Nervous System Adaptations Research Articles

Research progress on the effects of exposure to major persistent organic pollutants during pregnancy on the functional development of nervous system in children

Persistent Organic Pollutants (POPs) have the characteristics of resistance to environmental degradation, bioaccumulation and long-distance migration potential. Maternal exposure to POPs during pregnancy can enter the fetal blood circulation through the placental barrier, and have a potential impact on the functional development of the nervous system of the offspring. This in turn leads to the occurrence and development of neurological defects and diseases in adulthood. The purpose of this paper is to elucidate the effects of exposure to three major POPs (organochlorine compounds, perfluoroalkyl and polyfluoroalkyl substances, and polybrominated diphenyl ethers) during pregnancy on the functional development of the nervous system (social emotions, cognition, language, exercise, and adaptability) in children, and to provide reference for subsequent studies.

Facial recognition, laterality judgement, alexithymia and resulting central nervous system adaptations in chronic primary headache and facial pain-A systematic review and meta-analysis.

Patients with chronic headaches and chronic oro-facial pain commonly present psychosocial issues that can affect social interactions. A possible reason could be that patients with these disorders might present impairments in facial recognition, laterality judgement and also alexithymia. However, a systematic review summarizing the effects of facial emotion recognition, laterality judgement and alexithymia in individuals with headaches and oro-facial pain is still not available. The main objective of this systematic review (SR) and meta-analysis (MA) was to compile and synthesize the evidence on the occurrence of alexithymia, deficits in laterality or left-right (LR) recognition and/or facial emotion recognition (FER) in patients with chronic headache and facial pain. Electronic searches were conducted in five databases (up to September 2023) and a manual search to identify relevant studies. The outcomes of interest were alexithymia scores, speed and accuracy in LR and/or FER, or any other quantitative data assessing body image distortions. The screening process, data extraction, risk of bias and data analysis were performed by two independent assessors following standards for systematic reviews. From 1395 manuscripts found, only 34 studies met the criteria. The overall quality/certainty of the evidence was very low. Although the results should be interpreted carefully, individuals with chronic headaches showed significantly higher levels of alexithymia when compared to healthy individuals. No conclusive results were found for the other variables of interest. Although the overall evidence from this review is very low, people with chronic primary headaches and oro-facial pain could be regularly screened for alexithymia to guarantee appropriate management.

Vertigo During Pregnancy: A Narrative Review of the Etiology, Pathophysiology, and Treatment.

From the time of conception until the time of labor, a woman's body and mind undergo a variety of hormonal and other changes. Patients may also experience vertigo and a lack of balance during this period. Disabling and physically painful, these symptoms may strike at any moment. Pregnancy-related vertigo has been the focus of several studies. We looked at the research on vertigo in pregnant women in detail. This narrative review aims to examine the causes, pathophysiology, and current treatments for vertigo during pregnancy. Vertigo during pregnancy has a diverse etiology, with typical causes including hormonal changes and modifications in vascular dynamics. Vertigo may start to appear due to pathophysiological mechanisms involving vestibular and central nervous system adaptations. Numerous alternatives for treatment are available, including dietary changes, vestibular therapy, medicines, and surgical procedures. The thorough assessment of the current research on vertigo during pregnancy provided by this narrative review will help medical practitioners make wise clinical decisions.

Autonomic nervous system activity in response to stress and cardiac coherence breathing exercise depending on body composition differences

ABSTRACT This study investigated the effects of stress and cardiac coherence breathing exercises on psychological and psychophysiological responses, and also determined whether these effects differed depending on body composition. The study participants included 33 individuals with a favourable body composition in the fit group and 25 individuals with a less favourable body composition in the unfit group. Before the experiment, the participants completed psychological questionnaires to determine psychological differences at baseline. We recorded an electrocardiogram to analyze heart rate variability (HRV) for five minutes under three conditions: rest, an arithmetic task to induce stress, and a breathing exercise. This was followed by measurements of stress, anxiety, relaxation, and confidence using the visual analogue scale. Baseline analyses revealed that the fit group had lower depression, state and trait anxiety, and stress levels than the unfit group. The HRV indices of the standard deviation of the N-N interval (SDNN) and the root mean square of successive difference (RMSSD) decreased during the arithmetic task with increased stress and heart rate. In contrast, the breathing exercise increased SDNN, RMSSD, total power, and low-frequency power, reduced anxiety and stress, and increased relaxation and confidence. The stress condition and breathing exercise affected the groups differently. The fit group demonstrated a more significant increase in sympathetic activity during stress situations, followed by a greater increase in parasympathetic activity and recovery from stress during the breathing exercise. These findings illustrate that individuals with a more favourable body composition may have greater autonomic nervous system adaptability.

