Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Autism spectrum disorder during French COVID-19 lockdown: The importance of individualized support.

AIM: This observational and repeated measures study assesses the impact of the first, most restrictive, COVID-19 lockdown in France on children with autism spectrum disorder (ASD) and their families. METHOD: During the first COVID-19 lockdown, families of ASD children enrolled in the day-care centre of the child and adolescent psychiatry department of the Tours University Hospital were contacted weekly. A total of 95 parents took part in this study between the 18th of March and the 8th of May 2020. Advice and personalized support materials were provided by professionals involved in children's care. Questions regarding clinical outcomes were addressed to parents, and their assessments were reported on a 5-point Likert scale. Two time points were considered: the first 3 weeks and the three last weeks of the lockdown period. RESULTS: No difference was highlighted between clinical scores collected at the beginning and at the end of the lockdown. No effect of intellectual disability, accommodation type (house or apartment) or parental status was observed. The reasons for the relatively minor impact of the COVID-19 lockdown observed in this study are discussed. CONCLUSIONS: Individualized and regular support provided by caregivers, familiar with ASD children's clinical specificities, in the context of a trusted relationship with parents may have contributed to the stability of this population. This 'tailor-made' approach should be promoted, in order to help support families of ASD children in this challenging period.

Design and characterization of a triazole-based growth hormone secretagogue receptor modulator inhibiting the glucoregulatory and feeding actions of ghrelin.

The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that regulates essential physiological functions. In particular, activation of GHSR in response to its endogenous agonist ghrelin promotes food intake and blood glucose increase. Therefore, compounds aimed at blocking GHSR signaling constitute potential options against obesity-related metabolic disorders. We have previously developed potent ligands of GHSR based on a triazole scaffold. Here, we report a new 3,4,5-trisubstituted 1,2,4-triazole compound, named JMV 6616, that potently blocks GHSR activity in vitro and in vivo. Specifically, in HEK293T cells JMV 6616 behaves as an inverse agonist since it binds to GHSR and inhibits its ghrelin-independent signaling. Accordingly, using purified labeled GHSR assembled into lipid nanodiscs we found that JMV 6616 decreases GHSR-catalyzed G protein activation and stabilizes an inactive receptor conformation. Importantly, JMV 6616 also acts on native GHSR since it blocks the insulinostatic effect of ghrelin in pancreatic islets. In mice, JMV 6616 inhibits blood glucose-raising effects of ghrelin treatment and the orexigenic actions of acute ghrelin administration. Together, our data suggest that this triazole-derived modulator of GHSR holds promise to mitigate several pathological features associated with eating and metabolic disorders.

Relationship between Behavioral and Objective Measures of Sound Intensity in Normal-Hearing Listeners and Hearing-Aid Users: A Pilot Study.

Background: For hearing-impaired individuals, hearing aids are clinically fit according to subjective measures of threshold and loudness. The goal of this study was to evaluate objective measures of loudness perception that might benefit hearing aid fitting. Method: Seventeen adult hearing aid users and 17 normal-hearing adults participated in the study. Outcome measures including categorical loudness scaling, cortical auditory evoked potentials (CAEPs), and pupillometry. Stimuli were 1-kHz tone bursts presented at 40, 60, and 80 dBA. Results: Categorical loudness scaling showed that loudness significantly increased with intensity for all participants (p < 0.05). For CAEPs, high intensity was associated with greater P1, N1, and P2 peak amplitude for all listeners (p < 0.05); a significant but small effect of hearing aid amplification was observed. For all participants, pupillometry showed significant effects of high intensity on pupil dilation (p < 0.05); there was no significant effect of hearing aid amplification. A Focused Principal Component analysis revealed significant correlations between subjective loudness and some of the objective measures. Conclusion: The present data suggest that intensity had a significant impact on loudness perception, CAEPs, and pupil response. The correlations suggest that pupillometry and/or CAEPs may be useful in determining comfortable amplification for hearing aids.

Reduced production of isoprostanes by peri-pancreatic adipose tissue from Zucker fa/fa rats as a new mechanism for ß-cell compensation in insulin resistance and obesity.

