance on evaluation and algorithms to assess infants who may benefit from initiation and advancement of oral feeding versus awaiting further maturation.

Generalized Camera-Based Infant Sleep-Wake Monitoring in NICUs: A Multi-Center Clinical Trial.

The infant sleep-wake behavior is an essential indicator of physiological and neurological system maturity, the circadian transition of which is important for evaluating the recovery of preterm infants from inadequate physiological function and cognitive disorders. Recently, camera-based infant sleep-wake monitoring has been investigated, but the challenges of generalization caused by variance in infants and clinical environments are not addressed for this application. In this paper, we conducted a multi-center clinical trial at four hospitals to improve the generalization of camera-based infant sleep-wake monitoring. Using the face videos of 64 term and 39 preterm infants recorded in NICUs, we proposed a novel sleep-wake classification strategy, called consistent deep representation constraint (CDRC), that forces the convolutional neural network (CNN) to make consistent predictions for the samples from different conditions but with the same label, to address the variances caused by infants and environments. The clinical validation shows that by using CDRC, all CNN backbones obtain over 85% accuracy, sensitivity, and specificity in both the cross-age and cross-environment experiments, improving the ones without CDRC by almost 15% in all metrics. This demonstrates that by improving the consistency of the deep representation of samples with the same state, we can significantly improve the generalization of infant sleep-wake classification.

Listening Preference for Child-Directed Speech Versus Time-Reversed Speech in Moderate-Preterm Infants Compared to Full-Term Infants.

The purpose of the present study was to examine whether there is a listening preference for child-directed speech (CDS) over backward speech in moderate-preterm infants (MPIs). Eighteen MPIs of gestational age of 32.0 weeks (range: 32-34.06 weeks), chronological age of 8.09 months, and maturation age of 6.48 months served as the experimental group. The two control groups consisted of a total of 36 infants-20 full-term infants matched for chronological age and 16 full-term infants matched for maturation age. The infants were tested using the central fixation procedure and were presented with 16 trials of CDS and backward speech. A follow-up was conducted 5 years after the initial experiment using a developmental and a five-item parent questionnaire. MPIs did not demonstrate a preference for CDS over backward speech, whereas both control groups demonstrated a listening preference for CDS over backward speech. MPIs showed a delayed use of first words and word combinations and lower scores on the five-item questionnaire compared to term infants. Twelve MPIs (67%) did not demonstrate a preference for CDS over backward speech. Four of them (33%) were later diagnosed with neurodevelopmental disorders. The lack of preference for CDS over backward speech in the MPIs group suggests delayed developmental pattern of speech processing compared to full-term peers. Delays in neurological maturation as well as listening experience in an unregulated environment outside the uterus during a sensitive period of brain development may affect the recognition of phonological and prosodic patterns that support listening preference for speech over backward speech.

Newborn Neurological Assessment, Basics of Clinical Practices

The purpose of a neurological examination of the newborn is to determine a normal neurological condition and to detect abnormal conditions. The examination includes assessment of the central and peripheral nervous system and observation of posture, muscle tone, strength, reflexes and symmetry. Abnormal assessments may indicate neurological problems. As a rule, neurological maturity varies according to gestational age. Systematic physical examinations usually detect neurological defects. Early detection is crucial as plasticity is greater in early life. Despite developments in neuroimaging and neurophysiological technologies, clinical neurological examinations still have their importance. Performing a timely neurological assessment can speed up the diagnostic process and enable the swift administration of advantageous therapies. This is specifically applicable in situations that require therapeutic hypothermia to be initiated within six hours or sooner, as evaluation of neurologic status plays a crucial part in identifying the necessity for intervention. Neurophysiological technologies can be difficult due to immaturity and reduced myelination in neonates. This article aims to provide readers with a better understanding of the few basic concepts of neurological assessment in neonates.

Biological and cognitive mechanisms and the role of culture in theory of mind development: In need of an integrative, biocultural perspective?

