Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Comparison between continued inpatient treatment versus day patient treatment after short inpatient care in early onset anorexia nervosa (COTIDEA trial): a study protocol for a non-inferiority randomised controlled trial.

BACKGROUND: In children with early-onset anorexia nervosa (first symptoms before 13 years old, EO-AN), experts recommend initial outpatient treatment but in-patient treatment (IP) is frequently indicated due to acute medical instability or for those who have not improved with outpatient treatment. This IP can target either a partial weight restauration or a total weight normalization (return to the previous BMI growth trajectory). There are no evidence in the literature on which is the better therapeutic option in EOAN. But as long length of stay induce social isolation, with elevated costs, we wonder if a stepped-care model of daypatient treatment (DP) after short IP stabilisation may be a treatment option as effective as full-time IP to target weight normalization. We designed a two-arm randomised controlled trial testing the non-inferiority of a stepped-care model of DP after short IP stabilisation versus full-time IP. METHODS: Eighty-eight children aged 8 to 13 years suffering from EOAN with initial severe undernutrition will be randomly allocated to either IP treatment as usual or a stepped care DP model both targeting weight normalization. Assessments will be conducted at inclusion, somatic stabilization, weight normalization, 6 months and 12 months post randomisation. The primary outcome will be BMI at 12 months post-randomisation. Secondaries outcomes will included clinical (tanner stage), biological (prealbumin, leptin, total ghrelin and IGF1) and radiological (bone mineralization and maturation) outcomes, eating symptomatology and psychiatric assessments, motivation to change, treatment acceptability and quality of life assessments, cost-utility and cost-effectiveness analyses. DISCUSSION: COTIDEA will provide rigorous evaluation of treatment alternative to full-time inpatient treatment to allow a reduction of social iatrogenic link to hospital length of stay and associated costs. TRIAL REGISTRATION: Trial is registered on ClinicalTrials.gov (NCT04479683).

[Therapeutic approaches for sleep and rhythms disorders in children with ASD]. / Approches thérapeutiques des troubles du sommeil et des rythmes chez l'enfant avec TSA.

Sleep disturbances are extremely common (40-86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm - primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome - to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (-39.6 minutes) compared to placebo (-12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.

Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

Psychometric properties of the French Version of the Social Responsiveness Scale in autism spectrum disorder with or without attention deficit hyperactivity disorder.

OBJECTIVES: The Social Responsiveness Scale (SRS) is an instrument that is commonly used to screen for Autism Spectrum Disorder (ASD). Attention Deficit Hyperactive Disorder (ADHD) frequently occurs with ASD and both disorders share some phenotypic similarities. In the present study, we aimed to determine the psychometric properties of the French version of the Social Responsiveness Scale (SRS) and its 5 subscales (social awareness, social cognition, social communication, social motivation, and autistic mannerisms) to discriminate between children with ADHD and those with ASD (differential diagnosis) and children with ADHD from those with a dual diagnosis of ADHD and ASD (comorbid diagnosis). METHOD: SRS total scores and the 5 subscores of the SRS were compared between 4 groups of children: ADHD (n=32), ASD+ADHD (n=30), ASD (n=31) and typical neurodevelopment (TD; n=30) children. The discriminant validity was estimated using the Area Under the ROC Curves (AUC). RESULTS: SRS Social cognition (AUC=0.73) and Autistic mannerisms (AUC=0.70) subscores were the most discriminating for differential diagnosis of ASD and ADHD. SRS total scores (AUC=0.70), and Social communication (AUC=0.66) and Autistic mannerisms (AUC=0.75) subscores were the most discriminating for comorbid diagnosis of ASD among ADHD children. CONCLUSION: The SRS autistic mannerisms subscore was found to be clinically relevant for both differential diagnosis of ASD and ADHD and comorbid diagnoses of ASD among ADHD children but with a modest discriminant power.

CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

[Computerized oculomotor training in dyslexia: A randomized, crossover clinical trial in pediatric population]. / Rééducation oculomotrice informatisée dans la dyslexie : essai clinique randomisé en crossover en population pédiatrique.

