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.

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.

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.

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.

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.

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.

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.

Aripiprazole for treating irritability in children & adolescents with autism: A systematic review.

BACKGROUND & OBJECTIVES: No clear therapeutic benefits of antipsychotics have been reported for the treatment of behavioural symptoms in autism. This systematic review provides an assessment of evidence for treating irritability in autism by aripiprazole. METHODS: The databases of MEDLINE/PubMed and Google Scholar were searched for relevant articles about the effect of aripiprazole in children with autism. The articles were searched according to the inclusion and exclusion criteria specifed for this review. All the double-blind, controlled, randomized, clinical trials examining the efficacy of aripiprazole for treating children and adolescents with autism were included. RESULTS: From the 93 titles identified, 26 were irrelevant and 58 were evaluated for more details. Only five articles met the inclusive criteria. The evidence from precise randomized double blind clinical trials of aripiprazole for the treatment of autism in children and adolescents was convincing enough to recommend aripiprazole. Adverse effects were not very common and were usually mild. INTERPRETATION & CONCLUSIONS: Current evidence suggests that aripiprazole is as effective and safe as risperidone for treating irritability in autism. However, further studies with larger sample size and longer duration are required.

Interest towards human, animal and object in children with autism spectrum disorders: an ethological approach at home.

Autistic spectrum disorders (ASD) are characterised by attention deficits in communication and social interactions and a lack of interest in people. Data are mostly based on clinical situations. However, recent studies have shown a more mixed situation where children with ASD (ASD children) displayed interest towards humans, in both experimental and natural settings. The aim of this study was to assess the interest of ASD children in a natural standardised home setting. Here, we hypothesised that ASD children would display more interest towards animate stimuli-human and pet-when in the child's home than in the lab experimental setting. We used an ethological approach involving observations, a methodological alternative to lab static techniques, to investigate the behaviour of ninety 6- to 12-year-old ASD and typical development (TD) children. Our results were consistent with those of the literature revealing that the ASD children displayed interest towards animate stimuli as did children with TD children. Interestingly, while the ASD children showed higher interest towards humans, e.g. their parent, than the TD children did, they showed less interest towards pet compared to the TD children. Our results suggested that animals are not inherently easy to decode for ASD children, in contrast with previous experiences where a pet was regarded as a more attractive partner, easier to be understood. At last, the ASD children changed more frequently their focus point than the TD children did. These differences may be explained by the reduced attention skills in ASD or the study's context. To conclude, larger exploratory studies in natural settings conducted beyond ordinary human to human interactions are crucial for better understanding of the underlying mechanisms involved in social interactions in ASD.

Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives.

Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests.

Quality of life and mental disorders of adolescents living in French residential group homes.

Here, the quality of life (QoL) of adolescents living in residential group homes (RGHs), is compared to QoL of a general adolescent population, and links between QoL and the presence of mental disorders are examined. Adolescents living in RGHs reported a significantly lower perception of their overall QoL compared to the general adolescent population. The presence of mental disorders was significantly and negatively associated with QoL scores. Some indices of QoL (physical and psychological well-being, relationship with teachers) did not show differences with the general population, indicating that mental health needs or lack of wellbeing are expressed in unusual ways.

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.

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.

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.

Brain pathways mediating the pro-aggressive effect of the steroid sulfatase (Sts) gene.

STS is the single enzyme that converts all steroid sulfates into their free steroid forms. Initiation of attack behavior against conspecific male mice appeared to be linked to Sts. Here we have confirmed the role of Sts through an association study with attack behavior. Previous studies indicated a positive correlation between the initiation of attack behavior and liver STS concentration levels in male mice, but this finding was not compatible with established knowledge of STS mechanisms. High STS concentrations induce low concentrations of sulfated steroids. Sulfated and un-sulfated steroids are GABA(A) receptor agonists and NMDA receptor positive allosteric modulators. This synaptic pattern of functioning can generate attack behavior and we have confirmed here that an injection of the sulfated steroid dehydroepiandrosterone sulfate (DHEA-S) increases attack behavior. To solve the paradox, we measured the transcription activity of the genes underlying the pathways involved in the hydrolysis of sulfated steroids and leading to the formation of un-conjugated steroids in the mouse brain. We observed that the genes monitoring the steroid biosynthesis pathways exhibited a transcription pattern resulting in an increased sulfotransferase activity in the attacking males that could counterbalance the de-sulfating activity of Sts in the attacking mice.

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.

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.

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.