The present paper attempts a comprehensive approach to the biological, cognitive, as well as cultural foundations of theory of mind development. A critical analysis and synthesis of contemporary research findings serves as a basis for revisiting key theoretical accounts regarding the nature and development of this valuable sociocognitive faculty. Are the findings best interpreted within frameworks which consider developmental change and individual differences in the domain-general cognitive abilities (executive functions) that may underlie performance on theory of mind tasks (processing account)? Or is it more fruitful to discuss the development of theory of mind based on domain-specific mechanisms or capacities: an innate, modular mechanism that is underpinned by neurological maturation (modularity theories), or an inborn capacity to form naïve, intuitive theories about the mind, which are then subject to conceptual change as a function of experience (theory theory account), or a mechanism that serves simulations of mental states and related attributions (simulation theories)? Where possible, biological and neurocognitive processes, and experiential influences are discussed in combination. A disentanglement of general cultural influences from more proximal, social or familial effects on theory of mind development is also attempted. The aim is to highlight the value of an integrative, interdisciplinary approach to its study: a biocultural perspective could essentially serve this purpose by shifting attention to the interplay of biological, cognitive, and environmental forces shaping the lifespan dynamics of human theory of mind.

The effect of hypertension in pregnancy and central nervous system anomalies on fetal brain development

Objectives: The aim of this study was to investigate whether maternal hypertension affects fetal brain maturation, and to examine whether treatment with magnesium sulfate has a protective effect on the fetal brain. Methods: A total of 26 fetuses, including 11 dead fetuses of pregnant women who were found to have hypertension and whose pregnancy was terminated due to this reason, and 15 fetuses who did not have this risk factor but died for various reasons as the control group, were included in the study. Brain tissue samples were evaluated for the presence of morphological and histopathological changes, as well as apoptotic cells. The morphologies of the samples were examined in sections stained with hematoxylin-eosin (H&E), and apoptosis was examined with light microscopy by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. Results: In the control group, it was observed that the brain tissue had a morphological structure compatible with the development weeks. In the hypertension group, there were no bleeding foci and brain tissues mostly preserved morphological features similar to control patients. While edema was detected in 45.4% of the infants in the hypertension group, no edema was observed in 54.6%. In the hypertension group, Grade 1 necrosis was observed in 63.6% of the samples, Grade 2 necrosis was observed in 9.1%, and no necrosis was observed in 27.3% of the samples. Conclusions: Based on the findings of this study, it can be concluded that maternal hypertension increases neurological maturation by causing vasodilation in the fetal brain, increasing blood flow, and decreasing cell death.

The value of some indices of heart rate variability in the diagnosis of fetal growth retardation

Fetal growth retardation (FGR) is one of the most serious problems in current perinatology. This pathology leads not only to the deterioration of perinatal outcomes but also significantly increases morbidity during adult life. FGR is known to be featured by its delayed “neurological maturation”. This is manifested in a decrease in autonomic nervous regulation according to the fetal heart rate variability (HRV) scores and indices. The objective: to study HRV in fetuses with normal biometric indices compared to similar parameters of growth retarded fetuses. Materials and methods. The 47 pregnant women who had fetuses with normal biometric indices (I group) and 33 patients with fetal growth retardation (II group) were included in the study. The investigation of the fetal HRV was performed by processing the R–R intervals obtained via non-invasive electrocardiogram (ECG) and involved the following indices: STV (short term variations), LTV (long term variations), AC/DC (acceleration capacity/deceleration capacity), TP (total power), SI (stress index), SDNN (standard deviation of normal to normal intervals), EnRE (entropy of the time series), D2 (correlation dimension of the time series), Z (temporary irreversibility) і FL (measure of fuzzy logic, integrated measure of HRV). Results. The obtained data indicated that the indices of fetal HRV were reduced in the patients with FGR. These indices have utility in screening programs for the detection of fetal intrauterine nutrition and growth disturbances. The results of the study allow us to believe that the ability to accelerate heart rate patterns is partly preserved even during FGR. This may indicate a very ancient phylogenetic nature of the reaction of the heart system of the fetus to its motile activity. However, decelerations according to the DC were typical for FGR. A non-invasive fetal ECG could become a useful supplementary method in the current methods’ spectrum used in perinatal medicine. Conclusions. Therefore, the development of algorithms for the diagnosis of FGR requires the inclusion of the following HRV indices: STV, LTV, DC, TP, SI, SDNN, D2, Z, and FL. These biophysical markers of FGR can be used as a screening program in conditions of lack of access to high-quality ultrasound diagnostics or be a valuable addition to existing perinatal strategies.

Impact of electronic devices used at an early age on language

The acquisition of language in infants is largely the result of the process of brain maturation, as well as environmental stimulation. Currently, society is in an era of technology and use of electronic devices from an early age. The aim of this study was to demonstrate if the amount of time of use of electronic devices in children under 5 years of age affects language development. An observational, comparative, survey-type study was carried out in 269 infants of both sexes, with an age range of 6 to <60 months. The language development section of the Child Development Scale (EDI) was used. A logistic regression was performed to determine the strength of association between the factors to be studied. 269 participants were included, of which 224 (83.2%) presented their level of neurological maturation, 44 infants (16.4%) presented laged development and one (0.4%) was classified as having developmental delay. It was found that the number of daily hours that an electronic device is used behaved as a risk factor by increasing the risk of delayed language development by 1.37 times for each hour of exposure (OR: 1.37, CI95%: 1.15-1.62). It was shown that a greater number of hours of use of electronic devices is a risk factor for delayed language development in children under 5 years of age. Therefore, it is vital to limit its use in this population.

Prevention and treatment of behavioural and learning disorders with sensory integration therapy

Sensory integration disorders, which are often hidden in the background of learning and/or behavioural disorders, can cause serious difficulties in the daily activities of the students, in the implementation of learning and/or behaviour. Upon hearing the term ‘sensory integration’, two interpretations appear in the minds of professionals. On interpretation refers to the integration, sensory interconnection coordination and interdependence of sensory systems as a typical, neurological maturation process that provides the basis for subsequent learning and behavioural organisation processes. Based on a second interpretation, ‘sensory integration’ is a therapeutic methodology, diagnostic, and therapeutic procedure that provides assistance to people who are lagging behind in the maturation of sensing systems and perception processes. Learning and/ or behavioural disorders can be caused by impaired information acquisition processes, sensory modulation, and integration in the nervous system. The following study comprehensively presents the diagnostic process and the relationship between the learning and behavioural differences related to sensory integration disorders.

Non-pharmacological interventions for sleep promotion in hospitalized children.

Non-pharmacological interventions for sleep promotion in hospitalized children.

Atypical development and the cultural background underlying neurological maturation

Learning, attention, hyperactivity, and autism spectrum disorders have common neurological roots. They are manifested in differences in the development and functioning of the neurological processes involved in neurological maturation. Neurological maturation is a product of the cultural evolution of Homo Sapiens. The transition to an agricultural, ranching lifestyle required behavior and cognitive functions that were markedly different from the previous foraging, nomad lifestyle. The result was a more precise and reliable ability to control and think systematically, which later became the base of literacy. The recent spread of learning difficulties, control disorders, and autism spectrum are due to the vulnerability of brain functions that are very new to human development, most of all executive functions. There are significant changes in culture since the last century, whereby the developing nervous system receives less natural cultural developmental effects but more harmful agents than before. Changes in the environment change the way the brain develops. Atypical neurological development is a consequence and a sign of a new era. It is only considered a disorder if education fails to find an appropriate response to the challenge.

On the Importance of Being Flexible: Dynamic Brain Networks and Their Potential Functional Significances.

