Melatonin in Neurodevelopmental Disorders: A Critical Literature Review.

The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its physiological effects are considered to understand better the role of melatonin in typical and atypical neurodevelopment. Then, several neurodevelopmental disorders occurring during infancy, such as autism spectrum disorder or neurogenetic disorders associated with autism (including Smith-Magenis syndrome, Angelman syndrome, Rett's syndrome, Tuberous sclerosis, or Williams-Beuren syndrome) and neurodevelopmental disorders occurring later in adulthood like bipolar disorder and schizophrenia, are discussed with regard to impaired melatonin production and circadian rhythms, in particular, sleep-wake rhythms. This article addresses the issue of overlapping symptoms that are commonly observed within these different mental conditions and debates the role of abnormal melatonin production and altered circadian rhythms in the pathophysiology and behavioral expression of these neurodevelopmental disorders.

Natural IgG Anti-F (ab')2 Autoantibody Activity in Children with Autism.

Background: Many and diverse autoimmune abnormalities have been reported in children with autism. Natural autoantibodies (NAAbs) play important immunoregulatory roles in recognition of the immune self. The objective of this study was to examine the presence of NAAbs in the sera of children with autism and across severity subgroups of autistic behavioral impairments. Methods: NAAbs were titrated in sera through an ELISA procedure in 60 low-functioning children with autism and 112 typically developing controls matched for age, sex and puberty. Results: Serum titers of IgG anti-F(ab')2 autoantibodies were significantly lower in children with autism compared to typically developing controls (p < 0.0001), and were significantly negatively associated with autism severity (p = 0.0001). This data appears to be related more specifically to autism than to intellectual disability, given that IgG anti-F(ab')2 levels were significantly negatively correlated with IQ scores in the autism group (p = 0.01). Conclusions: This is the first report in autism of abnormally low natural anti-F(ab')2 autoantibody activity. The findings suggest a dysfunction of self-recognition mechanisms which may play a role in the pathogenesis of autism, especially for the severely affected children. These findings strengthen the hypothesis of an autoimmune process in autism and open the prospect of alternative medical treatment. Further neuroimmunological research is warranted to understand the exact mechanisms underlying this reduced natural IgG anti-F (ab')2 autoantibody activity, and to assess its impact on the pathophysiology and behavioral expression of autism.

Detection of Morphological Abnormalities in Schizophrenia: An Important Step to Identify Associated Genetic Disorders or Etiologic Subtypes.

Current research suggests that alterations in neurodevelopmental processes, involving gene X environment interactions during key stages of brain development (prenatal period and adolescence), are a major risk for schizophrenia. First, epidemiological studies supporting a genetic contribution to schizophrenia are presented in this article, including family, twin, and adoption studies. Then, an extensive literature review on genetic disorders associated with schizophrenia is reviewed. These epidemiological findings and clinical observations led researchers to conduct studies on genetic associations in schizophrenia, and more specifically on genomics (CNV: copy-number variant, and SNP: single nucleotide polymorphism). The main structural (CNV) and sequence (SNP) variants found in individuals with schizophrenia are reported here. Evidence of genetic contributions to schizophrenia and current knowledge on genetic syndromes associated with this psychiatric disorder highlight the importance of a clinical genetic examination to detect minor physical anomalies in individuals with ultra-high risk of schizophrenia. Several dysmorphic features have been described in schizophrenia, especially in early onset schizophrenia, and can be viewed as neurodevelopmental markers of vulnerability. Early detection of individuals with neurodevelopmental abnormalities is a fundamental issue to develop prevention and diagnostic strategies, therapeutic intervention and follow-up, and to ascertain better the underlying mechanisms involved in the pathophysiology of schizophrenia.

Predictors of cognitive, behavioural and academic difficulties in NF1.

The impact of the Neurofibromatosis type 1 (NF1) on cognition have been subject to much clinical investigation, but environmental modifiers of disease expression have not yet been systematically investigated. The aim of this paper is to determine the role of demographic and environmental factors such as age, sex, socioeconomic status, parental NF1 status and neurological complications on the cognitive, behavioural and academic outcomes in NF1. Participants included 206 children aged 4-18 years seen within the Manchester clinical research NF1 service. Multiple linear regression models were used to study the effect of the hypothesized predictor variables on cognitive, behavioural and academic outcomes. Relative to population norms, 80% of the NF1 sample demonstrated significantly lower scores in at least one cognitive, behavioural or academic domains. Family history of NF1 and lower SES were independently associated with poorer cognitive, behavioural and academic outcomes. Neurological problems such as epilepsy and hydrocephalus were associated with lower IQ and academic skills. Cognitive and behavioural phenotypes emerge commonly via a complex interplay between genes and environmental factors, and this is true also of a monogenic condition such as NF1. Early interventions and remedial education may be targeted to risk groups such those with familial NF1, families with lower SES and those with associated neurological comorbidities.

Autism Spectrum and Other Neurodevelopmental Disorders in Children of Immigrants: A Brief Review of Current Evidence and Implications for Clinical Practice.

Children of immigrants may have higher neurodevelopmental risks than those of non-immigrant populations. Yet, some evidence suggests that this group may receive late diagnosis, and therefore miss beneficial early interventions. Clinicians may misattribute symptoms of disorders to other social, behavioral or language problems. Likewise, there might be cultural differences in parents' likelihood of perceiving or reporting first developmental concerns to clinicians. Population-based standardized screening may play an important role in addressing ethnic inequalities in the age at diagnosis, although further research focusing on cross-cultural use is necessary. Once children are diagnosed, clinicians may rely on culturally sensitive procedures (translation services, cultural mediators) to increase the accessibility of interventions and improve adherence among immigrant families. In this brief review, we provide an overview about what is currently known about the epidemiology and risk factors of neurodevelopmental disorders, paying special attention to autism spectrum disorder (ASD), in children of immigrants and suggest the necessity of population-based screening and culturally sensitive care.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Premigration social adversity and autism spectrum disorder.

BACKGROUND: Several studies suggest significant relationships between migration and autism spectrum disorder (ASD) but there are discrepant results. Given that no studies to date have included a pathological control group, the specificity of the results in ASD can be questioned. AIMS: To compare the migration experience (premigration, migratory trip, postmigration) in ASD and non-ASD pathological control groups, and study the relationships between migration and autism severity. METHOD: Parents' and grandparents' migrant status was compared in 30 prepubertal boys with ASD and 30 prepubertal boys without ASD but with language disorders, using a questionnaire including Human Development Index (HDI)/Inequality-adjusted Human Development Index (IHDI) of native countries. Autism severity was assessed using the Child Autism Rating Scale, Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised scales. RESULTS: The parents' and grandparents' migrant status frequency did not differ between ASD and control groups and was not associated with autism severity. The HDI/IHDI values of native countries were significantly lower for parents and grandparents of children with ASD compared with the controls, especially for paternal grandparents. Furthermore, HDI/IDHI levels from the paternal line (father and especially paternal grandparents) were significantly negatively correlated with autism severity, particularly for social interaction impairments. CONCLUSIONS: In this study, parents' and/or grandparents' migrant status did not discriminate ASD and pathological control groups and did not contribute either to autism severity. However, the HDI/IHDI results suggest that social adversity-related stress experienced in native countries, especially by paternal grandparents, is potentially a traumatic experience that may play a role in ASD development. A 'premigration theory of autism' is then proposed.

Anxiety disorders in children with high intellectual potential.

BACKGROUND: Several studies have reported anxiety disorders in children with high intellectual potential (HIP). However, there are discrepant results possibly as a result of methodological biases (different/absent definitions of HIP, small sample sizes, non-validated/adapted/specific tools for assessing anxiety and a single observational source). AIMS: To examine more thoroughly the relationships between HIP and anxiety in large samples of children using clear definitions of HIP, different observational sources and specific assessments of anxiety. METHOD: Children with HIP (n = 211, total IQ ≥130) were compared with children without HIP (n = 397, total IQ <130) for anxiety using different observational sources (child psychiatric diagnosis, parental evaluation and child's self-evaluation). Intellectual functioning was assessed using the Wechsler Intelligence Scale. RESULTS: There were significantly more children with HIP who had anxiety disorders than children without HIP based on the child psychiatric diagnosis. Moreover, based on the child's self-evaluation, children with a high Verbal Comprehension Index (VCI ≥130) were significantly more anxious than children with a VCI <130, whereas children with a high Perceptual Reasoning Index (PRI ≥130) were significantly less anxious than children with a PRI <130. Finally, there was no significant relationship between levels of intellectual functioning and anxiety according to parental observation. CONCLUSIONS: The results highlight the importance of using multiple observational sources and conducting analyses on different dimensions of intellectual functioning (such as VCI and PRI), rather than only on the composite total IQ score. High verbal potential might be a factor of vulnerability for anxiety, whereas high perceptual reasoning might be a protective factor. Further studies are necessary to understand better the mechanisms underlying these results.