OBJECTIVE: Several studies have reported abnormal oculomotor capacities leading to reading/writing difficulties among dyslexic children. However, no randomized clinical trial has been conducted to determine whether oculomotor training improves reading/writing skills of these children. The present study aims to evaluate the efficacy of computer-based oculomotor training among dyslexic children. METHOD: Crossover randomized trial with enrollment from January 12, 2015 to July 24, 2015, and follow-up to February 4, 2016. Eleven children (aged 7 to 12 years old) with dyslexia were included in a French psychiatric unit. The computer-based oculomotor training consisted of exercises focused on control of saccadic movements (reflexes and voluntary saccades), vergences and visual attention and memory. At baseline, 3 and 6 months, participants were assessed on reading and writing skills as well as phonological skills, visuo-attentional skills and verbal memory using the French batterie analytique du langage écrit (BALE). Saccadic and antisaccadic ocular movements (latencies and gains) were recorded using a specific device. Several Anova models were performed to test whether oculomotor training improves reading, writing and phonological, verbal memory and visuo-attentional skills. Our analyses were considered exploratory (alpha at 5%). RESULTS: No effect of oculomotor training was found on reading skills. However, oculomotor training was associated with a short-term effect (after 3 months of training) on several tests measuring phonological skills (syllabic suppression; P-value=0.022), visuo-attentional skills (search of anarchic verbal cues; P-value=0.035) and verbal memory (digit span backward; P-value=0.022) and with a long-term effect (3 months after the end of the 3 months of training) on a measure of writing skills (regular words; P-value=0.019). Finally, training was associated with an increase of saccadic latencies indicating an increase of visuo-attentional skills (P-value=0.026). CONCLUSIONS: Our results suggested that computer-based oculomotor training might be effective on writing skills and several cognitive skills among dyslexic children, but future clinical trials are needed to confirm our results.

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.

Social cognition in autism is associated with the neurodevelopment of the posterior superior temporal sulcus.

OBJECTIVE: The posterior superior temporal sulcus (pSTS) plays a critical role in the 'social brain'. Its neurodevelopment and relationship with the social impairment in autism spectrum disorders (ASD) are not well understood. We explored the relationship between social cognition and the neurodevelopment of the pSTS in ASD. METHOD: We included 44 adults with high-functioning ASD and 36 controls. We assessed their performances on the 'Reading the mind in the eyes' test (for 34 of 44 subjects with ASD and 30 of 36 controls), their fixation time on the eyes with eye tracking (for 35 of 44 subjects with ASD and 30 of 36 controls) and the morphology of the caudal branches of the pSTS (length and depth), markers of the neurodevelopment, with structural MRI. RESULTS: The right anterior caudal ramus of the pSTS was significantly longer in patients with ASD compared with controls (52.6 mm vs. 38.3 mm; P = 1.4 × 10-3 ; Cohen's d = 0.76). Its length negatively correlated with fixation time on the eyes (P = 0.03) in the ASD group and with the 'Reading the mind in the eyes' test scores in both groups (P = 0.03). CONCLUSION: Our findings suggest that the neurodevelopment of the pSTS is related to the ASD social impairments.

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design. METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry. RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ. CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Inpatient target discharge weight for early-onset anorexia nervosa: Restoring premorbid BMI percentile to improve height prognosis.

OBJECTIVE: Early-onset anorexia nervosa (EO-AN) is characterized by restricted food intake leading to low body weight, emerging before 14 years old. Most patients reaching a target body mass index (BMI) around the 25th percentile at hospitalization discharge display an incomplete prospective height catch-up. A better understanding of height prognosis determinants is required. METHODS: In 74 children with an EO-AN, we collected height and weight premorbidly, at hospitalization, and at discharge, 6 months, 12 months, and at longer-term follow-up of 36 months. We defined a height prognosis parameter (HPP) as the difference between the height percentile at follow-up times and the premorbid height percentile. We explored the relationship between weight parameters and height catch-up at follow-up with linear regression analyses. RESULTS: A higher weight suppression (WS) - i.e., difference between premorbid and current BMI - at admission and discharge was associated with lower HPP - i.e., a greater loss of height - at 12 months and 36 months follow-up. Similarly, a higher premorbid BMI percentile was associated with a lower HPP at 12 and 36 months. CONCLUSION: Target discharge weight for EO-AN patients should be tailored and based on premorbid BMI trajectory to improve height prognosis.

Minibeam radiation therapy: A micro- and nano-dosimetry Monte Carlo study.