During early stages of type 2 diabetes, named prediabetes, pancreatic ß-cells compensate for insulin resistance through increased insulin secretion in order to maintain normoglycemia. Obesity leads to the development of ectopic fat deposits, among which peri-pancreatic white adipose tissue (pWAT) can communicate with ß-cells through soluble mediators. Thus we investigated whether pWAT produced oxygenated lipids, namely isoprostanes and neuroprostanes and whether they can influence ß-cell function in obesity. In the Zucker fa/fa rat model, pWAT and epididymal white adipose tissue (eWAT) displayed different inflammatory profiles. In obese rats, pWAT, but not eWAT, released less amounts of 5-F2t-isoprostanes, 15-F2t-isoprostanes, 4-F4t-neuroprostanes and 10-F4t-neuroprostane compared to lean animals. These differences could be explained by a greater induction of antioxidant defenses enzymes such as SOD-1, SOD-2, and catalase in pWAT of obese animals compared to eWAT. In addition, sPLA2 IIA, involved in the release of isoprostanoids from cellular membranes, was decreased in pWAT of obese animals, but not in eWAT, and may also account for the reduced release of oxidized lipids by this tissue. At a functional level, 15-F2t-isoprostane epimers, but not 5-F2t-isoprostanes, were able to decrease glucose-induced insulin secretion in pancreatic islets from Wistar rats. This effect appeared to be mediated through activation of the thromboxane A2 receptor and reduction of cAMP signaling in pancreatic islets. In conclusion, through the removal of an inhibitory tone exerted by isoprostanes, we have shown, for the first time, a new mechanism allowing ß-cells to compensate for insulin resistance in obesity that is linked to a biocommunication between adipose tissue and ß-cells.

Neural repetition suppression to vocal and non-vocal sounds.

Adaptation to the sensory environment is essential in everyday life, to anticipate future events and quickly detect and respond to changes; and to distinguish vocal variations in congeners, for communication. The aim of the current study was to explore the effects of the nature (vocal/non-vocal) of the information to be encoded, on the establishment of auditory regularities. In electrophysiology, neural adaptation is measured by the 'Repetition Positivity' (RP), which refers to an increase in positive potential, with the increasing number of repetitions of a same stimulus. The RP results from the combined variation of several ERP components; the P1, the first positivity (∼100 ms) may reflect the onset of repetition effects. We recorded auditory evoked potentials during a roving paradigm in which trains of 4, 8 or 16 repetitions of the same stimulus were presented. Sequences of vocal and non-vocal complex stimuli were delivered, to study the influence of the type of stimulation on the characteristics of the brain responses. The P1 to each train length, and the RP responses were recorded between 90 and 200 ms, reflecting adaptation for both vocal and non-vocal stimuli. RP was not different between vocal and non-vocal sequences (in latency, amplitude and spatial organization) and was found to be similar to that found in previous studies using pure tones, suggesting that the repetition suppression phenomena is somehow independent of the nature of the stimulus. However, results showed faster stabilization of the P1 amplitude for non-vocal stimuli than for vocal stimuli, which require more repetitions. This revealed different dynamics for the establishment of regularity encoding for non-vocal and vocal stimuli, indicating that the richness of vocal sounds may require further processing before full neural adaptation occurs.

Liver-Expressed Antimicrobial Peptide 2 antagonizes the insulinostatic effect of ghrelin in rat isolated pancreatic islets.

The hormone ghrelin is the endogenous agonist of the G protein-coupled receptor (GPCR) termed growth hormone secretagogue receptor (GHSR). Ghrelin inhibits glucose-stimulated insulin secretion by activating pancreatic GHSR. Recently, Liver-Expressed Antimicrobial Peptide 2 (LEAP2) was recognized as an endogenous GHSR ligand that blocks ghrelin-induced actions. Nonetheless, the effect of LEAP2 on glucose-stimulated insulin secretion from pancreatic islets is unknown. We aimed at exploring the activity of LEAP2 on glucose-stimulated insulin secretion. Islets of Langerhans isolated from rat pancreas were exposed to glucose in the presence or in the absence of LEAP2 and ghrelin and then insulin secretion was assayed. LEAP2 did not modulate glucose-stimulated insulin secretion. However, LEAP2 blocked the insulinostatic action of ghrelin. Our data show that LEAP2 behaves as an antagonist of pancreatic GHSR.

When Alterations in Social Cognition Meet Subjective Complaints in Autism Spectrum Disorder: Evaluation With the "ClaCoS" Battery.

