Guillaume Bronsard

Pain Reactivity and Plasma β-Endorphin in Children and Adolescents with Autistic Disorder

Background Reports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism. Methodology/Principal Findings The study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity. Conclusions/Significance The greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain.

Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of 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.

Aggression in Low Functioning Children and Adolescents with Autistic Disorder

Background Parents, caregivers and mental health professionals have often reported violence and aggression in children or adolescents with autistic disorder. However, most of these observations derived from anecdotal reports, and studies on frequency and characterization of aggression in autism remain limited. Our objective was to better characterize and understand the different types of aggressive behaviors displayed by a large group of individuals with autism in different observational situations. Methodology/Findings The study was conducted on 74 children and adolescents with autism and 115 typically developing control individuals matched for sex, age and pubertal stage. Other-Injurious Behaviors (OIB) were assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and a child psychiatrist during blood drawing) using validated scales. The frequency of OIB was significantly higher in individuals with autism compared to typically developing control individuals during the blood drawing (23% vs. 0%, P<0 .01). The parents observed significantly less OIB in their children than caregivers (34% vs. 58%, P<0.05). In addition, the most frequent concurrent behaviors occurring just before the appearance of OIB in individuals with autism were anxiety-related behaviors and excitation according to the parental as well as the caregiver observation. Conclusions/Significance The results suggest that in a stressful situation, such as the blood drawing, individuals with autism release their stress through behaviors such as OIB, whereas typically developing individuals regulate and express their stress through cognitive skills such as mental coping strategies, symbolization skills with representation and anticipation of the stressful situation, social interaction and verbal or non-verbal communication. The findings underline also the key role of the environment in assessing OIB and developing therapeutic perspectives, with an individual who modulates his/her behavior according to the environment, and an environment that perceives this behavior and reacts to it with different tolerance thresholds according to the observers.

Altered circadian patterns of salivary cortisol in low-functioning children and adolescents with autism

BACKGROUND Reports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism. METHODS The study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day 1, 1600 h, 0800 h-Day 2 for 46 individuals with autism and 27 controls, and 0800 h-Day 1, 1100 h, 1600 h, 2400 h, 0800 h-Day 2 for 13 individuals with autism and 20 controls). Overnight (2000 h-0800 h) urinary cortisol excretion was also measured. RESULTS The autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day 2 compared to Day 1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups. CONCLUSION Anticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day 2 versus 0800 h-Day 1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety.

Modulation of Brain β-Endorphin Concentration by the Specific Part of the Y Chromosome in Mice

Background Several studies in animal models suggest a possible effect of the specific part of the Y-chromosome (YNPAR) on brain opioid, and more specifically on brain β-endorphin (BE). In humans, male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are also reported. This suggests gender differences in BE associated with genetic factors and more precisely with YNPAR. Methodology/Principal Findings Brain BE levels and plasma testosterone concentrations were measured in two highly inbred strains of mice, NZB/BlNJ (N) and CBA/HGnc (H), and their consomic strains for the YNPAR. An indirect effect of the YNPAR on brain BE level via plasma testosterone was also tested by studying the correlation between brain BE concentration and plasma testosterone concentration in eleven highly inbred strains. There was a significant and major effect (P<0.0001) of the YNPAR in interaction with the genetic background on brain BE levels. Effect size calculated using Cohens procedure was large (56% of the total variance). The variations of BE levels were not correlated with plasma testosterone which was also dependent of the YNPAR. Conclusions/Significance The contribution of YNPAR on brain BE concentration in interaction with the genetic background is the first demonstration of Y-chromosome mediated control of brain opioid. Given that none of the genes encompassed by the YNPAR encodes for BE or its precursor, our results suggest a contribution of the sex-determining region (Sry, carried by YNPAR) to brain BE concentration. Indeed, the transcription of the Melanocortin 2 receptor gene (Mc2R gene, identified as the proopiomelanocortin receptor gene) depends on the presence of Sry and BE is derived directly from proopiomelanocortin. The results shed light on the sex dependent differences in brain functioning and the role of Sry in the BE system might be related to the higher frequency of autistic disorder in males.

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

AbstractIt 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.All 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.Eight 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.

The Autism Psychodynamic Evaluation of Changes (APEC) scale: a reliability and validity study on a newly developed standardized psychodynamic assessment for youth with Pervasive Developmental Disorders.

The present study was designed to examine the reliability and validity of the Autism Psychodynamic Evaluation of Changes (APEC) scale, developed to assess the evolution in individuals with autism under treatment. The APEC scale focuses on the key role of impairment in body image construction, which requires cross-modal sensory integration through emotional communication with motor representations. Thus, the body image construction is associated simultaneously with spatial and temporal organization and allows the emergence of self- and others-representations. The use of the APEC scale, with its seven domains (expression of emotion in relationships, eye contact, body image, graphic productions, exploration of space and objects, time perception, and verbal language), underlines the importance in autistic disorder of anxieties related to body and spatial representations, and of impairment in the body ego construction which is closely linked to the emergence of individuation/separation processes. This study was conducted on 73 children and adolescents with autistic disorder. They were recruited in day care facilities where two caregivers independently gave their ratings based on their clinical observation on a daily basis during the same month. Analyses included assessing construct validity through correspondence analyses and inter-rater reliability using kappa coefficients. The APEC scale offers a reliable and validated psychodynamic assessment of interest for professionals (such as child psychiatrists, caregivers, therapists or teachers) and researchers working with children, adolescents and adults with autistic disorder, especially in the follow-up of their evolution. The APEC scale provides an approach at the interface of psychoanalysis and neuroscience, and is also of interest for clinical and developmental psychology. Using the APEC scale in a range of different practical and research settings will foster links between psychoanalytic perspectives and educational training for children with autistic disorder, and will contribute to the dialogue between psychoanalysis, neuroscience and psychology.

Addressing, understanding and treating conduct disorders in adolescents through psychoanalysis and neuroscience: towards a disappearance of sex-differences

Based on our findings showing that female adolescents in resident group homes exhibit externalized disorders at the same rate as male adolescents, explanatory hypotheses are developed from neuroscience (genetics and endocrinology) and from psychoanalysis (psychopathological and environmental approach). In particular, the place of the psychoanalytic approach in improving our understanding of such results is discussed with regard first to the clinical context and then to the research context. This article underlines that both approaches in psychoanalysis and neuroscience can, and maybe have to/should, coexist in child psychiatry.