1. Ambrose K, Simpson K, Adams D. The Impact of Anxiety on the Participation of Children on the Autism Spectrum. Journal of autism and developmental disorders. 2021.

Anxiety is common in children on the autism spectrum, however its impacts are not fully understood. Participation is an important outcome, linked to the health and wellbeing of children. This study examined the relationship between anxiety and participation using parent reports for 131 children on the autism spectrum, aged 6-13 years. Hierarchical multiple regressions explored child and family factors in relation to participation in Home and Community settings. Anxiety was a unique, significant predictor of the frequency of children’s participation (but not involvement in activities) in both settings, when controlling for autism characteristics, communication skills and family income. Anxiety symptomatology may contribute to the less frequent participation of children on the autism spectrum in home and community activities.

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2. Andica C, Kamagata K, Kirino E, Uchida W, Irie R, Murata S, Aoki S. Neurite orientation dispersion and density imaging reveals white matter microstructural alterations in adults with autism. Molecular autism. 2021; 12(1): 48.

BACKGROUND: Evidences suggesting the association between behavioral anomalies in autism and white matter (WM) microstructural alterations are increasing. Diffusion tensor imaging (DTI) is widely used to infer tissue microstructure. However, due to its lack of specificity, the underlying pathology of reported differences in DTI measures in autism remains poorly understood. Herein, we applied neurite orientation dispersion and density imaging (NODDI) to quantify and define more specific causes of WM microstructural changes associated with autism in adults. METHODS: NODDI (neurite density index [NDI], orientation dispersion index, and isotropic volume fraction [ISOVF]) and DTI (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity [RD]) measures were compared between autism (N = 26; 19 males and 7 females; 32.93 ± 9.24 years old) and age- and sex-matched typically developing (TD; N = 25; 17 males and 8 females; 34.43 ± 9.02 years old) groups using tract-based spatial statistics and region-of-interest analyses. Linear discriminant analysis using leave-one-out cross-validation (LDA-LOOCV) was also performed to assess the discriminative power of diffusion measures in autism and TD. RESULTS: Significantly lower NDI and higher ISOVF, suggestive of decreased neurite density and increased extracellular free-water, respectively, were demonstrated in the autism group compared with the TD group, mainly in commissural and long-range association tracts, but with distinct predominant sides. Consistent with previous reports, the autism group showed lower FA and higher MD and RD when compared with TD group. Notably, LDA-LOOCV suggests that NDI and ISOVF have relatively higher accuracy (82%) and specificity (NDI, 84%; ISOVF, 88%) compared with that of FA, MD, and RD (accuracy, 67-73%; specificity, 68-80%). LIMITATIONS: The absence of histopathological confirmation limit the interpretation of our findings. CONCLUSIONS: Our results suggest that NODDI measures might be useful as imaging biomarkers to diagnose autism in adults and assess its behavioral characteristics. Furthermore, NODDI allows interpretation of previous findings on changes in WM diffusion tensor metrics in individuals with autism.

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3. Beebani G, Fabian N, Bhatia N, Sivananthan M. Case Report: Clozapine-Induced Myocarditis in a Patient with Autism Spectrum Disorder and Schizophrenia. Journal of autism and developmental disorders. 2021.

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4. Besterman AD, Althoff T, Elfferich P, Gutierrez-Mejia I, Sadik J, Bernstein JA, van Ierland Y, Kattentidt-Mouravieva AA, Nellist M, Abramson J, Martinez-Agosto JA. Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity. PLoS genetics. 2021; 17(7): e1009651.

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS.

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5. Breaux R, Eadeh HM, Swanson CS, McQuade JD. Adolescent Emotionality and Emotion Regulation in the Context of Parent Emotion Socialization Among Adolescents with Neurodevelopmental Disorders: A Call to Action with Pilot Data. Research on child and adolescent psychopathology. 2022; 50(1): 77-88.