PURPOSE: Minibeam radiation therapy (MBRT) is an innovative strategy based on a distinct dose delivery method that is administered using a series of narrow (submillimetric) parallel beams. To shed light on the biological effects of MBRT irradiation, we explored the micro- and nanodosimetric characteristics of three promising MBRT modalities (photon, electron, and proton) using Monte Carlo (MC) calculations. METHODS: Irradiation with proton (100 MeV), electron (300 MeV), and photon (effective energy of 69 keV) minibeams were simulated using Geant4 MC code and the Geant4-DNA extension, which allows the simulation of energy transfer points with nanometric accuracy. As the target of the simulations, cells containing spherical nuclei with or without a detailed description of the DNA (deoxyribonucleic acid) geometry were placed at different depths in peak and valley regions in a water phantom. The energy deposition and number of events in the cell nuclei were recorded in the microdosimetry study, and the number of DNA breaks and their complexity were determined in the nanodosimetric study, where a multi-scale simulation approach was used for the latter. For DNA damage assessment, an adapted DBSCAN clustering algorithm was used. To compare the photon MBRT (xMBRT), electron MBRT (eMBRT), and proton MBRT (pMBRT) approaches, we considered the treatment of a brain tumor located at a depth of 75 mm. RESULTS: Both mean energy deposition at micrometric scale and DNA damage in the "valley" cell nuclei were very low as compared with these parameters in the peak region at all depths for xMBRT and at depths of 0 to 30 mm and 0 to 50 mm for eMBRT and pMBRT, respectively. Only the charged minibeams were favorable for tumor control by producing similar effects in peak and valley cells after 70 mm. At the micrometer scale, the energy deposited per event pointed to a potential advantage of proton beams for tumor control, as more aggressive events could be expected at the end of their tracks. At the nanometer scale, all three MBRT modalities produced direct clustered DNA breaks, although the majority of damage (>93%) was composed of isolated single strand breaks. The pMBRT led to a significant increase in the proportion of clustered single strand breaks and double-strand breaks at the end of its range as compared to the entrance (7% at 75 mm vs 3% at 10 mm) in contrast to eMBRT and xMBRT. In the latter cases, the proportions of complex breaks remained constant, irrespective of the depth and region (peak or valley). CONCLUSIONS: Enhanced normal tissue sparing can be expected with these three MBRT techniques. Among the three modalities, pMBRT offers an additional gain for radioresistant tumors, as it resulted in a higher number of complex DNA damage clusters in the tumor region. These results can aid understanding of the biological mechanisms of MBRT.

Minibeam radiation therapy at a conventional irradiator: Dose-calculation engine and first tumor-bearing animals irradiation.

PURPOSE: Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator. METHODS: A Monte Carlo (Geant4)-based dose calculation engine was developed. It was then benchmarked against a series of dosimetric measurements performed with gafchromic films. Two voxelized rat phantoms (ROBY, computer tomography) were used to evaluate the treatment plan of F98 tumor-bearing rats. The response of a group of 7 animals receiving a unilateral irradiation of 58 Gy was compared to a group of non-irradiated controls. RESULTS: The good agreement between calculations and the experimental data allowed the validation of the dose-calculation engine. The latter was first used to compare the dose distributions in computer tomography images of a rat's head and in a digital model of a rat's head (ROBY), obtaining a good general agreement. Finally, with respect to the in vivo experiment, the increase of mean survival time of the treated group with respect to the controls was modest but statistically significant. CONCLUSIONS: The developed dosimetric tools were used to reliably guide the first MBRT treatments of intracranial glioma-bearing rats outside synchrotrons. The significant tumor response obtained with respect to the non-irradiated controls, despite the heterogenous dose coverage of the target, might indicate the participation of non-targeted effects.

[Assessment and management of gender dysphoria in children and adolescents]. / Évaluation et prise en charge d'une dysphorie de genre chez l'enfant et l'adolescent.

Gender dysphoria, originally called gender identity disorder, is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress and social, academic, and other important forms of isolation. This state is also known as transgender or transsexualism and is recognized as a medical disease. Adults with gender dysphoria can benefit from psychological, medical, and surgical care. However, gender dysphoria rarely occurs in adulthood but rather emerges in childhood or adolescence, generating deep social and academic difficulties, especially at puberty. For the last 10years, the management of gender dysphoria in children and adolescents has developed in several countries, specifically in Europe, but remains under-recognized in France. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients. This article reviews the clinical criteria helping diagnose gender dysphoria and presents the different steps in the assessment and management of these patients in accordance with international guidelines.

[Is age at onset associated with executive dysfunction in obsessive-compulsive disorder?]. / Fonctions exécutives dans le trouble obsessionnel compulsif: effet de l'âge de début des troubles.

In obsessive-compulsive disorder (OCD), clinical, neurobiological and genetic differences have been reported according to age at onset (AAO). Given the importance of identifying homogeneous subtypes in complex hete-rogeneous disorders such as OCD, it would be particularly useful to identify a specific cognitive profile associated with early-onset OCD. Although impaired cognition has repea-tedly been demonstrated in OCD patients, discrepancies between studies have hampered the identification of a precise cognitive dysfunction. Executive dysfunction has often been reported, but findings have not always been replicated. The aim of this study was to assess executive functions in 30 patients according to their AAO. The sample consisted of 15 early-onset and 15 late-onset OCD patients and 22 normal controls, matched for age, sex and socio-economic status. Various aspects of executive function were assessed with five neuropsychological tests: Tower of London, Trail Making Test, Verbal Fluency, Design Fluency and Association Fluen-cy. The 30 OCD patients obtained lower total scores than the controls in the Tower of London test and association fluen-cy task (p<0.05 and p<0.001, respectively). Impairments were more marked for the early-onset group, with no effect of gender or age at interview. Deficits in specific aspects of frontal lobe function were found in the OCD group and were particularly pronounced within the early-onset group. These findings confirm clinical data suggesting that OCD patients can be subtyped according to age at onset and that OCD patients present unusual cognitive characteristics. They also support the hypothesis that early-onset OCD might be a rele-vant subgroup characterised both by a particular clinical profile and by specific cognitive characteristics.