Background: Deficit in social communication is a core feature in Autism Spectrum Disorder but remains poorly assessed in classical clinical practice, especially in adult populations. This gap between needs and practice is partly due to a lack of standardized evaluation tools. The multicentric Research group in psychiatry GDR3557 (Institut de Psychiatrie) developed a new battery for social cognitive evaluation named "ClaCoS," which allows testing the main components of social cognition: Emotion Recognition, Theory of Mind, Attributional Style, and Social Perception and Knowledge. It further provides an assessment of subjective complaints in social cognition. Methods: We compared the social cognition abilities of 45 adults with Autism Spectrum Disorder without intellectual disability and 45 neurotypically developed volunteers using the "ClaCoS" battery, in order to determine its relevance in the evaluation of social cognition impairments in autism. A correlational approach allowed us to test the links between subjective complaints and objectively measured impairments for the different components of social cognition. Results: As expected, the Autism Spectrum Disorder group showed deficits in all four components of social cognition. Moreover, they reported greater subjective complaints than controls regarding their social abilities, correlated to the neuropsychological assessments. Conclusion: The "ClaCoS" battery is an interesting tool allowing to assess social impairments in autism and to specify the altered components, for a better adjustment of tailored social cognition training programs. Our results further suggest that people with Autism Spectrum Disorder have a good social cognitive insight, i.e., awareness into social cognitive functioning, and may thus benefit from social cognitive training tools.

Emotional visual mismatch negativity: a joint investigation of social and non-social dimensions in adults with autism.

Unusual behaviors and brain activity to socio-emotional stimuli have been reported in Autism Spectrum Disorder (ASD). Atypical reactivity to change and intolerance of uncertainty are also present, but little is known on their possible impact on facial expression processing in autism. The visual mismatch negativity (vMMN) is an electrophysiological response automatically elicited by changing events such as deviant emotional faces presented among regular neutral faces. While vMMN has been found altered in ASD in response to low-level changes in simple stimuli, no study has investigated this response to visual social stimuli. Here two deviant expressions were presented, neutral and angry, embedded in a sequence of repetitive neutral stimuli. vMMN peak analyses were performed for latency and amplitude in early and late time windows. The ASD group presented smaller amplitude of the late vMMN to both neutral and emotional deviants compared to the typically developed adults (TD) group, and only the TD group presented a sustained activity related to emotional change (i.e., angry deviant). Source reconstruction of the vMMNs further revealed that any change processing elicited a reduced activity in ASD group compared to TD in the saliency network, while the specific processing emotional change elicited activity in the temporal region and in the insula. This study confirms atypical change processing in ASD and points to a specific difficulty in the processing of emotional changes, potentially playing a crucial role in social interaction deficits. Nevertheless, these results require to be further replicated with a greater sample size and generalized to other emotional expressions.

Early Intervention in Severe Autism: Positive Outcome Using Exchange and Development Therapy.

Early intervention programs positively affect key behaviors for children with autism spectrum disorder (ASD). However, most of these programs do not target children with severe autistic symptomatology associated with intellectual disability (ID). This study aimed to investigate the psychological and clinical outcomes of children with severe autism and ID enrolled in the Tailored and Inclusive Program for Autism-Tours (TIPA-T). The first step of the TIPA-T is the Exchange and Development Therapy (EDT): an individual neurofunctional intervention consisting of one-to-one exchanges between a child and a therapist taking place in a pared-down environment. It aims to rehabilitate psychophysiological abilities at the roots of social communication through structured sequences of "social play." Cognitive and socio-emotional skills and general development were evaluated with the Social Cognitive Evaluation Battery scale and the Brunet-Lézine Scale-Revised, respectively, before and after 9 months of intervention in 32 children with ASD and ID. Autistic symptomatology was evaluated with the Behavior Summarized Evaluation-Revised scale at five time-points in a subset of 14 children, both in individual and group settings. Statistically significant post-intervention improvements were found in cognitive and socio-emotional skills. All but one child showed improvements in at least one social domain, and 78% of children gained one level in at least four social domains. Twenty-nine children improved in cognitive domains, with 66% of children improving in at least three cognitive domains. Autistic symptomatology evaluated in one-to-one settings significantly decreased with therapy; this reduction was observed in more than 85% of children. In group settings, autistic symptomatology also decreased in more than 60% of children. Global developmental age significantly increased by 3.8 months. The TIPA-T, including EDT in particular, improves socio-emotional skills of most children with ASD and reduces autistic symptomatology, yet with heterogeneous outcomes profiles, in line with the strong heterogeneity of profiles observed in ASD. At the group level, this study highlights the benefits of the TIPA-T for children with severe autism and associated ID. Assessment of autistic core symptoms showed an improvement of social interaction, both in one-to-one and group evaluations, demonstrating the generalizability of the skills learned during the EDT.

Development of Nonpeptidic Inverse Agonists of the Ghrelin Receptor (GHSR) Based on the 1,2,4-Triazole Scaffold.