Organization of sensorimotor activity in anterior cruciate ligament reconstructed individuals: an fMRI conjunction analysis.

Anterior cruciate ligament reconstruction (ACLR) is characterized by persistent involved limb functional deficits that persist for years despite rehabilitation. Previous research provides evidence of both peripheral and central nervous system adaptations following ACLR. However, no study has compared functional organization of the brain for involved limb motor control relative to the uninvolved limb and healthy controls. The purpose of this study was to examine sensorimotor cortex and cerebellar functional activity overlap and non-overlap during a knee motor control task between groups (ACLR and control), and to determine cortical organization of involved and uninvolved limb movement between groups. Eighteen participants with left knee ACLR and 18 control participants performed a knee flexion/extension motor control task during functional magnetic resonance imaging (fMRI). A conjunction analysis was conducted to determine the degree of overlap in brain activity for involved and uninvolved limb knee motor control between groups. The ACLR group had a statistically higher mean percent signal change in the sensorimotor cortex for the involved > uninvolved contrast compared to the control group. Brain activity between groups statistically overlapped in sensorimotor regions of the cortex and cerebellum for both group contrasts: involved > uninvolved and uninvolved > involved. Relative to the control group, the ACLR group uniquely activated superior parietal regions (precuneus, lateral occipital cortex) for involved limb motor control. Additionally, for involved limb motor control, the ACLR group displayed a medial and superior shift in peak voxel location in frontal regions; for parietal regions, the ACLR group had a more posterior and superior peak voxel location relative to the control group. ACLR may result in unique activation of the sensorimotor cortex via a cortically driven sensory integration strategy to maintain involved limb motor control. The ACLR group's unique brain activity was independent of strength, self-reported knee function, and time from surgery.

Evidence- and data-driven classification of low back pain via artificial intelligence: Protocol of the PREDICT-LBP study.

In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The "PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain" (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18-55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs.

Autonomic Nervous System Adaptation and Circadian Rhythm Disturbances of the Cardiovascular System in a Ground-Based Murine Model of Spaceflight.

Whether in real or simulated microgravity, Humans or animals, the kinetics of cardiovascular adaptation and its regulation by the autonomic nervous system (ANS) remain controversial. In this study, we used hindlimb unloading (HU) in 10 conscious mice. Blood pressure (BP), heart rate (HR), temperature, and locomotor activity were continuously monitored with radio-telemetry, during 3 days of control, 5 days of HU, and 2 days of recovery. Six additional mice were used to assess core temperature. ANS activity was indirectly determined by analyzing both heart rate variability (HRV) and baroreflex sensitivity (BRS). Our study showed that HU induced an initial bradycardia, accompanied by an increase in vagal activity markers of HRV and BRS, together with a decrease in water intake, indicating the early adaptation to fluid redistribution. During HU, BRS was reduced; temperature and BP circadian rhythms were altered, showing a loss in day/night differences, a decrease in cycle amplitude, a drop in core body temperature, and an increase in day BP suggestive of a rise in sympathetic activity. Reloading induced resting tachycardia and a decrease in BP, vagal activity, and BRS. In addition to cardiovascular deconditioning, HU induces disruption in day/night rhythmicity of locomotor activity, temperature, and BP.

Influence of Earth magnetic field on animal nervous system evolution

The aim of the present study was to demonstrate the impacts of earth magnetic field (ErMF) on animal nervous system evolution especially electric and histological properties of nerves. We have applied for the first time, as far as we know, a correlation betwen the influence of ErMF and temperature on supraconductor-like behavior in the siatic nerves of four species. Our question point to answer to the a possible link between magnetic change and climate change and to explain in part the possible implication of both parameters in animal nervous system adaptation and evolution. Our results seem to support the existence of a link between ErMF variation and superconductor-like behavior in nerves. The found link does not mean that the ErMF is fully responsible of the histological, electric properties of nerves and climate changes. The data reveal a decrease in nerve resistivity in chameleon and frog, chick and rabbit; showing a superconductor-like behaviour. Analysis of electrical properties demonstrated a clear grade shift at critical temperature (Tc) from poikilotherm (average of ΔT = 11.50) to homeotherm (average of ΔT = 38.00); indicating adaptive nerves changes during evolution confirmed by the increase of Schwann cells number.

Neurobiology and changing ecosystems: Toward understanding the impact of anthropogenic influences on neurons and circuits.

Rapid anthropogenic environmental changes, including those due to habitat contamination, degradation, and climate change, have far-reaching effects on biological systems that may outpace animals' adaptive responses. Neurobiological systems mediate interactions between animals and their environments and evolved over millions of years to detect and respond to change. To gain an understanding of the adaptive capacity of nervous systems given an unprecedented pace of environmental change, mechanisms of physiology and behavior at the cellular and biophysical level must be examined. While behavioral changes resulting from anthropogenic activity are becoming increasingly described, identification and examination of the cellular, molecular, and circuit-level processes underlying those changes are profoundly underexplored. Hence, the field of neuroscience lacks predictive frameworks to describe which neurobiological systems may be resilient or vulnerable to rapidly changing ecosystems, or what modes of adaptation are represented in our natural world. In this review, we highlight examples of animal behavior modification and corresponding nervous system adaptation in response to rapid environmental change. The underlying cellular, molecular, and circuit-level component processes underlying these behaviors are not known and emphasize the unmet need for rigorous scientific enquiry into the neurobiology of changing ecosystems.

Impact of the industrial environment on the health of workers in titanium and magnesium production

The results of a study of the health status of employees of metallurgical enterprises under the conditions of exposure to rare earth elements (on the example of employees of titanium and magnesium production) are presented. 107 workers (men) of the observation group exposed to harmful production factors and 72 employees of the administrative apparatus without exposure to harmful production factors were examined. An analysis of the working conditions of workers, research on the content of rare earth elements in the air of the working area and in bioassays, and a sociological survey were carried out. The general clinical, biochemical, immunological parameters of the blood of workers in the titaniummagnesium production were studied. A functional study of the cardiovascular, respiratory, digestive, and nervous systems was performed. According to the results obtained, the final class of working conditions at the workplace corresponded to classes 3.1–3.3. Exceeding the MPC of rare earth elements and estimated safe exposure levels have not been identified. An increase in the content of europium, which can replace calcium and magnesium in the body, was found in the workers of the observation group. The revealed dysfunction of the autonomic nervous system and impaired adaptation of the body are formed as a result of exposure of workers in the titanium-magnesium production to a harmful production environment. Exposure of chemicals in workers causes a change in humoral immunity in the form of hyperproduction of IgA, and with an experience of more than 5 years, activation of cellular immunity (increased absolute phagocytosis, CD16+56+ and CD3+25+). Recorded changes in the parameters of rhinomanometry and spirography in the observation group may indicate the presence of the process of aseptic inflammation in the airways under the combined effect of irritating chemicals and rare earth elements. Low-symptomatic or asymptomatic liver damage, characterized by non-specific structural changes (hepatomegaly, increased echogenicity) and a laboratory symptom complex of a simultaneous increase in AlAt and AsAt, LDH. The emerging dysfunction of the cardiovascular and respiratory systems is transformed into cardiorespiratory and hepatopulmonary pathology, increasing the risk of sudden death. The combined impact of production factors «rejuvenates» the age of formation of production-related and occupational diseases, contributes to the loss of professional working capacity by employees even before retirement age.

Brain adaptation following various unilateral vocal fold paralysis treatments: A magnetic resonance imaging based longitudinal case series.