To date, only three studies have examined the role of emotion socialization in the emotional functioning of youth with neurodevelopmental disorders. As such, this review article with pilot data sought to provide a call to action and first step in addressing this limited research body. Pilot data was collected with 18 adolescents (Mage = 13.5, SD = 1.6; 70% male) with a neurodevelopmental disorder and their primary caregiver. All adolescents were diagnosed with attention-deficit/hyperactivity disorder and displayed a range of comorbid disorders: autism spectrum disorder (27.8%), anxiety (66.7%), depression (44.4%), and disruptive behavior disorders (50%). Adolescents and caregivers completed a conflict discussion task while physiological, observational, and self-report measures of emotion socialization and emotional functioning were measured. Observed supportive parent emotion socialization behaviors were significantly associated with more observed adaptive emotion regulation strategies, and decreased observed and adolescent-reported negative affect, whereas non-supportive emotion socialization behaviors were associated with more observed negative affect and less observed adaptive emotion regulation strategies. Our pilot findings support growing research suggesting that adaptive parent emotion socialization practices can help foster less negative emotionality and better emotion regulation in youth with neurodevelopment disorders. We make a call to action for more emotion socialization research focused on youth with neurodevelopmental disorders, and propose four important directions for future research: 1) Research examining emotion socialization behaviors during daily life, 2) Understanding the nuanced role of emotion socialization practices, 3) Considering diversity in emotion socialization practices with clinical populations, and 4) Longitudinal and intervention research studies.

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6. Deckmann I, Santos-Terra J, Fontes-Dutra M, Körbes-Rockenbach M, Bauer-Negrini G, Schwingel GB, Riesgo R, Bambini-Junior V, Gottfried C. Resveratrol prevents brain edema, blood-brain barrier permeability, and altered aquaporin profile in autism animal model. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2021; 81(7): 579-604.

Autism spectrum disorder can present a plethora of clinical conditions associated with the disorder, such as greater brain volume in the first years of life in a significant percentage of patients. We aimed to evaluate the brain water content, the blood-brain barrier permeability, and the expression of aquaporin 1 and 4, and GFAP in a valproic acid-animal model, assessing the effect of resveratrol. On postnatal day 30, Wistar rats of the valproic acid group showed greater permeability of the blood-brain barrier to the Evans blue dye and a higher proportion of brain water volume, prevented both by resveratrol. Prenatal exposition to valproic acid diminished aquaporin 1 in the choroid plexus, in the primary somatosensory area, in the amygdala region, and in the medial prefrontal cortex, reduced aquaporin 4 in medial prefrontal cortex and increased aquaporin 4 levels in primary somatosensory area (with resveratrol prevention). Valproic acid exposition also increased the number of astrocytes and GFAP fluorescence in both primary somatosensory area and medial prefrontal cortex. In medial prefrontal cortex, resveratrol prevented the increased fluorescence. Finally, there was an effect of resveratrol per se on the number of astrocytes and GFAP fluorescence in the amygdala region and in the hippocampus. Thus, this work demonstrates significant changes in blood-brain barrier permeability, edema formation, distribution of aquaporin 1 and 4, in addition to astrocytes profile in the animal model of autism, as well as the use of resveratrol as a tool to investigate the mechanisms involved in the pathophysiology of autism spectrum disorder.

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7. Dickson KS, Lind T, Jobin A, Kinnear M, Lok H, Brookman-Frazee L. Correction to: A Systematic Review of Mental Health Interventions for ASD: Characterizing Interventions, Intervention Adaptations, and Implementation Outcomes. Administration and policy in mental health. 2021; 48(5): 884-908.

Due to the errors occurred in the originally published version, this article is being reprinted in its entirety as Correction. All errors have been corrected. It is the correct version.

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8. Duncan A, Liddle M, Stark LJ. Iterative Development of a Daily Living Skills Intervention for Adolescents with Autism Without an Intellectual Disability. Clinical child and family psychology review. 2021; 24(4): 744-64.

Daily living skill deficits commonly co-occur in individuals with autism spectrum disorder (ASD). These deficits in adolescence are associated with poor outcomes, in both employment and independent living skills as adults. Currently, there are no interventions that directly target daily living skill acquisition in adolescents with ASD without an intellectual disability to facilitate a successful transition to adulthood. In this paper, we discuss the development, refinement, and initial efficacy studies of Surviving and Thriving in the Real World (STRW), a 14-session group treatment for both adolescents with ASD and their parent/caregiver that promotes attainment of critical daily living skills. We summarize initial feasibility studies that have been instrumental in the iterative development of STRW. The structure, core treatment elements, and content of STRW are described in detail. Lastly, we discuss the transition of the in-person STRW intervention to STRW-telehealth, which allows for adolescents with ASD to work on daily living skills in their own home with support from a therapist.

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9. Esentürk OK, Yarımkaya E. WhatsApp-Based Physical Activity Intervention for Children With Autism Spectrum Disorder During the Novel Coronavirus (COVID-19) Pandemic: A Feasibility Trial. Adapted physical activity quarterly : APAQ. 2021; 38(4): 569-84.

The aim of this study was to evaluate the feasibility and potential efficacy of a WhatsApp-based physical activity for children with autism spectrum disorder (ASD). Fourteen parents and their children with ASD participated in the study. The intervention included parents conducting physical activities with their children with ASD for 4 weeks. Physical activity contents were provided to parents via the WhatsApp group. The data were collected through the Leisure Time Exercise Questionnaire and a feasibility questionnaire adapted from previous studies examining the feasibility of web-based physical activities. Parents reported that WhatsApp-based physical activities were a feasible intervention to increase the physical activity level of their children with ASD and stated that the contents of the physical activity shared in the WhatsApp group were useful. The findings provided preliminary evidence for the use of WhatsApp-based physical activities to increase the physical activity level of children with ASD who stay at home due to the pandemic.

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10. Hom CL, Walsh D, Fernandez G, Tournay A, Touchette P, Lott IT. Cognitive assessment using the Rapid Assessment for Developmental Disabilities, Second Edition (RADD-2). Journal of intellectual disability research : JIDR. 2021; 65(9): 831-48.

BACKGROUND: Individuals with developmental disabilities (DD) often have severe impairments and maladaptive behaviours that make it difficult to reliably assess their cognitive abilities. Given these challenges, the Rapid Assessment of Developmental Disabilities, Second Edition (RADD-2), was designed to measure general cognitive ability in this population. The purpose of this study is to demonstrate the battery’s psychometric properties when used with individuals with DD who have challenging behavioural and psychiatric conditions and for those who have limited verbal skills. METHOD: The cognitive and adaptive behaviour skills of 193 children and adults with DD and considerable medical, behavioural and/or psychiatric problems were evaluated using the first and second editions of the RADD, Kaufmann Brief Intelligence Test – 2nd Edition, and Scales of Independent Behaviour – Revised Edition. Medication side effects and challenging behaviours were assessed using the Aberrant Behaviour Checklist. RESULTS: There were no floor or ceiling effects on the RADD-2. Both the nonverbal index and total scores had strong concurrent validity with other abbreviated tests of intellectual ability and good discriminant validity from measures of adaptive behaviour and medication side effects. RADD-2 scores also had strong criterion validity as they successfully differentiated between all levels of intellectual functioning. Age and sex did not differentially affect RADD-2 performance, and the co-occurrence of psychiatric conditions did not negatively affect performance. The only medical condition associated with lower RADD-2 performance was epilepsy. CONCLUSIONS: The RADD-2 can quantify the differential cognitive abilities of individuals with DD, even for those with minimal communication skills, challenging behaviours or severe medication side effects that can typically complicate assessment. This brief cognitive battery can be used to measure changes due to interventions, on the one hand, and progression of neurological disease, on the other.

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11. Hurley MJ, Deacon RMJ, Chan AWE, Baker D, Selwood DL, Cogram P. Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice. Brain : a journal of neurology. 2022; 145(1): 76-82.

Fragile X syndrome is the most common inherited intellectual disability and mono-genetic cause of autism spectrum disorder. It is a neurodevelopmental condition occurring due to a CGG trinucleotide expansion in the FMR1 gene. Polymorphisms and variants in large-conductance calcium-activated potassium channels are increasingly linked to intellectual disability and loss of FMR protein causes reduced large-conductance calcium-activated potassium channel activity leading to abnormalities in synapse function. Using the cannabinoid-like large-conductance calcium-activated potassium channel activator VSN16R we rescued behavioural deficits such as repetitive behaviour, hippocampal dependent tests of daily living, hyperactivity and memory in a mouse model of fragile X syndrome. VSN16R has been shown to be safe in a phase 1 study in healthy volunteers and in a phase 2 study in patients with multiple sclerosis with high oral bioavailability and no serious adverse effects reported. VSN16R could therefore be directly utilized in a fragile X syndrome clinical study. Moreover, VSN16R showed no evidence of tolerance, which strongly suggests that chronic VSN16R may have great therapeutic value for fragile X syndrome and autism spectrum disorder. This study provides new insight into the pathophysiology of fragile X syndrome and identifies a new pathway for drug intervention for this debilitating disorder.

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12. Kawano J, Fujino H. Dohsa-hou intervention for reciprocal interpersonal interaction for a girl with Kabuki syndrome and autism spectrum disorder. Clinical case reports. 2021; 9(6): e04296.

Although available evidence for psychosocial treatment for patients with Kabuki syndrome is limited, Dohsa-hou, a psychomotor therapy, could be a treatment option for autism spectrum disorder associated with the disorder.

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13. Kerr-Gaffney J, Hayward H, Jones EJH, Halls D, Murphy D, Tchanturia K. Autism symptoms in anorexia nervosa: a comparative study with females with autism spectrum disorder. Molecular autism. 2021; 12(1): 47.

BACKGROUND: Recent research suggests a link between autism spectrum disorder (ASD) and anorexia nervosa (AN). Individuals with AN show high scores on measures of ASD symptoms, relative to individuals without AN, however, there are currently no studies directly comparing women with AN to women with ASD. The aim of the current study was to examine profiles of ASD symptoms in young women in the acute and recovered stages of AN, women with ASD, and typically developing controls (TD), on both self-report and clinical interview measures. METHODS: Four groups of participants aged 12-30 years were included (n = 218): AN, recovered AN (REC), ASD, and TD. Group differences on the Social Responsiveness Scale, 2nd edition (SRS-2), 10-item Autism Quotient (AQ-10), and the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) were examined. To explore similarities and differences in specific symptom profiles associated with AN and ASD, individual item endorsement on the ADOS-2 was also examined in AN, REC, and ASD. RESULTS: Across measures, women with ASD showed the highest scores, and TDs the lowest. Generally, individuals with AN and REC showed intermediate levels of ASD symptoms, scoring between the other two groups. However, AN and ASD did not differ on restricted interests and repetitive behaviour subscales. The ADOS-2 item ‘quality of social response’ adequately discriminated between ASD and non-ASD participants. LIMITATIONS: A full diagnostic assessment for ASD was not provided for participants with AN/REC, nor were eating disorders assessed in the ASD group. Therefore, some diagnostic overlap between groups is possible. The cross-sectional design is another limitation. CONCLUSIONS: The results suggest similarities in scores on both self-report and clinical interview measures in AN and ASD. However, individual ADOS-2 item analyses also revealed subtle differences, particularly in reciprocal social interaction. ASD symptoms may be a combination of both state and trait features in AN.

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14. Lin Y, Yerukala Sathipati S, Ho SY. Predicting the Risk Genes of Autism Spectrum Disorders. Frontiers in genetics. 2021; 12: 665469.

Autism spectrum disorder (ASD) refers to a wide spectrum of neurodevelopmental disorders that emerge during infancy and continue throughout a lifespan. Although substantial efforts have been made to develop therapeutic approaches, core symptoms persist lifelong in ASD patients. Identifying the brain temporospatial regions where the risk genes are expressed in ASD patients may help to improve the therapeutic strategies. Accordingly, this work aims to predict the risk genes of ASD and identify the temporospatial regions of the brain structures at different developmental time points for exploring the specificity of ASD gene expression in the brain that would help in possible ASD detection in the future. A dataset consisting of 13 developmental stages ranging from 8 weeks post-conception to 8 years from 26 brain structures was retrieved from the BrainSpan atlas. This work proposes a support vector machine-based risk gene prediction method ASD-Risk to distinguish the risk genes of ASD and non-ASD genes. ASD-Risk used an optimal feature selection algorithm called inheritable bi-objective combinatorial genetic algorithm to identify the brain temporospatial regions for prediction of the risk genes of ASD. ASD-Risk achieved a 10-fold cross-validation accuracy, sensitivity, specificity, area under a receiver operating characteristic curve, and a test accuracy of 81.83%, 0.84, 0.79, 0.84, and 72.27%, respectively. We prioritized the temporospatial features according to their contribution to the prediction accuracy. The top identified temporospatial regions of the brain for risk gene prediction included the posteroventral parietal cortex at 13 post-conception weeks feature. The identified temporospatial features would help to explore the risk genes that are specifically expressed in different brain regions of ASD patients.

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15. Mita M, Nozaka K, Miyakoshi N, Shimada Y. Open tibial shaft fracture in a boy with autism spectrum disorder treated using a ring external fixator: A case report. Trauma case reports. 2021; 34: 100502.

