Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Haptic and visuo-haptic impairments for object recognition in children with autism spectrum disorder: focus on the sensory and multisensory processing dysfunctions.

Dysfunctions in sensory processing are widely described in individuals with autism spectrum disorder (ASD), although little is known about the developmental course and the impact of these difficulties on the learning processes during the preschool and school ages of ASD children. Specifically, as regards the interplay between visual and haptic information in ASD during developmental age, knowledge is very scarce and controversial. In this study, we investigated unimodal (visual and haptic) and cross-modal (visuo-haptic) processing skills aimed at object recognition through a behavioural paradigm already used in children with typical development (TD), with cerebral palsy and with peripheral visual impairments. Thirty-five children with ASD (age range: 5-11 years) and thirty-five age-matched and gender-matched typically developing peers were recruited. The procedure required participants to perform an object-recognition task relying on only the visual modality (black-and-white photographs), only the haptic modality (manipulation of real objects) and visuo-haptic transfer of these two types of information. Results are consistent with the idea that visuo-haptic transfer may be significantly worse in ASD children than in TD peers, leading to significant impairment in multisensory interactions for object recognition facilitation. Furthermore, ASD children tended to show a specific deficit in haptic information processing, while a similar trend of maturation of visual modality between the two groups is reported. This study adds to the current literature by suggesting that ASD differences in multisensory processes also regard visuo-haptic abilities necessary to identify and recognise objects of daily life.

Network over-connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: A diffusion MRI study.

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other-DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other-DD including intellectual disability and language disorder) according to DSM-IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (DNUM ) and the tract-averaged fractional anisotropy (DFA ) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other-DD groups. The network differences resulted in an over-connectivity pattern (i.e., higher DNUM and DFA values) in the ASD group with a significance of P < 0.05. No contra-comparison results were found. The over-connectivity pattern in ASD occurred in networks primarily involving the fronto-temporal nodes, known to be crucial for social-skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network-based diffusion study comparing toddlers with ASD and those with other-DD. Results indicate the detection of different connectivity patterns in ASD and other-DD at an age when clinical differential diagnosis is often challenging. Hum Brain Mapp 38:2333-2344, 2017. © 2017 Wiley Periodicals, Inc.

Are children born after assisted reproductive technology at increased risk of autism spectrum disorders? A systematic review.

STUDY QUESTION: Are children born after assisted reproductive technology (ART) at increased risk of autism spectrum disorders (ASD)? SUMMARY ANSWER: There is no evidence that ART significantly increases the risk of ASD in the offspring. WHAT IS KNOWN ALREADY: A few systematic reviews have explored the correlation between assisted conception and ASD with inconclusive results, partly due to the heterogeneity of diagnostic criteria and methodology in the different studies. STUDY DESIGN, SIZE, DURATION: Systematic review of 7 observational studies (2 cohort and 5 case-control) encompassing 9216 subjects diagnosed with ASD published since 2000. MATERIALS, SETTING, METHODS: Literature searches were conducted to retrieve observational studies on the risk of ASD in ART population. Databases searched included PubMed, EMBASE and PsycINFO. In order to obtain more consistent results, we only included the studies in which (i) subjects with either infantile autism or ASD could be identified according to international classification systems and (ii) the diagnosis was obtained from hospital records. Seven studies matched the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Four out of seven studies, including the two with the best quality scores, did not show an association between ART and ASD. The two papers supporting an increased risk of autism following ART had the lowest quality scores, due to major methodological limitations. Only one paper showed a protective role of ART. LIMITATIONS, REASONS FOR CAUTION: In spite of the strict inclusion criteria applied as to the diagnosis of ASD, the papers selected are heterogeneous in many aspects including study design, definitions of ART, data source and analysed confounders. WIDER IMPLICATIONS OF THE FINDINGS: At present, there is no evidence that ART is significantly associated with ASD and hence that current health policies should be modified. The divergent results of some of the studies suggest that further prospective, large and high-quality studies are still needed. STUDY FUNDING/COMPETING INTEREST(S): This work was supported, in part, by the Italian Ministry of Health and by Tuscany Region. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Lower gray matter volumes of frontal lobes and insula in adolescents with anorexia nervosa restricting type: Findings from a Brain Morphometry Study.

BACKGROUND: Brain atrophy in anorexia nervosa (AN) is one of the most marked structural brain changes observed in mental disorders. In this study, we propose a whole brain analysis approach to characterize global and regional cerebral volumes in adolescents with restricting-type anorexia nervosa (AN-r). METHODS: A total of 48 adolescent females (age range 13-18 years) were enrolled in the study (24 right-handed AN-r in the early stages of the illness and treated in the same clinical setting and 24 age-matched healthy controls [HC]). High-resolution T1-weighted magnetic resonance images were acquired. Cerebral volumes, including the total amounts of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were obtained with the Statistical Parametric Mapping software (SPM8); specific cortical regional volumes were computed by applying an atlas-based cortical parcellation to the SPM8 GM segments. Analysis of variance (ANOVA) was performed to identify any significant between-group differences in global and regional brain volumes. RESULTS: The analyses revealed reduced total GM volumes (p = 0.02) and increased CSF (p = 0.05) in AN-r, compared with HC. No significant between-group difference was found in WM volumes. At the regional level, significantly lower GM volumes in both frontal lobes (p = 0.006) and in the left insula (p = 0.016) were detected. No significant relationships were found between cerebral volumes and duration of illness, psychiatric comorbidities, psychopharmacological treatment, prepubertal phase, or presence of amenorrhea. CONCLUSIONS: The topographic distribution of GM reduction in a homogenous group of AN-r involves regions responsible for the emotional and cognitive deficits associated with the illness. These findings are discussed in relation to the roles of the insular cortex and the frontal lobes.

Transdiagnostic vs. disorder-focused perspective in children and adolescents with eating disorders: Findings from a large multisite exploratory study.

BACKGROUND: The transdiagnostic model of eating disorders (ED) proposes common cognitive mechanisms in patients with ED psychopathology. Little is known about their role in the maintenance of ED in children and adolescents. This study aimed to determine whether the relationships between key factors (low self-esteem, weight and shape control, clinical perfectionism, interpersonal problems, distress and mood instability) and core maintaining mechanisms (binge-eating and restraint) would support a transdiagnostic theory in young patients. METHODS: A total of 419 patients (mean age 14.7 ±â€¯2.14 years; age range: 7-18 years; males 13.8%) diagnosed with an ED were assessed in six Italian clinical centers in 2013. Multiple comparisons between ED diagnosis, correlation analysis and principal component analysis (PCA) were performed. RESULTS: Of the entire collective, 51.5% of patients were diagnosed with Anorexia Nervosa (AN), 12.3% were diagnosed with Bulimia Nervosa (BN) and 36.2% with Eating Disorder Not Otherwise Specified (EDNOS). In PCA, the core ED mechanisms, dietary restraint and binge eating, acted as poles of attraction of the other variables. The AN group was particularly linked to restraint and the BN group was particularly related to "Bulimia". Considering the diagnostic subtypes, there were no significant differences between the anorexic binge-purging group, bulimic purging group and bulimic non-purging group, which constituted a unique cluster related to affective, interpersonal problems and to perfectionism, indicating a very homogeneous subgroup. Restricting anorexic group (AN-R), related to shape concern and anxious-depressed mood, was not linked to the other subtypes. EDNOS appeared to be opposed to the AN-R group; the binge eating disorder group appeared to be independent from others. CONCLUSION: Our results suggest the presence of both specific and transdiagnostic mechanisms in ED subtypes, whose knowledge is of relevance for clinical practice.

Prevalence of Autism Spectrum Disorder in a large Italian catchment area: a school-based population study within the ASDEU project.

AIMS: This study aims to estimate Autism Spectrum Disorders (ASD) prevalence in school-aged children in the province of Pisa (Italy) using the strategy of the ASD in the European Union (ASDEU) project. METHODS: A multistage approach was used to identify cases in a community sample (N = 10 138) of 7-9-year-old children attending elementary schools in Pisa - Italy. First, the number of children with a disability certificate was collected from the Local Health Authority and an ASD diagnosis was verified by the ASDEU team. Second, a Teacher Nomination form (TN) to identify children at risk for ASD was filled in by teachers who joined the study and the Social Communication Questionnaire (SCQ) was filled in by the parents of children identified as positive by the TN; a comprehensive assessment, which included the Autism Diagnostic Observation Schedule-Second Edition, was performed for children with positive TN and SCQ⩾9. RESULTS: A total of 81 children who had a disability certificate also had ASD (prevalence: 0.79%, i.e. 1/126). Specifically, 66 children (57 males and nine females; 62% with intellectual disability -ID-) were certified with ASD, whereas another 15 (11 males and four females; 80% with ID) were recognised as having ASD among those certified with another neurodevelopmental disorder. Considering the population of 4417 (children belonging to schools which agreed to participate in the TN/SCQ procedure) and using only the number of children certified with ASD, the prevalence (38 in 4417) was 0.86%, i.e. one in 116. As far as this population is concerned, the prevalence rises to 1% if we consider the eight new cases (six males and two females; no subject had ID) identified among children with no pre-existing diagnoses and to 1.15%, i.e., one in 87, if probabilistic estimation is used. CONCLUSIONS: This is the first population-based ASD prevalence study conducted in Italy so far and its results indicate a prevalence of ASD in children aged 7-9 years of about one in 87. This finding may help regional, national and international health planners to improve ASD policies for ASD children and their families in the public healthcare system.

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder.

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.

Disentangling the initiation from the response in joint attention: an eye-tracking study in toddlers with autism spectrum disorders.

Joint attention (JA), whose deficit is an early risk marker for autism spectrum disorder (ASD), has two dimensions: (1) responding to JA and (2) initiating JA. Eye-tracking technology has largely been used to investigate responding JA, but rarely to study initiating JA especially in young children with ASD. The aim of this study was to describe the differences in the visual patterns of toddlers with ASD and those with typical development (TD) during both responding JA and initiating JA tasks. Eye-tracking technology was used to monitor the gaze of 17 children with ASD and 15 age-matched children with TD during the presentation of short video sequences involving one responding JA and two initiating JA tasks (initiating JA-1 and initiating JA-2). Gaze accuracy, transitions and fixations were analyzed. No differences were found in the responding JA task between children with ASD and those with TD, whereas, in the initiating JA tasks, different patterns of fixation and transitions were shown between the groups. These results suggest that children with ASD and those with TD show different visual patterns when they are expected to initiate joint attention but not when they respond to joint attention. We hypothesized that differences in transitions and fixations are linked to ASD impairments in visual disengagement from face, in global scanning of the scene and in the ability to anticipate object's action.

Basal ganglia and restricted and repetitive behaviours in Autism Spectrum Disorders: current status and future perspectives.

This editorial offers a concise overview of the recent structural magnetic resonance imaging studies that evaluate the basal ganglia (BG) volumes in autism spectrum disorders (ASD). The putative relationship between the repetitive or stereotyped behaviours of ASD and BG volumes is also explored, with a focus on possible translational approaches.

[Anorexia nervosa and hyperactivity in adolescence: psychiatric and internal medicine features]. / Anoressia nervosa e iperattività in adolescenza: correlati psichiatrici e internistici.

AIM: The aim of the present study was to verify the influence of hyperactivity on internistic and psychiatric parameters in early onset anorexia nervosa restricting type (ANR). METHODS: Seventy-three adolescent females (mean age 13.5 years, SD: 2.27) with a diagnosis of ANR (DSM-IV-TR) were consecutively enrolled in the Child and Adolescent Eating Disorders Unit of the IRCCS-Stella Maris and assessed by an extensive clinical protocol. All patients completed: psychiatric evaluation for description of the DCA and comorbidities; pediatric assessment including complete auxological data, blood pressure, heart rate and other electro/echo cardiographic and biohumoral parameters. The hyperactivity was estimated by the application of the "Structured Interview for Anorexic and Bulimic Disorder-Expert Form" (Item 40) in the context of clinical observation. Subjects were identified according to their level of hyperactive (ANR+H) and non-hyperactive (ANR-H) activity. RESULTS: In the ANR+H group heart rate, leptin, sodium, potassium and gamma plasma proteins significantly differ compared to the group ANR-H. Patients with hyperactivity also have a complete form of ANR in 94% of cases compared with 66.7% of non-hyperactive; significant differences were found also in thought and attention CBCL and YSR subscales, combined with major internalizing problems. CONCLUSION: This study provides preliminary data which can orient research towards the development of specific treatments for the hyperactivity, in order to improve the prognosis and thus avoid the chronicity of the disorder and the development of complications in adult life.

Brain anatomy of autism spectrum disorders II. Focus on amygdala.

This brief review encompasses the key findings of structural Magnetic Resonance Imaging (sMRI) research on amygdala volume in autism spectrum disorders (ASD). We also highlight the possible correlation between the autistic behavioural phenotype and amygdala alteration.

Brain anatomy of autism spectrum disorders I. Focus on corpus callosum.

This brief review aims to examine the structural magnetic resonance imaging (sMRI) studies on corpus callosum in autism spectrum disorders (ASD) and discuss the clinical and demographic factors involved in the interpretation of results.

The CBCL 1.5-5 and the identification of preschoolers with autism in Italy.

AIMS: To study the potential use of child behaviour checklist (CBCL) 1.5-5 scales for the early identification of preschoolers at risk of autism. METHODS: CBCL scores of three groups of preschoolers were compared: (1) an experimental group of 101 preschoolers with autism spectrum disorder (ASD); (2) a control group of 95 preschoolers with other psychiatric disorders (OPD); (3) a control group of 117 preschoolers with typical development (TD). One-way analysis of variance (ANOVA), logistic regression with odds ratio (OR) and receiver operating characteristic (ROC) analyses were performed. RESULTS: ANOVA revealed that ASD and OPD had significantly higher scores in almost all CBCL scales than TD. ASD presented significantly higher scores than OPD on Withdrawn, Attention Problems and Pervasive Developmental Problems (PDP) scales. Logistic regression analysis demonstrated that these same CBCL scales have validity in predicting the presence of an ASD towards both TD and OPD. ROC analysis indicated high sensitivity and specificity for PDP (0.85 and 0.90) and Withdrawn (0.89 and 0.92) scales when ASD is compared to TD. Specificity (0.60 for PDP and 0.65 for Withdrawn) decreases when comparing ASD and OPD CONCLUSIONS: The PDP and Withdrawn scales have a good predictive validity so that they could be proposed as a first-level tool to identify preschoolers at risk of autism in primary care settings. Problems regarding the lower specificity when comparing ASD v. OPD are discussed.

Assessment of selective homing and contribution to vessel formation of cryopreserved peripherally injected bone marrow mononuclear cells following experimental myocardial damage.

In view of a potential clinical use we aimed this study to assess the selective homing to the injured myocardium and the definitive fate of peripherally injected labeled and previously cryopreserved Bone Marrow Mononuclear cells (BMMNCs). The myocardial damage (cryoinjury) was produced in 59 rats (45 treated, 14 controls). From 51 donor rats 4.4 x 10(9) BMMNCs were isolated and cryopreserved (slow-cooling protocols); the number of CD34+ and the viability of pooled cells was assessed by flow-cytometry analysis before and after cryopreservation and simulated delivery through a 23G needle. Seven days after injury, BMMNCs were thawed, labeled with PKH26 dye and peripherally injected (20 x 10(6) cells in 500 microl) in recipient rats. Two weeks after experimental injury, the heart, lungs, liver, kidneys, spleen and thymus were harvested to track transplanted cells. Except a small amount in the spleen, PKH26+ cells were found only in the infarcted myocardium of the treated animals. Typical vascular structures CD34+ were found in the infarcted areas of all animals; treated rats showed a significantly higher number of these structures if compared with untreated. Morphological ultra-structural examination of infarcted areas confirmed in treated rats the presence of early-stage PKH26+ vascular structures derived from injected BMMNCs. The estimated mean CD34+ cells loss due to the cryopreservation procedure and to the system of delivery was 0.24% and 0.1%, respectively, confirming the feasibility of the procedure. This study supports the possible therapeutic use of cryopreserved peripherally injecetd BMMNCs as a source of CD34+ independent vascular structures following myocardial damage.

Controlled-release transdermal apomorphine treatment for motor fluctuations in Parkinson's disease.

This study evaluated the efficacy in Parkinson's disease (PD) of a new pharmacologic preparation of apomorphine included in microemulsions and administered by transdermal route, which provides a constant release of the drug for several hours (Apo-TD). Twenty-one PD patients with motor fluctuations were treated with L-dopa alone, with L-dopa plus oral dopamine-agonists, or with L-dopa plus Apo-TD. Apo-TD improved UPDRS-III and tapping test scores in "off" conditions, and reduced duration of "off" periods; no improvement in "on" conditions occurred. We conclude that Apo-TD shows its efficacy particularly by reducing "off" period duration and disability rather than improving motor performances in "on" conditions and therefore it seems a promising treatment for uncontrolled "off" phases in PD patients.

Nocturnal anomalous movement reduction and sleep microstructure analysis in parkinsonian patients during 1-night transdermal apomorphine treatment.

This study analyzed the macrostructure and microstructure of sleep in 12 parkinsonian patients under basal conditions (T0) and during 1-night treatment (T1) with a new formulation of apomorphine. This new formulation consisted in a microemulsion of apomorphine administered by the transdermal route, able to provide a constant release of the drug over several hours (APO-TD). Sleep analysis at T1 compared with T0 revealed a 16% increment of total sleep time, a 12% increment of sleep efficiency, a 16% increment of stage 3 and 4 non-REM sleep, a 15% reduction of periodic limb movements index, a 22% reduction of arousal index, and a 23% reduction of cycling alternating patterns/non-REM. We conclude that APO-TD may be able to reduce nocturnal anomalous movements, akinesia, and rigidity in Parkinson's disease, and may reduce the disturbed sleep typical of Parkinson's disease.