GHSR controls, among others, growth hormone and insulin secretion, adiposity, feeding, and glucose metabolism. Therefore, an inverse agonist ligand capable of selectively targeting GHSR and reducing its high constitutive activity appears to be a good candidate for the treatment of obesity-related metabolic diseases. In this context, we present a study that led to the development of several highly potent and selective inverse agonists of GHSR based on the 1,2,4-triazole scaffold. We demonstrate that, depending on the nature of the substituents on positions 3, 4, and 5, this scaffold leads to ligands that exert an intrinsic inverse agonist activity on GHSR-catalyzed G protein activation through the stabilization of a specific inactive receptor conformation. Thanks to an in vivo evaluation, we also show that one of the most promising ligands not only exerts an effect on insulin secretion in rat pancreatic islets but also affects the orexigenic effects of ghrelin in mice.

Development of cortical auditory responses to speech in noise in unilaterally deaf adults following cochlear implantation.

BACKGROUND: For patients with single-sided deafness (SSD), restoration of binaural function via cochlear implant (CI) has been shown to improve speech understanding in noise. The objective of this study was to investigate changes in behavioral performance and cortical auditory responses following cochlear implantation. DESIGN: Prospective longitudinal study. SETTING: Tertiary referral center. METHODS: Six adults with SSD were tested before and 12 months post-activation of the CI. Six normal hearing (NH) participants served as experimental controls. Speech understanding in noise was evaluated for various spatial conditions. Cortical auditory evoked potentials were recorded with /ba/ stimuli in quiet and in noise. Global field power and responses at Cz were analyzed. RESULTS: Speech understanding in noise significantly improved with the CI when speech was presented to the CI ear and noise to the normal ear (p<0.05), but remained poorer than that of NH controls (p<0.05). N1 peak amplitude measure in noise significantly increased after CI activation (p<0.05), but remained lower than that of NH controls (p<0.05) at 12 months. After 12 months of CI experience, cortical responses in noise became more comparable between groups. CONCLUSION: Binaural restoration in SSD patients via cochlear implantation improved speech performance noise and cortical responses. While behavioral performance and cortical auditory responses improved, SSD-CI outcomes remained poorer than that of NH controls in most cases, suggesting only partial restoration of binaural hearing.

Brain responses to change in phonological structures of varying complexity in children and adults.

Language-related change-detection processes are often investigated using syllables that are very simple in terms of phonological structure. However, phonological complexity is known to be challenging for young typically developing children and pathological populations. We investigated brain correlates of phonological processing and their age-related changes with a passive change-detection protocol including stimuli of varying phonological complexity, which allowed comparing responses to simple and complex phonological deviancies. Mismatch Negativity (MMN) and Late Discriminative Negativity (LDN) responses were recorded in both school-age children (n = 22) and adults (n = 24). MMN was similar for simple and complex phonological deviancy in both groups, whereas LDN appeared to be modulated by phonological complexity, albeit with different patterns according to age. In response to complex phonological change, children displayed a larger LDN response with a typical fronto-central scalp distribution, while adults showed an additional right-posterior activity but no larger amplitude than for simple change. Thus, LDN appears to be a good electrophysiological index of phonological complexity processing. This study validated the use of the LDN through this protocol for the investigation of phonological complexity processing throughout the development.

Staffing needs for unscheduled activity in obstetrics and gynecology.

INTRODUCTION: To determine a minimum threshold of medical staffing needs (obstetricians-gynecologists, anesthesiologists-resuscitation specialists, nurse-anesthetists, pediatricians, and midwives) to ensure the safety and quality of care for unscheduled obstetrics-gynecology activity. MATERIALS AND METHODS: Face to face meetings of French healthcare professionals involved in perinatal care in different types of practices (academic hospital, community hospital or private practice) who belong to French perinatal societies: French National College of Gynecologists-Obstetricians (CNGOF), the French Society of Anesthesia and Resuscitation Specialists (SFAR), the French Society of Neonatology (SFN), the French Society of Perinatal Medicine (SFMP), the National College of French Midwives (CNSF), and the French Federation of Perinatal Care Networks (FFRSP). RESULTS: Different minimum thresholds for each category of care provider were proposed according to the number of births/year in the facility. These minimum thresholds can be modulated upwards as a function of the level of care (Level 1, 2 or 3 for perinatal centers), existence of an emergency department, and responsibilities as a referral center for maternal-fetal and/or surgical care. For example, an obstetrics-gynecology department handling 3000-4500 births per year without serving as a referral center must have an obstetrician-gynecologist, an anesthesiologist-resuscitation specialist, a nurse-anesthetist, and a pediatrician onsite specifically to provide care for unscheduled obstetrics-gynecology needs and a second obstetrician-gynecologist available within a time compatible with security requirements 24/7; the number of midwives always present (24/7) onsite and dedicated to unscheduled care is 5.1 for 3000 births and 7.2 for 4500 births. A maternity unit's occupancy rate must not exceed 85 %. CONCLUSION: The minimum thresholds proposed here are intended to improve the safety and quality of care of women who require unscheduled care in obstetrics-gynecology or during the perinatal period.

