Neurodevelopment

Neurodegenerative disorders can alter neural circuitry long before symptoms appear, but the path from early changes to later pathologies is obscure. In this issue of Neuron, Capizzi et al. (2021) show how early axonal growth defects in Huntington's disease create vulnerability to later degeneration.

Developmental disorders such as autism have generally been theorized as due to some kind of modular “deficit” or “dysfunction”—typically of cortical origin, i.e., failures of “theory of mind”, of the “mirror neuron system”, of “weak central coherence” or of the balance of “empathizing” and “systemizing”, just to list a few. The broad array of autonomic and sensorimotor differences experienced and reported by people with autism have by such theories typically been sidelined as “co-morbidities,” possibly sharing genetic causes, but rendered as incidental and decisively behaviorally irrelevant symptoms—surely disconnected from cognition.
This article entertains the idea that the development of cortically based mental processes and autonomous control relies on the complexities and proper function of the peripheral nervous systems. Through such an “embodied” lens the heterogeneous symptoms of autism invites new interpretations. We propose here that many behavioral-level findings can be re-defined as downstream effects of how developing nervous systems attempt to cope and adapt to the challenges of having various noisy, unpredictable, and unreliable peripheral inputs.

Iron deficiency and iron-deficiency anemia are the main worldwide nutritional disorders. A good level of prenatal iron is essential for the correct child neurodevelopment but this association has been poorly investigated. To gather the scientific evidence on the relation between prenatal iron status and child neurodevelopment. To emphasize the importance of personalize the dose and type of supplementation.
Wide search strategy was performed in electronic databases for English language articles with no limitations as regards the language or date of publication. Additional studies were selected by hand search. The inclusion criteria were pregnant women without high-risk pregnancy and their children as study population and neurodevelopment as the main outcome. Six RCTs and 13 observational studies were included. The majority concluded that deficit or excess iron during pregnancy injures the mental and psychomotor development of child. Other authors found no association of low iron level with troubles in neurodevelopment, recommended multi-micronutrients instead of iron alone and/or showed inconsistent results. Both iron deficiency as its excess are harmful for the child neurodevelopment. The prenatal iron supplementation should be adjusted for each woman, taking into account the iron stores, some genetic mutation and other health habits.

A dysfunction in the excitatory–inhibitory (E/I) coordination in neuronal assembly has been proposed as a possible neurobiological mechanism of Autistic Spectrum Disorder (ASD). However, the potential impact of this mechanism in cognitive performance is not fully explored. Since the main consequence of E/I dysfunction is an impairment in oscillatory activity and its underlying cognitive computations, we assessed the electroencephalographic activity of ASD and typically developing (TD) subjects during a working-memory task. We found that ASD subjects committed more errors than TD subjects. Moreover, TD subjects demonstrated a parametric modulation in the power of alpha and theta band while ASD subjects did not demonstrate significant modulations. The preceding leads to significant differences between the groups in both the alpha power placed on the occipital cortex and the theta power placed on the left premotor and the right prefrontal cortex. The impaired theta modulation correlated with autistic symptoms. The results indicated that ASD may present an alteration in the recruitment of the
oscillatory activity during working-memory, and this alteration could be related to the physiopathology of the disorder.

The current rise of neurodevelopmental disorders poses a critical need to detect risk early in order to rapidly intervene. One of the tools pediatricians use to track development is the standard growth chart. The growth charts are somewhat limited in predicting possible neurodevelopmental issues. They rely on linear models and assumptions of normality for physical growth data – obscuring key statistical information about possible neurodevelopmental risk in growth data that actually has accelerated, non-linear rates-of-change and variability encompassing skewed distributions. Here, we use new analytics to profile growth data from 36 newborn babies that were tracked longitudinally for 5 months. By switching to incremental (velocity-based) growth charts and combining these dynamic changes with underlying fluctuations in motor performance – as the transition from spontaneous random noise to a systematic signal – we demonstrate a method to detect very early stunting in the development of voluntary neuromotor control and to flag risk of neurodevelopmental derail.