[Suicide attempts in children under 12 years of age]. / Tentatives de suicide chez les enfants de moins de 12 ans.

Suicide attempts (SA) in children are often considered rare and poorly studied. The aim of this study was to explore the clinical characteristics of SA in children under 12 years of age. A retrospective assessment was conducted in 30 consecutive SAs reported in children under 12 years of age admitted to the emergency department at the Robert-Debré University Hospital (Paris, France) from 2007 to 2010 and the Regional University Hospital (Besançon, France) from 2000 to 2008. All suicide attempters were directly assessed at the somatic and psychiatric level. Patients were 8-11 years old (mean, 10.2±0.8). The sex ratio was 0.9 boys for 1 girl. The leading SA methods were poisoning by medication (53.3%), hanging or strangulation (23.3%), jumping from a height (16.7%), poisoning by chemicals (3.3%), and lesions inflicted by sharp objects (3.3%). In addition, SAs were characterized by high lethality (43.7%) contrasting with their low to moderate suicidal intentionality (43.8% and 56.2%, respectively). In conclusion, we reported that SA in children differs from those of adolescents by their greater lethality related to the methods used, but contrasting with the low intentionality mentioned by these patients.

Innovative surgical approach for the Pierre Robin anomalad: subperiosteal release of the floor of the mouth musculature.

The Pierre Robin anomalad presenting with severe respiratory distress is a difficult situation still associated with a significant mortality rate. A surgical approach based on a new idea is described. The concept is that the musculature of the floor of the mouth is under increased tension and pushes the tongue upward and backward with secondary respiratory obstruction. The surgical approach consists of a subperiosteal release of the musculature of the floor of the mouth through a 2-cm submental incision. So far this procedure has been used in four patients with severe obstruction, and marked improvement has occurred postoperatively in all cases. This surgical technique is simple and is associated with little morbidity. It should lessen the need for tracheostomy, which carries a greater morbidity, especially in newborns. We think that this new surgical approach can significantly improve the outcome of the severe form of Pierre Robin anomalad.

[Cardiovascular risks and management during Attention Deficit Hyperactivity Disorder treatment with methylphenidate]. / Risques cardiovasculaires et conduite à tenir dans le traitement du trouble déficit de l'attention/hyperactivité avec le méthylphénidate.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common of the pediatric neuropsychiatric disorders. Methylphenidate is an important element of therapeutic strategies for ADHD. Clinicians are interested in the safety of methylphenidate. Because this drug raises heart rate and blood pressure, concerns have been raised about its cardiovascular safety. Concerns were based on case reports of sudden cardiac death in methylphenidate users, plausible pharmacological pathways involving well-established stimulant effects on heart rate and blood pressure. Until recently, data were limited to a number of observational studies too small to examine serious cardiac events. In the past two years, large retrospective, population-based cohort studies were performed. These studies did not show any evidence that methylphenidate was associated with an increase in risk of myocardial infarction, sudden cardiac death, or stroke. Treatment of children with methylphenidate is not significantly associated with an increase in the short term or mid-term risk of severe cardiac events. For many, available data now will be seen as reassuring. But gaps persist in the methodical and comprehensive assessments of the safety of methylphenidate. Analyses cannot be generalized to children with long-term use of stimulants. Furthermore, long-term effects of slight increases in heart rate or blood pressure are unknown. Stimulant administration continues to have a detectable adrenergic effect even after years of treatment. In the MTA study, greater cumulative stimulant exposure was associated with a higher heart rate at years 3 and 8. Although less severe, such adverse cardiac events are nonetheless alarming to patients. This adrenergic effect may have clinical implications, especially for individual patients with underlying heart abnormalities and it deserves further investigation. More research is necessary to optimize a safe use of methylphenidate regarding its cardiovascular effects. In light of the controversies surrounding the increase in the number of children being diagnosed with ADHD, the broad use of methylphenidate in these patients, and cardiovascular concerns about it, this article addresses topics of clinical significance. For ease of use by practitioners, the article summarizes the guidelines stated by the European Medicines Agency over the appropriate pretreatment evaluation and cardiovascular assessment. It advocates a thorough history and physical examination before initiating methylphenidate to treat patients with ADHD, with an emphasis on the identification of risk factors for sudden death. A cardiac sub-specialist consultation is mandatory in case of history or physical examination findings. In other cases, an electrocardiographic screening is recommended in order to check out previously unrecognized heart disease.