In this theoretical review, we begin by discussing brains and minds from a dynamical systems perspective, and then go on to describe methods for characterizing the flexibility of dynamic networks. We discuss how varying degrees and kinds of flexibility may be adaptive (or maladaptive) in different contexts, specifically focusing on measures related to either more disjoint or cohesive dynamics. While disjointed flexibility may be useful for assessing neural entropy, cohesive flexibility may potentially serve as a proxy for self-organized criticality as a fundamental property enabling adaptive behavior in complex systems. Particular attention is given to recent studies in which flexibility methods have been used to investigate neurological and cognitive maturation, as well as the breakdown of conscious processing under varying levels of anesthesia. We further discuss how these findings and methods might be contextualized within the Free Energy Principle with respect to the fundamentals of brain organization and biological functioning more generally, and describe potential methodological advances from this paradigm. Finally, with relevance to computational psychiatry, we propose a research program for obtaining a better understanding of ways that dynamic networks may relate to different forms of psychological flexibility, which may be the single most important factor for ensuring human flourishing.

Neonatal neurobehavior in infants with autism spectrum disorder.

To investigate neurobehavioral maturation for neonates who are later diagnosed with autism spectrum disorder (ASD). In a prospective longitudinal design, neonatal neurobehavior was examined monthly in 1- to 3-month-old infants at elevated and low familial likelihood of ASD (n=60). At 2 years, infants were seen for a clinical best-estimate evaluation, resulting in 18 infants with ASD and 36 typically developing infants. Repeated-measures analysis of variance models were conducted to examine the effects of age, diagnostic group, and their interactions. Neurobehavioral maturation of infants diagnosed with ASD was largely comparable to typically developing infants from 1 to 3 months, with the exception of the development of attention. Object-focused attention was significantly attenuated for infants with ASD beginning at 2 to 3 months and was predictive of social-communication skills 2 years later. This is the first study to prospectively examine neonatal neurobehavior of infants at an elevated familial likelihood of ASD who later received a diagnosis. Despite relatively intact neurological and behavioral maturation in the neonatal period, attention to objects emerged as a key early indicator of ASD. This suggests a complex attentional vulnerability within the first 3 months of life that may be associated with cascading sequelae of social-communication challenges and the emergence of ASD.

VP24.04: The delayed fetal neurological maturation in women with threatened preterm labour

VP24.04: The delayed fetal neurological maturation in women with threatened preterm labour

Culture and the organization of infant sleep: A study in the Netherlands and the U.S.A.

This study investigates differences in the amount and structure of infant sleep in two cultural places with previously documented, divergent parental beliefs and practices. Eight-month-old infants (n = 24 per site) were recruited from towns in the Netherlands and the eastern U.S.A. To evaluate sleep, infants’ physical activity was recorded at home for 24 h using a miniature actigraph, while parents kept a diary of infant activities. Measures derived from actigraphy include total sleep, longest sleep episode, longest wake episode, number of sleep episodes, and percent of sleep during nighttime, as well as time in the stages of Quiet and Active Sleep. Measures based on the parental diaries include most of these aspects as well, except those related to sleep stages. Results based on the more precise actigraphy method indicate that (1) the Dutch infants averaged 13.65 h of sleep per 24 h, 1.67 h more than the U.S. infants; this difference was mostly due to daytime sleep; (2) The Dutch infants’ longest wake episode averaged less than that of the U.S. infants, while their longest sleep episode appeared slightly longer. (3) The Dutch infants, compared to the U.S. sample, spent more time in the Quiet, rather than the Active phase of sleep; (4) They began their Quiet sleep earlier in the evening than did their U.S. counterparts. Measures derived from parental diaries are largely in agreement with the actigraph findings. These results are consistent with reported and observed practices and beliefs in the two communities. The pattern of differences – less apparent maturity among the Dutch in the amount of sleep, but greater apparent maturity in the structure of sleep -- illustrates that behavioral and neurological maturity can be assessed only in the context of the developing child’s adaptation to the specific demands and affordances of the culturally structured developmental niche.

Oportunidades domiciliares no desenvolvimento motor infantil: produção científica da área da saúde

Introdução: O desenvolvimento infantil compreende um processo de transformação complexo, dinâmico devido a interações passíveis de transformações, além de contínuo e progressivo, o qual inicia na concepção, envolvendo aspectos que permeiam o crescimento físico, maturação neurológica, comportamental, cognitiva, social e afetiva da criança Objetivo: analisar as características da produção científica acerca da utilização do instrumento Affordances in the home environment for motor development (AHEMD). Método: revisão bibiliométrica e cientométrica realizada nas bases de dados eletrônicas Publisher Medline (PubMed), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Elsevier SciVerse Scopus (SCOPUS), Web of Science Coleção Principal Clarivate Analytcs (WoS), e na Scientific Electronic Library Online (SciELO) no mês de janeiro de 2018 que incluiu estudos primários nos idiomas inglês, português ou espanhol. Resultados: 38 produções aplicaram o AHEMD para avaliação das oportunidades do ambiente, sendo que 39,5% das produções (n = 15) para crianças de 3 a 18 meses e 60,5% (n = 23) produções para crianças de 18 a 42 meses, com maior frequência 47,4% (n = 18) para estudos transversais, 76,4% (n = 29) procedentes do Brasil, 50% (n = 19) no período entre 2014 a 2017 e 50% (n = 19) com autoria multiprofissional. Observou-se que a avaliação das oportunidades presentes no ambiente domiciliar utilizando as versões do AHEMD fez-se com crianças de diferentes características, cenários e contextos sociais com pontuações de dimensões e total classificadas desde muito fracas a suficientes. Conclusão: obteve-se o panorama da aplicação do instrumento AHEMD com lacuna de estudos longitudinais e com populações com condições clínicas, coerente aos agravos de notificação pelos sistemas de informações que indicam os problemas de saúde pública na população infantil.

Chronic cough in children

A chronic cough in children is defined in the British Thoracic Society guidelines as a cough of 8 weeks or more. The aetiology of a chronic cough in children differs from adult populations, due to decreased cough reflex control in children, differences in airway anatomy and physiology, and immunological and neurological maturation changes. The three most common causes of chronic cough in adults (asthma, gastro-oesophageal reflux, and upper airway cough syndrome) account for less than 10% of the causes in children. Thus, it is important to assess and manage chronic cough in children differently.

Mental illness pathogenia: Anxiety disorders, an evolutive vision

IntroductionThere are many authors that follow and develop Pinel-hypotheses about unitary psychosis, joining recent discoveries in neuropathology and neurochemistry, supporting the vision of mental illness as neurodevelop disorders. The classification they suggest, distinguishes early, late neurodevelop disorders, and those related to traumatic factors, what determine an evolutive vision of this pathology. In terms of anxiety symptoms/disorders, they have been usually associated with categorical pathology, and treated focus on symptoms,unfortunately relapses are very frequent.ObjectivesProving that the evolutive vision may ease a change on the intervention of anxiety disorders, that would propound different therapeutic alternatives.MethodsA bibliographic search was performed from different databases, showing throw aspects related to main etiopathogenic theories about anxiety disorders from an evolutive vision.ResultsEvolutive-Psychology raises that anxiety is a concomitant process to development, that grows progressively and is necessary to induce changes in it. However a high level of anxiety might block that process or causes alterations. In that sense, anxiety-disorders may be related to an excess of anxiety that provoke a fault in present handling mechanisms. According to classic dynamic-theories, these mechanisms are associated with defence concept, but now we can link them to neurobiological development. From this point, there exists an asymmetric neurological maturation through childhood-adolescence that translates different manifestations of anxiety along development, initially more related with external contemption and relationship with caregiver, but later with hormonal pulses, physical changes and separation from family.ConclusionsThe evolutive vision allows to understand development fluctuation of anxiety symptoms along the growth process, more accurately than categorical classic tendency.DisclosureNo significant relationships.