Autism has been defined as a disorder of social cognition, interaction and communication where ritualistic, repetitive behaviors are commonly observed. But how should we understand the behavioral and cognitive differences that have been the main focus of so much autism research? Can high-level cognitive processes and behaviors be identified as the core issues people with autism face, or do these characteristics perhaps often rather reflect individual attempts to cope with underlying physiological issues?  Much research presented in this volume will point to the latter possibility, i.e. that people on the autism spectrum cope with issues at much lower physiological levels pertaining not only to Central Nervous Systems (CNS) function, but also to peripheral and autonomic systems (PNS, ANS) (Torres, Brincker, et al. 2013).  The question that we pursue in this chapter is what might be fruitful ways of gaining objective measures of the large-scale systemic and heterogeneous effects of early atypical neurodevelopment; how to track their evolution over time and how to identify critical changes along the continuum of human development and aging. 

We suggest that the study of movement variability—very broadly conceived as including all minute fluctuations in bodily rhythms and their rates of change over time (coined micro-movements (Figure 1A-B) (Torres, Brincker, et al. 2013))—offers a uniquely valuable and entirely objectively quantifiable lens to better assess, understand and track not only autism but cognitive development and degeneration in general. This chapter presents the rationale firstly behind this focus on micro-movements and secondly behind the choice of specific kinds of data collection and statistical metrics as tools of analysis (Figure 1C).
In brief the proposal is that the micro-movements (defined in Part I – Chapter 1), obtained using various time scales applied to different physiological data-types (some examples in Figure 1), contain information about layered influences and temporal adaptations, transformations and integrations across anatomically semi-independent subsystems that crosstalk and interact. Further, the notion of sensorimotor re-afference is used to highlight the fact that these layered micro-motions are sensed and that this sensory feedback plays a crucial role in the generation and control of movements in the first place. In other words, the measurements of various motoric and rhythmic variations provide an access point not only to the “motor systems”, but also access to much broader central and peripheral sensorimotor and regulatory systems. Lastly, we posit that this new lens can also be used to capture influences from systems of multiple entry points or collaborative control and regulation, such as those that emerge during dyadic social interactions.

HIV in children is a serious and growing problem in sub-Saharan Africa. At present very little is known about the neurological complications of human immunodeficiency virus (HIV)-infected children in South Africa. The aim of this study was to determine the extent and prevalence of neurodevelopmental delay in a group of HIV-positive children in Soweto, South Africa, as well as to determine what factors were predictive of neurodevelopmental delay. One hundred and twenty-two consecutive HIV-positive children under 2.5 years of age were assessed using the Bayley Scales of Infant Development II. Ethical approval and informed consent were obtained prior to testing. The children assessed in this study were extremely delayed in both motor and cognitive development. Seventy-two per cent of the children had severe motor delay and 52% had severe cognitive delay. The mean age of the children was 18.5 months (±8.1). The mean CD4 count was 14.4% (±8.8) and only 16% of the children were receiving highly active antiretroviral therapy (HAART). Weight, height and head circumference Z-scores were also very low in this group of children, with both stunting and wasting being extremely common. Neurodevelopmental delay was very common in this group of children. Motor development was affected more severely than cognitive development. Weight-forage , age and whether the child was on HAART were the most important factors in predicting cognitive and motor development. Poverty and poor socioeconomic status of families of HIV-infected children may well be additional developmental risk factors.

Midline astroglia in the cerebral cortex develop earlier than other astrocytes through mechanisms that are still unknown. We show that radial glia in dorsomedial cortex retract their apical endfeet at midneurogenesis and translocate to the overlaying pia, forming the indusium griseum. These cells require the fibroblast growth factor receptor 1 (Fgfr1) gene for their precocious somal translocation to the dorsal midline, as demonstrated by inactivating the Fgfr1 gene in radial glial cells and by RNAi knockdown of Fgfr1 in vivo. Dysfunctional astroglial migration underlies the callosal dysgenesis in conditional Fgfr1 knockout mice, suggesting that precise targeting of astroglia to the cortex has unexpected roles in axon guidance. FGF signaling is sufficient to induce somal translocation of radial glial cells throughout the cortex; furthermore, the targeting of astroglia to dorsolateral cortex requires FGFr2 signaling after neurogenesis. Hence, FGFs have an important role in the transition from radial glia to astrocytes by stimulating somal translocation of radial glial cells.