Construct Validity and Cross Validity of a Test Battery Modeling Autism Spectrum Disorder (ASD) in Mice.

Modeling in other organism species is one of the crucial stages in ascertaining the association between gene and psychiatric disorder. Testing Autism Spectrum Disorder (ASD) in mice is very popular but construct validity of the batteries is not available. We presented here the first factor analysis of a behavioral model of ASD-like in mice coupled with empirical validation. We defined fourteen measures aligning mouse-behavior measures with the criteria defined by DSM-5 for the diagnostic of ASD. Sixty-five mice belonging to a heterogeneous pool of genotypes were tested. Reliability coefficients vary from .68 to .81. The factor analysis resulted in a three- factor solution in line with DSM criteria: social behavior, stereotypy and narrowness of the field of interest. The empirical validation with mice sharing a haplo-insufficiency of the zinc-finger transcription factor TSHZ3/Tshz3 associated with ASD shows the discriminant power of the highly loaded items.

Molecular investigation, using chromosomal microarray and whole exome sequencing, of six patients affected by Williams Beuren syndrome and Autism Spectrum Disorder.

Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as "overfriendliness" and "hyersociability". WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic.Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin.The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in "typical" WBS patients: therefore, the terms "overfriendliness" and "hypersociability" appear to be a misleading oversimplification.The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.

Exploring Self-Consciousness From Self- and Other-Image Recognition in the Mirror: Concepts and Evaluation.

A historical review of the concepts of self-consciousness is presented, highlighting the important role of the body (particularly, body perception but also body action), and the social other in the construction of self-consciousness. More precisely, body perception, especially intermodal sensory perception including kinesthetic perception, is involved in the construction of a sense of self allowing self-other differentiation. Furthermore, the social other, through very early social and emotional interactions, provides meaning to the infant's perception and contributes to the development of his/her symbolization capacities. This is a necessary condition for body image representation and awareness of a permanent self in a time-space continuum (invariant over time and space). Self-image recognition impairments in the mirror are also discussed regarding a comprehensive developmental theory of self-consciousness. Then, a neuropsychological and neurophysiological approach to self-consciousness reviews the role of complex brain activation/integration pathways and the mirror neuron system in self-consciousness. Finally, this article offers new perspectives on self-consciousness evaluation using a double mirror paradigm to study self- and other- image and body recognition.

Self-other recognition impairments in individuals with schizophrenia: a new experimental paradigm using a double mirror.

Clinical observations suggest early self-consciousness disturbances in schizophrenia. A double mirror combining the images of two individuals sitting on each side of the mirror was used to study self-other differentiation in 12 individuals with early onset schizophrenia (EOS) and 15 individuals with adult onset schizophrenia (AOS) compared to 27 typically developing controls (TDC) matched on age and sex. The effects of intermodal sensory perception (visual-tactile and visual-kinesthetic) on self-other recognition were also studied. The results showed that EOS and AOS individuals, independently of age and schizophrenia severity, were centered on their own image compared to TDC, with both significant earlier self-recognition and delayed other-recognition during the visual recognition task. In addition, there was no significant effect of intermodal sensory stimulation on self-other recognition in EOS and AOS patients, whereas self-centered functioning was significantly increased by visual-tactile stimulation and decreased by visual-kinesthetic stimulation in TDC. The findings suggest that self-other recognition impairments might be a possible endophenotypic trait of schizophrenia.

Relationships Between Self-Injurious Behaviors, Pain Reactivity, and ß-Endorphin in Children and Adolescents With Autism.

OBJECTIVE: Autism and certain associated behaviors including self-injurious behaviors (SIB) and atypical pain reactivity have been hypothesized to result from excessive opioid activity. The objective of this study was to examine the relationships between SIB, pain reactivity, and ß-endorphin levels in autism. METHODS: Study participants were recruited between 2007 and 2012 from day care centers and included 74 children and adolescents diagnosed with autism (according to DSM-IV-TR, ICD-10, and CFTMEA) and intellectual disability. Behavioral pain reactivity and SIB were assessed in 3 observational situations (parents at home, 2 caregivers at day care center, a nurse and child psychiatrist during blood drawing) using validated quantitative and qualitative scales. Plasma ß-endorphin concentrations were measured in 57 participants using 2 different immunoassay methods. RESULTS: A high proportion of individuals with autism displayed SIB (50.0% and 70.3% according to parental and caregiver observation, respectively). The most frequent types of SIB were head banging and hand biting. An absence or decrease of overall behavioral pain reactivity was observed in 68.6% and 34.2% of individuals with autism according to parental and caregiver observation, respectively. Those individuals with hyporeactivity to daily life accidental painful stimuli displayed higher rates of self-biting (P < .01, parental evaluation). No significant correlations were observed between ß-endorphin level and SIB or pain reactivity assessed in any of the 3 observational situations. CONCLUSIONS: The absence of any observed relationships between ß-endorphin level and SIB or pain reactivity and the conflicting results of prior opioid studies in autism tend to undermine support for the opioid theory of autism. New perspectives are discussed regarding the relationships found in this study between SIB and hyporeactivity to pain.

Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders.

In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause-effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep-wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep-wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

Melatonin: Pharmacology, Functions and Therapeutic Benefits.

BACKGROUND: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. METHODS: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. RESULTS: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. CONCLUSION: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy.

Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on an extensive review of single-gene disorders, copy number variants, and other chromosomal disorders), and consequently to propose a hierarchical diagnostic strategy with a stepwise evaluation, helping general practitioners/pediatricians and child psychiatrists to collaborate with geneticists and neuropediatricians, in order to search for genetic disorders associated with ASD. The first step is a clinical investigation involving: (i) a child psychiatric and psychological evaluation confirming autism diagnosis from different observational sources and assessing autism severity; (ii) a neuropediatric evaluation examining neurological symptoms and developmental milestones; and (iii) a genetic evaluation searching for dysmorphic features and malformations. The second step involves laboratory and if necessary neuroimaging and EEG studies oriented by clinical results based on clinical genetic and neuropediatric examinations. The identification of genetic disorders associated with ASD has practical implications for diagnostic strategies, early detection or prevention of co-morbidity, specific treatment and follow up, and genetic counseling.

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice.

We hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures.

Exploring "psychic transparency" during pregnancy: a mixed-methods approach.

BACKGROUND: Psychic transparency is described as a psychic crisis occurring during pregnancy. The objective was to test if it was clinically detectable. METHODS: Seven primiparous and seven nulliparous subjects were recorded during 5 min of spontaneous speech about their dreams. 25 raters from five groups (psychoanalysts, psychiatrists, general practitioners, pregnant women and medical students) listened to the audiotapes. They were asked to rate the probability of the women being pregnant or not. Their ability to discriminate the primiparous women was tested. The probability of being identified correctly or not was calculated for each woman. A qualitative analysis of the speech samples was performed. RESULTS: No group of rater was able to correctly classify pregnant and non-pregnant women. However, the raters' choices were not completely random. The wish to be pregnant or to have a baby could be linked to a primiparous classification whereas job priorities could be linked to a nulliparous classification. CONCLUSIONS: It was not possible to detect Psychic transparency in this study. The wish for a child might be easier to identify. In addition, the raters' choices seemed to be connected to social representations of motherhood.

The Prevalence of Mental Disorders Among Children and Adolescents in the Child Welfare System: A Systematic Review and Meta-Analysis.

It remains unclear whether children and adolescents in the child welfare system (CWS) exhibit a higher prevalence of mental disorders compared with the general population. The objective of this study was to perform a systematic review and meta-analysis to assess the prevalence of mental disorders in the CWS.A ll of the epidemiological surveys assessing the prevalence of mental disorders in children and adolescents in the CWS were included. The pooled prevalence was estimated with random effect models. Potential sources of heterogeneity were explored using meta-regression analyses.E ight studies provided prevalence estimates that were obtained from 3104 children and adolescents. Nearly 1 child or adolescent of every 2 (49%; 95% confidence interval (CI) 43-54) was identified as meeting criteria for a current mental disorder. The most common mental disorder was disruptive disorder (27%; 95% CI 20-34), including conduct disorder (20%; 95% CI 13-27) and oppositional defiant disorder (12%; 95% CI 10-14). The prevalence of attention-deficit/hyperactivity disorder was estimated to be 11% (95% CI 6-15). The prevalence estimates of anxiety and depressive disorders were 18% (95% CI 12-24) and 11% (95% CI 7-15). Posttraumatic stress disorder had the lowest prevalence (4%; 95% CI 2-6). High prevalences of mental disorders in the CWS were reported, which highlights the need for the provision of qualified service. The substantial heterogeneity of our findings is indicative of the need for accurate epidemiological data to effectively guide public policy.