AimExamination of central compensatory mechanisms following peripheral vocal nerve injury and recovery is essential to build knowledge about plasticity of the neural network underlying phonation. The objective of this prospective multiple-cases longitudinal study is to describe brain activity in response to unilateral vocal fold paralysis (UVFP) management and to follow central nervous system adaptation over time in three patients with different nervous and vocal recovery profiles.Materials and methodsParticipants were enrolled within 3 months of the onset of UVFP. Within 1 year of the injury, the first patient did not recover voice or vocal fold mobility despite voice therapy, the second patient recovered voice and mobility in absence of treatment and the third patient recovered voice and vocal fold mobility following an injection augmentation with hyaluronic acid in the paralyzed vocal fold. These different evolutions allowed comparison of individual outcomes according to nervous and vocal recovery. All three patients underwent functional magnetic resonance imaging (fMRI task and resting-state) scans at three (patient 1) or four (patients 2 and 3) time points. The fMRI task included three conditions: a condition of phonation and audition of the sustained [a:] vowel for 3 s, an audition condition of this vowel and a resting condition. Acoustic and aerodynamic measures as well as laryngostroboscopic images and laryngeal electromyographic data were collected.Results and conclusionThis study highlighted for the first time two key findings. First, hyperactivation during the fMRI phonation task was observed at the first time point following the onset of UVFP and this hyperactivation was related to an increase in resting-state connectivity between previoulsy described phonatory regions of interest. Second, for the patient who received an augmentation injection in the paralyzed vocal fold, we subsequently observed a bilateral activation of the voice-related nuclei in the brainstem. This new observation, along with the fact that for this patient the resting-state connectivity between the voice motor/sensory brainstem nuclei and other brain regions of interest correlated with an aerodynamic measure of voice, support the idea that there is a need to investigate whether the neural recovery process can be enhanced by promoting the restoration of proprioceptive feedback.

How Does Stroke Affect Skeletal Muscle? State of the Art and Rehabilitation Perspective.

Long-term disability caused by stroke is largely due to an impairment of motor function. The functional consequences after stroke are caused by central nervous system adaptations and modifications, but also by the peripheral skeletal muscle changes. The nervous and muscular systems work together and are strictly dependent in their structure and function, through afferent and efferent communication pathways with a reciprocal “modulation.” Knowing how altered interaction between these two important systems can modify the intrinsic properties of muscle tissue is essential in finding the best rehabilitative therapeutic approach. Traditionally, the rehabilitation effort has been oriented toward the treatment of the central nervous system damage with a central approach, overlooking the muscle tissue. However, to ensure greater effectiveness of treatments, it should not be forgotten that muscle can also be a target in the rehabilitation process. The purpose of this review is to summarize the current knowledge about the skeletal muscle changes, directly or indirectly induced by stroke, focusing on the changes induced by the treatments most applied in stroke rehabilitation. The results of this review highlight changes in several muscular features, suggesting specific treatments based on biological knowledge; on the other hand, in standard rehabilitative practice, a realist muscle function evaluation is rarely carried out. We provide some recommendations to improve a comprehensive muscle investigation, a specific rehabilitation approach, and to draw research protocol to solve the remaining conflicting data. Even if a complete multilevel muscular evaluation requires a great effort by a multidisciplinary team to optimize motor recovery after stroke.

Long-read assembly of the Chinese indigenous Ningxiang pig genome and identification of genetic variations in fat metabolism among different breeds.

Advances in long-read sequencing technology and genome assembly provide an opportunity to improve the pig genome and reveal the full range of structural variations (SVs) between local Chinese and European pigs. To date, little is known about the genomes of some unique Chinese indigenous breeds, such as the Ningxiang pig. Here, we report the sequencing and assembly of a highly contiguous Ningxiang pig genome (NX) via an integration of PacBio single-molecule real-time sequencing, Illumina next-generation sequencing, BioNano optical mapping and Hi-C (chromosome conformation capture) approaches. The assembled genome comprises 2.44Gb with a contig N50 of 26.1Mb and 418 contigs in total. These contigs are organized into 121 scaffolds with a scaffold N50 of 139.0Mb. More than 99.1% of the assembled sequence could be localized to 19 pseudochromosomes and is annotated with 20,914 protein-coding genes and 34.04% repetitive sequences. Comparisons between the NX and European Duroc assemblies revealed many SVs in genes involved in the immune system, nervous system, lipid metabolism and environmental adaptation. The genetic variants include 47 Chinese domestic pig-specific SVs and the associated 74 genes may contribute to the differences in domestic traits compared to European pigs. Moreover, single nucleotide polymorphisms (SNPs) identified from whole genome resequencing data of 73 Chinese pigs, representing 17 geographically isolated breeds, showed their specific genetic variations, population structure and evolutionary patterns. Finally, we explore transcriptional regulation in the first intron of the MYL4 gene, as the genomic SV (281-bp deletion) in Ningxiang pig promotes its subcutaneous fat compared to European pig breeds. This work identifies a set of Asian-specific SVs and SNPs, which will be important resources for modern pig breeding and genetic conservation.

Higher neural demands on stimulus processing after prolonged hospitalization can be mitigated by a cognitively stimulating environment

Prolonged periods of complete physical inactivity or bed rest trigger various alterations in the functional and metabolic levels of the human body. However, bed rest-related adaptations of the central nervous system are less known and thoroughly studied. The aim of this study was to investigate brain electrophysiological changes using event-related potentials (ERPs) after 14 days of bed rest and 12 consecutive sessions of computerized cognitive training (CCT). Sixteen older (Mage= 60 years) healthy volunteers were randomly divided into a CCT treatment group and an active control group. All participants performed ERP measurements based on the foveal visual presentation of a circle on a black background before and after bed rest. After 14 days of bed rest, participants in the control group showed increased peak P1 amplitude (p = .012), decreased P1 latency (p = .024), and increased P2 amplitude (p = .036), while the CCT group also showed decreased P1 latency (p = .023) and decreased P2 latency (p = .049). Our results suggest that, even from a central adaptation perspective, prolonged periods of physical inactivity or bed rest trigger additional neural recruitment and should therefore be minimized, and that CCT may serve as a tool to mitigate this. Future research should focus on other aspects of central nervous system adaptation following periods of immobilization/hospitalization to improve our knowledge of influence of physical inactivity and its effects on cortical activity and to develop appropriate countermeasures to mitigate functional dysregulation.

Blood pressure in the chronically hypoxaemic fetus is regulated by α-adrenergic receptors on the peripheral vasculature.

Blood pressure in the chronically hypoxaemic fetus is regulated by α-adrenergic receptors on the peripheral vasculature.

Deep Neural Network Model of Hearing-Impaired Speech-in-Noise Perception.

Many individuals struggle to understand speech in listening scenarios that include reverberation and background noise. An individual's ability to understand speech arises from a combination of peripheral auditory function, central auditory function, and general cognitive abilities. The interaction of these factors complicates the prescription of treatment or therapy to improve hearing function. Damage to the auditory periphery can be studied in animals; however, this method alone is not enough to understand the impact of hearing loss on speech perception. Computational auditory models bridge the gap between animal studies and human speech perception. Perturbations to the modeled auditory systems can permit mechanism-based investigations into observed human behavior. In this study, we propose a computational model that accounts for the complex interactions between different hearing damage mechanisms and simulates human speech-in-noise perception. The model performs a digit classification task as a human would, with only acoustic sound pressure as input. Thus, we can use the model's performance as a proxy for human performance. This two-stage model consists of a biophysical cochlear-nerve spike generator followed by a deep neural network (DNN) classifier. We hypothesize that sudden damage to the periphery affects speech perception and that central nervous system adaptation over time may compensate for peripheral hearing damage. Our model achieved human-like performance across signal-to-noise ratios (SNRs) under normal-hearing (NH) cochlear settings, achieving 50% digit recognition accuracy at −20.7 dB SNR. Results were comparable to eight NH participants on the same task who achieved 50% behavioral performance at −22 dB SNR. We also simulated medial olivocochlear reflex (MOCR) and auditory nerve fiber (ANF) loss, which worsened digit-recognition accuracy at lower SNRs compared to higher SNRs. Our simulated performance following ANF loss is consistent with the hypothesis that cochlear synaptopathy impacts communication in background noise more so than in quiet. Following the insult of various cochlear degradations, we implemented extreme and conservative adaptation through the DNN. At the lowest SNRs (<0 dB), both adapted models were unable to fully recover NH performance, even with hundreds of thousands of training samples. This implies a limit on performance recovery following peripheral damage in our human-inspired DNN architecture.

Convergent Validity of the Central Sensitization Inventory in Chronic Whiplash-Associated Disorders; Associations with Quantitative Sensory Testing, Pain Intensity, Fatigue, and Psychosocial Factors.

Central sensitization is present in different pain conditions, including chronic whiplash-associated disorders. In the absence of a gold standard method of assessment to determine the presence of central sensitization, quantitative sensory testing is currently understood as an optimal proxy. Laboratory sensory testing is, however, not feasible in clinical practice, and the Central Sensitization Inventory was developed as an alternative. The aim of the current study was to evaluate the convergent validity of the Central Sensitization Inventory in chronic whiplash-associated patients by determining the association between the Central Sensitization Inventory and quantitative sensory testing, pain intensity, fatigue, and psychosocial factors. A total of 125 chronic whiplash-associated patients completed multiple questionnaires and were subjected to pressure pain thresholds and temporal summation. . The Central Sensitization Inventory showed a strong association with constructs of general psychopathology, anxiety, distress, depression, and somatization in chronic whiplash-associated disorders. Moderate correlations were found with fatigue and intrusive and avoidant phenomena after a variety of traumatic events. No significant association was found between the Central Sensitization Inventory and pressure pain thresholds and temporal summation, nor between the Central Sensitization Inventory and other pain measurements. Overall, we found that the Central Sensitization Inventory is better in identifying the psychosocial factors related to central sensitization in chronic whiplash-associated disorders than the central nervous system adaptations. Thus, the convergent validity of the Central Sensitization Inventory appears to be only partially present in chronic whiplash-associated disorders.

Role of Neurotrophic Factors BDNF and GDNF in Nervous System Adaptation to the Influence of Ischemic Factors.

We developed a complex in vitro model of ischemic damage. Analysis of hippocampal cell viability in primary cultures after modeling of various stress factors revealed the features of action of the main pathological factors of ischemia. Neurotrophic factors BDNF and GDNF produced pronounced neuroprotective effect during modeling both the complex ischemic damage and its individual pathophysiological components. Neurotrophic factor GDNF produced the most pronounced protective effect.

New Aspects of Central Nervous System Adaptation to Prenatal Hypoxia

New Aspects of Central Nervous System Adaptation to Prenatal Hypoxia

Eukaryotic Voltage-Gated Sodium Channels: On Their Origins, Asymmetries, Losses, Diversification and Adaptations.

The appearance of voltage-gated, sodium-selective channels with rapid gating kinetics was a limiting factor in the evolution of nervous systems. Two rounds of domain duplications generated a common 24 transmembrane segment (4 × 6 TM) template that is shared amongst voltage-gated sodium (Nav1 and Nav2) and calcium channels (Cav1, Cav2, and Cav3) and leak channel (NALCN) plus homologs from yeast, different single-cell protists (heterokont and unikont) and algae (green and brown). A shared architecture in 4 × 6 TM channels include an asymmetrical arrangement of extended extracellular L5/L6 turrets containing a 4-0-2-2 pattern of cysteines, glycosylated residues, a universally short III-IV cytoplasmic linker and often a recognizable, C-terminal PDZ binding motif. Six intron splice junctions are conserved in the first domain, including a rare U12-type of the minor spliceosome provides support for a shared heritage for sodium and calcium channels, and a separate lineage for NALCN. The asymmetrically arranged pores of 4x6 TM channels allows for a changeable ion selectivity by means of a single lysine residue change in the high field strength site of the ion selectivity filter in Domains II or III. Multicellularity and the appearance of systems was an impetus for Nav1 channels to adapt to sodium ion selectivity and fast ion gating. A non-selective, and slowly gating Nav2 channel homolog in single cell eukaryotes, predate the diversification of Nav1 channels from a basal homolog in a common ancestor to extant cnidarians to the nine vertebrate Nav1.x channel genes plus Nax. A close kinship between Nav2 and Nav1 homologs is evident in the sharing of most (twenty) intron splice junctions. Different metazoan groups have lost their Nav1 channel genes altogether, while vertebrates rapidly expanded their gene numbers. The expansion in vertebrate Nav1 channel genes fills unique functional niches and generates overlapping properties contributing to redundancies. Specific nervous system adaptations include cytoplasmic linkers with phosphorylation sites and tethered elements to protein assemblies in First Initial Segments and nodes of Ranvier. Analogous accessory beta subunit appeared alongside Nav1 channels within different animal sub-phyla. Nav1 channels contribute to pace-making as persistent or resurgent currents, the former which is widespread across animals, while the latter is a likely vertebrate adaptation.