This article proposes an approach to the brain's role in communication that treats the brain as the vehicle of a multi-scale embodiment of anticipation. Instead of conceptualizing anticipation as something a brain is able to do when circumstances seem to require it, this study proposes that anticipation is continuous and ongoing because to anticipate is an inherent design characteristic of the brain. Correspondingly, there is no anticipation module in the brain, and no focal lesion selectively abolishes the brain's propensity to anticipate. Anticipation is a wager based on previous experience. It readies a response to an event that has yet to occur. First, the anticipation is “embrained” in terms of covert neural representations, and then it is embodied in terms of rudiments of the embrained actions and expressions of feeling. This study applies this concept to conversation and shows that nested anticipations precede the dynamics of the actual encounter and continue at each turn as long as the conversation lasts.

The mammalian amygdala is a key emotional brain region for eliciting social behaviour and critically involved in anxiety and fear-related behaviours, and hence a focus of research on neurodevelopmental and stress-related disorders such as autism and anxiety. Recently, increasing evidence implicates host-microbe interactions in the aetiology of these conditions. Germ-free (GF) mice, devoid of any microbiota throughout organismal maturation, are a well-established tool to study the effects of absence of the microbiota on host physiology. A growing body of independently replicated findings confirm that GF animals demonstrate altered anxiety-related behaviour and impaired social behaviour. However, the underlying mechanisms of this interaction and the nature of the pathways involved are only insufficiently understood. To further elucidate the molecular underpinnings of microbe-brain interaction, we therefore exploiting unbiased, genome-wide transcriptional profiling to determine gene expression in the amygdala of GF and GF mice that have been colonised after weaning. Using RNA-sequencing and a comprehensive downstream analysis pipeline we studied the amygdala transcriptome and found significant differences at the level of differential gene expression, exon usage and RNA-editing. Most surprisingly, we noticed upregulation of several immediate early response genes such as Fos, Fosb, Egr2 or Nr4a1 in association with increased CREB signalling in GF mice. In addition, we found differential expression and recoding of several genes implicated in brain physiology processes such as neurotransmission, neuronal plasticity, metabolism and morphology.
In conclusion, our data suggest altered baseline neuronal activity in the amygdala of germ-free animals, which is established during early life and may have implications for understanding development and treatment of neurodevelopmental disorders.

Background: HIV/AIDS continues to be one of the greatest health challenges which sub-Saharan Africa faces. HIV is known to invade the central nervous system at the time of infection, and causes widespread damage. In children, this leads to a well-researched condition known as HIV encephalopathy, which affects all areas of neurodevelopment. Objectives: To discuss HIV encephalopathy in sub-Saharan Africa, and highlight the importance of early detection and intervention. Major findings: The effects of timely initiation of antiretroviral therapy on alleviating the impact of encephalopathy have been well described. Neurodevelopmental delay is a stage four disease indicator according to the World Health Organization (WHO), and therefore is a criterion for initiation of highly active antiretroviral therapy (HAART). HAART is often only administered according to the virologic and immunologic status of a child, as standardized neurodevelopmental assessment tools are not widely available in clinics in developing countries. When HAART initiation is dependent on immunologic status, it is often too late to prevent encephalopathy. To date, the only means of prevention of this condition is early initiation of HAART. Stringent guidelines for the commencement of this therapy have had to be followed due to a shortage of and lack of access to antiretrovirals, leading to late initiation of HAART, and widespread central nervous system encephalopathy. Conclusion: Early detection of encephalopathy is vital, so that children may commence treatment, and be referred for assessments in all facets of development in order to initiate intervention.

The limitations of current pharmacological treatments of
neurodegenerative disease have led to the extensive investigation of novel compounds and nonpharmacological approaches to modify the course of these conditions, whilst reducing drug side effects.The  definition of neuroprotection is complex and involves both preventing cell death and restoring function to damaged neurons, as well as restoring neuronal numbers. The development of drugs to slow or
prevent the progression of neurodegenerative diseases might logically evolve from an improved understanding of the etiology  and pathogenesis of these diseases. There have certainly been major advances in these areas over the past few years and the prospect for the introduction of “neuroprotective” therapies is much improved over previous years.