A Transnosographic Self-Assessment of Social Cognitive Impairments (ACSO): First Data.

Social cognition refers to the mental operations underlying social interactions. Given the major role of social cognitive deficits in the disability associated with severe psychiatric disorders, they therefore constitute a crucial therapeutic target. However, no easily understandable and transnosographic self-assessment scale evaluating the perceived difficulties is available. This study aimed to analyze the psychometric qualities of a new self-administered questionnaire (ACSo) assessing subjective complaints in different domains of social cognition from 89 patients with schizophrenia, schizoaffective disorders, bipolar disorders or autism. The results revealed satisfactory internal validity and test-retest properties allowing the computation of a total score along with four sub scores (attributional biases, social perception and knowledge, emotional perception and theory of mind). Moreover, the ACSo total score was correlated with other subjective assessments traditionally used in cognitive remediation practice but not with objective neuropsychological assessments of social cognition. In summary, the ACSo is of interest to complete the objective evaluation of social cognition processes with a subjective assessment adapted to people with serious mental illness or autism spectrum disorder.

Incomplete Gestation has an Impact on Cognitive Abilities in Autism Spectrum Disorder.

Extreme prematurity is known as a risk factor for autism spectrum disorder (ASD). However, the association between prematurity and ASD, for children born moderately and late preterm (MLPT) and those born early term (ET), is less established. This retrospective study aimed to characterize the phenotypic characteristics (i.e. behavioral profile and cognitive abilities) of 254 children with ASD, between 3 and 15 years of age, born MLPT (19 children), ET (60 children) and full term (175 children). MLPT and ET births do not modify ASD symptomatology, but modify cognitive development. The results highlight that incomplete gestation, i.e., MLPT or ET, has a negative impact on both verbal and nonverbal cognitive abilities, in children with neurodevelopmental vulnerability.

Cranio-Facial Characteristics in Children with Autism Spectrum Disorders (ASD).

Background: Cranio-facial anomalies frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm. The identification of differences in the facial phenotype of children with Autism Spectrum Disorders (ASD) may reflect alterations in embryologic brain development in children with ASD. Methods: we evaluated 33 caucasian children with ASD using a 2D computerized photogrammetry. Anthropometric euclidean measurements and landmarks located on the soft tissue of the face and head, were based on five cranio-facial indexes. Relationships between anthropometric z-scores and participant characteristics (i.e., age, Global IQ, severity of autistic symptoms measured using the CARS checklist) were assessed. Results: Cephalic index z-score differed significantly from 0 in our ASD group (p = 0.019). Moreover, a significant negative correlation was found between Facial Index z-score and CARS score (p = 0.003); conversely, a positive correlation was found between Interchantal Index z-score and CARS score (p = 0.028). Conclusion: our measurements shows a dolichocephalic head shape which is not correlated with autism severity. Importantly, two craniofacial markers were significantly correlated with autism severity: increased orbital hyperthelorism and decrease of height of the facial midline. These data support previous findings of craniofacial anomalies in autism spectrum disorder suggesting an "ASD facial phenotype" that could be used to improve ASD diagnoses.

Author Correction: 22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype.

Since the online publication of the above article, the authors have noted errors with the author list. The author names were listed as '(last name)(first name)' instead of '(first name)(last name)'.

N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor.

The ghrelin receptor or growth hormone secretagogue receptor (GHSR) is a G-protein-coupled receptor that controls growth hormone and insulin secretion, food intake, and reward-seeking behaviors. Liver-expressed antimicrobial peptide 2 (LEAP2) was recently described as an endogenous antagonist of GHSR. Here, we present a study aimed at delineating the structural determinants required for LEAP2 activity toward GHSR. We demonstrate that the entire sequence of LEAP2 is not necessary for its actions. Indeed, the N-terminal part alone confers receptor binding and activity to LEAP2. We found that both LEAP2 and its N-terminal part behave as inverse agonists of GHSR and as competitive antagonists of ghrelin-induced inositol phosphate production and calcium mobilization. Accordingly, the N-terminal region of LEAP2 is able to inhibit ghrelin-induced food intake in mice. These data demonstrate an unexpected pharmacological activity for LEAP2 that is likely to have an important role in the control of ghrelin response under normal and pathological conditions.

Autism is a prenatal disorder: Evidence from late gestation brain overgrowth.

This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum disorder (ASD) using prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms.