Sleep and Oxidative Stress: Current Perspectives on the Role of NRF2.

Sleep is a fundamental conserved physiological state across evolution, suggesting vital biological functions that are yet to be fully clarified. However, our understanding of the neural and molecular basis of sleep regulation has increased rapidly in recent years. Among various processes implicated in controlling sleep homeostasis, a bidirectional relationship between sleep and oxidative stress has recently emerged. One proposed function of sleep may be the mitigation of oxidative stress in both brain and peripheral tissues, contributing to the clearance of reactive species that accumulate during wakefulness. Conversely, reactive species, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), at physiological levels, may act as signaling agents to regulate redox-sensitive transcriptional factors, enzymes, and other effectors involved in the regulation of sleep. As a primary sensor of intracellular oxidation, the transcription factor NRF2 is emerging as an indispensable component to maintain cellular redox homeostasis during sleep. Indeed, a number of studies have revealed an association between NRF2 dysfunction and the most common sleep conditions, including sleep loss, obstructive sleep apnea, and circadian sleep disturbances. This review examines the evidence of the intricate link between oxidative stress and NRF2 function in the context of sleep, and highlights the potential of NRF2 modulators to alleviate sleep disturbances.

The Emerging Role of Flavonoids in Autism Spectrum Disorder: A Systematic Review.

Although autism spectrum disorder (ASD) is a multifaceted neurodevelopmental syndrome, accumulating evidence indicates that oxidative stress and inflammation are common features of ASD. Flavonoids, one of the largest and best-investigated classes of plant-derived compounds, are known to exert antioxidant, anti-inflammatory, and neuroprotective effects. This review used a systematic search process to assess the available evidence on the effect of flavonoids on ASD. A comprehensive literature search was carried out in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. A total of 17 preclinical studies and 4 clinical investigations met our inclusion criteria and were included in the final review. Most findings from animal studies suggest that treatment with flavonoids improves oxidative stress parameters, reduces inflammatory mediators, and promotes pro-neurogenic effects. These studies also showed that flavonoids ameliorate the core symptoms of ASD, such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination. However, there are no randomized placebo-controlled trials that support the clinical efficacy of flavonoids in ASD. We only found open-label studies and case reports/series, using only two flavonoids such as luteolin and quercetin. These preliminary clinical studies indicate that flavonoid administration may improve specific behavioral symptoms of ASD. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of flavonoids on features of ASD. These promising preliminary results may provide the rationale for future randomized controlled trials aimed at confirming these outcomes.

A Novel KCNN2 Variant in a Family with Essential Tremor Plus: Clinical Characteristics and In Silico Analysis.

BACKGROUND: Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants. AIM OF THE STUDY: to characterize the phenotype of an Italian family with ET and identify the genetic variant associated. METHODS: Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure. RESULTS: The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) (NM_021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.

Agomelatine: A Potential Multitarget Compound for Neurodevelopmental Disorders.

Agomelatine (AGM) is one of the latest atypical antidepressants, prescribed exclusively for the treatment of depression in adults. AGM belongs to the pharmaceutical class of melatonin agonist and selective serotonin antagonist ("MASS"), as it acts both as a selective agonist of melatonin receptors MT1 and MT2, and as a selective antagonist of 5-HT2C/5-HT2B receptors. AGM is involved in the resynchronization of interrupted circadian rhythms, with beneficial effects on sleep patterns, while antagonism on serotonin receptors increases the availability of norepinephrine and dopamine in the prefrontal cortex, with an antidepressant and nootropic effect. The use of AGM in the pediatric population is limited by the scarcity of data. In addition, few studies and case reports have been published on the use of AGM in patients with attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Considering this evidence, the purpose of this review is to report the potential role of AGM in neurological developmental disorders. AGM would increase the expression of the cytoskeleton-associated protein (ARC) in the prefrontal cortex, with optimization of learning, long-term memory consolidation, and improved survival of neurons. Another important feature of AGM is the ability to modulate glutamatergic neurotransmission in regions associated with mood and cognition. With its synergistic activity a melatoninergic agonist and an antagonist of 5-HT2C, AGM acts as an antidepressant, psychostimulant, and promoter of neuronal plasticity, regulating cognitive symptoms, resynchronizing circadian rhythms in patients with autism, ADHD, anxiety, and depression. Given its good tolerability and good compliance, it could potentially be administered to adolescents and children.

Neuropsychiatric Disorders in Pediatric Long COVID-19: A Case Series.

Few data are available regarding the incidence and the evolution of neuropsychiatric manifestations in children with a history of COVID-19. We herein report five consequent cases of pediatric patients with psychiatric and neurological symptoms of long COVID-19. All patients, mainly males, reported asymptomatic-to-mild COVID-19 and underwent home self-isolation. Abnormal movements, anxiety, and emotional dysregulation were the most recurrent symptoms observed from a few weeks to months after the resolution of the acute infection. A later onset was observed in younger patients. Blood tests and brain imaging resulted in negative results in all subjects; pharmacological and cognitive behavioral therapy was set. A multifactorial etiology could be hypothesized in these cases, as a result of a complex interplay between systemic and brain inflammation and environmental stress in vulnerable individuals. Longer follow-up is required to observe the evolution of neuropsychiatric manifestation in the present cohort and other young patients with previous SARS-CoV-2 infection.

A systematic review of coping strategies in parents of children with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Parents of children with attention deficit hyperactivity disorder (ADHD) use several coping strategies to deal with ADHD symptoms impacting family life. AIM: The aim of this systematic review was to summarize the coping strategies used by parents of children with ADHD, identify which tools are most frequently used to measure coping strategies, and examine factors influencing parental coping. METHOD: According to PRISMA guidelines, we searched for articles indexed in PubMed, EBSCOhost, Scopus, and Web of Science using a combination of expressions including "coping" AND "ADHD" OR "attention-deficit/hyperactivity disorder" AND "parent" OR "parenting" OR "caregiver". RESULTS: Fourteen empirical studies were identified as relevant to our research. Many different types of tools are used to assess coping strategies. We found that parents of ADHD children used more avoidant-focused coping strategies than parents of typical children. Mothers of ADHD children sought significantly more support and used more indirect means than mothers of typically developing (TD) children. CONCLUSIONS: This review underlines the importance of further exploring coping mechanisms of parents of children with ADHD in order to promote positive coping strategies for parents of children with ADHD, and to help such parents to identify people who can support them.

Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway.

Autism Spectrum Disorder (ASD) etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and the Kynurenine pathway; here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies have also identified some important polymorphisms in chromosome loci related to the human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates the Kynurenine pathway with an increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in the glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of the Kynurenine branch induces depletion of melatonin and serotonin, worsening ASD symptoms. Thus, in genetically predisposed subjects, aberrant neurodevelopment may derive from a complex interplay between inflammatory processes, mitochondrial dysfunction, oxidative stress and Kynurenine pathway overexpression. To validate this hypothesis a new translational research approach is necessary.

A systematic review of comorbidity between cerebral palsy, autism spectrum disorders and Attention Deficit Hyperactivity Disorder.

OBJECTIVES: The aim of this systematic review was to examine the incidence and prevalence of comorbidity between Cerebral Palsy (CP), Autism spectrum disorders (ASDs) and Attention-Deficit/Hyperactivity Disorder (ADHD). METHODS: We searched for articles indexed in PubMed, EBSCOhost, Scopus, Web of Science and other potentially relevant internet sources using a combination of expressions including "cerebral palsy" AND "autism" OR "ASD" OR "pervasive development disorder" AND "Attention Deficit Hyperactivity Disorder" OR "ADHD". RESULTS: We identified 2542 studies on CP and ASD and 998 studies on CP and ADHD. After screening titles and abstracts and removing duplicated studies, 47 full papers (CP and ASD n = 28; CP and ADHD n = 19) were downloaded and screened for eligibility. Twenty-eight (CP and ASD n = 16; CP and ADHD n = 12) studies were identified in the peer-review literature. Based on this systematic review, ASD and ADHD seem to be more common in people with CP than in the general population, yet the gold standard methods for diagnosing ASD or ADHD are not suitable for children with motor problems. CONCLUSIONS: Assessing the occurrence of ASD and ADHD would improve the significant cost of healthcare, therapies, and overall daily living for families with children affected by CP. However, psychometric studies are needed in the future to promote development of measures suitable for individuals with CP. In addition, this review highlights the paucity of peer-reviewed studies investigating the occurrence of ASD and ADHD in children with different CP subtypes or functional abilities, and there are still some open questions about pathogenic mechanisms common to CP, ASD and ADHD.

The Empathizing-Systemizing Theory and 'Extreme Male Brain' (EMB) Theory in Parents of Children with Autism Spectrum Disorders (ASD): An Explorative, Cross-Sectional Study.

The aim of this study was to evaluate whether empathizing and systemizing are part of the parental broad autism phenotype (BAP). Parents (N = 76) of preschool children with a diagnosis of ASD and parents (N = 48) of typically developing (TD) children completed the Empathy Quotient (EQ) and Systemizing Quotient-Revised (SQ-R) questionnaires. The E-S discrepancy (D score) was used to test for sex differences in five "brain types". Our results suggest that the E-S theory do not seem to be part of the BAP. However, a stronger drive to systemize than empathize (Type S brain) could be a highly inheritable cognitive endophenotype of mothers of children with ASD. This study should be repeated with a larger sample size.

Coping, stress and negative psychological outcomes in parents of children admitted to a pediatric neurorehabilitation care unit.

BACKGROUND: Parents' attitudes and psychological adjustment during their child's hospitalization in a pediatric neurorehabilitation care unit are key aspects for the child's adherence to care and the impact of the disease. AIM: The aim of this study was to examine the relationship between parenting stress, coping style, and negative psychological outcomes in families of children admitted for the first time to a pediatric neurorehabilitation care unit. DESIGN: This is an observational study. SETTING: Pediatric neurorehabilitation care unit. POPULATION: One hundred twenty-four parents of children diagnosed with neurodevelopmental or neurological conditions. METHODS: Parents completed standardized questionnaires assessing parenting stress, coping style, anxiety and depressive symptoms. RESULTS: We found that parents of children with neurodevelopmental conditions showed more emotion-focused coping strategies (P=0.016) and depressive symptoms (P=0.01) compared with parents of children with neurological conditions. Hierarchical regression analyses showed that emotion- and avoidance-oriented coping style and socioeconomic status are crucial factors in the adjustment process of parents of children with neurodevelopmental conditions. By contrast, parenting stress and child difficulties were the most significant predictors of negative psychological outcomes in parents with neurological conditions. CONCLUSIONS: This study sought to develop more understanding of the relationship among parenting stress, coping, and anxiety or depressive symptoms in parent of children hospitalized in a pediatric neurorehabilitation care unit. We suggest that examining parents may increase our understanding of the interplay between child and parent functioning in families with children admitted for the first time to a pediatric neurorehabilitation care unit. CLINICAL REHABILITATION IMPACT: Identify these predictors might help professionals to develop screening procedures to identify parent at high risk for anxiety or depression, and to conduct early interventions to reduce uncertainty and maladaptive coping strategies that may influences rehabilitation process.