Autism spectrum disorder covers a group of behaviorally defined disorders that may result in the patient having difficulty staying calm during medical treatments, due to anxiety-related overreactions. Tibial fractures are the third most common pediatric long-bone fracture. Conservative treatment is selected in many cases, but surgical treatment may be selected in cases of open fracture and no treatment policy has been established. We described the case of a 6-year-old boy with autism spectrum disorder who was unable to stay calm due to anxiety and required sedation. We diagnosed open tibial shaft fracture (Orthopaedic Trauma Association classification 42A1, 4F2A; Gustilo classification type 1). On the day of injury, we performed osteosynthesis using a ring external fixator and primary closure of the open wound. Full weight-bearing was permitted from immediately after surgery. No significant complications were observed postoperatively, and the external fixator was removed 84 days postoperatively. No abnormal alignment of the lower leg, leg-length discrepancy or range of motion disorder was identified. To the best of our knowledge, no other reports have described use of a ring external fixator for open tibial shaft fractures in children with autism spectrum disorder. Using a ring external fixator appears helpful for open tibial shaft fractures in children who are unable to stay calm due to autism spectrum disorder, because there is no need to limit weight-bearing immediately after surgery. For Gustilo classification type 1 pediatric open fracture, primary closure of the open wound is safe after sufficient bone fixation.

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16. Ratnayake I, Shooshtari S, Chateau D, Kristjanson M. Complete physical examinations in Manitoba adults with an intellectual or developmental disability: A retrospective cohort study. Journal of applied research in intellectual disabilities : JARID. 2021; 34(6): 1582-91.

BACKGROUND: Complete physical examinations (CPE) can identify health disparities in persons with intellectual or developmental disabilities. The objective of this study was to determine and compare rates of CPE among Manitoba adults with and without intellectual or developmental disabilities over time and to identify factors that were associated with receiving a CPE. METHOD: A retrospective cohort study using linked administrative health and non-health data from 1995 to 2015 was conducted. Poisson and logistic regression were used to calculate CPE rates and examine factors associated with CPE. RESULTS: The rates of CPE are decreasing over time and are higher among Manitobans with an intellectual or developmental disability. Characteristics such as being male, living rurally, low socioeconomic status, and high continuity of care led to lower odds of receiving a CPE. CONCLUSIONS: The current state of CPE provision to adults with intellectual or developmental disabilities in Manitoba is encouraging but needs improvement.

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17. Tassanakijpanich N, McKenzie FJ, McLennan YA, Makhoul E, Tassone F, Jasoliya MJ, Romney C, Petrasic IC, Napalinga K, Buchanan CB, Hagerman P, Hagerman R, Casanova EL. Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series. Journal of medical genetics. 2021.

BACKGROUND: While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55-200 repeats) of the FMR1 gene may be overlooked. OBJECTIVE: To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype. METHODS: We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS. RESULTS: Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity. CONCLUSION: Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

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18. Zoltowski AR, Lyu I, Failla M, Mash LE, Dunham K, Feldman JI, Woynaroski TG, Wallace MT, Barquero LA, Nguyen TQ, Cutting LE, Kang H, Landman BA, Cascio CJ. Cortical Morphology in Autism: Findings from a Cortical Shape-Adaptive Approach to Local Gyrification Indexing. Cerebral cortex (New York, NY : 1991). 2021; 31(11): 5188-205.

It has been challenging to elucidate the differences in brain structure that underlie behavioral features of autism. Prior studies have begun to identify patterns of changes in autism across multiple structural indices, including cortical thickness, local gyrification, and sulcal depth. However, common approaches to local gyrification indexing used in prior studies have been limited by low spatial resolution relative to functional brain topography. In this study, we analyze the aforementioned structural indices, utilizing a new method of local gyrification indexing that quantifies this index adaptively in relation to specific sulci/gyri, improving interpretation with respect to functional organization. Our sample included n = 115 autistic and n = 254 neurotypical participants aged 5-54, and we investigated structural patterns by group, age, and autism-related behaviors. Differing structural patterns by group emerged in many regions, with age moderating group differences particularly in frontal and limbic regions. There were also several regions, particularly in sensory areas, in which one or more of the structural indices of interest either positively or negatively covaried with autism-related behaviors. Given the advantages of this approach, future studies may benefit from its application in hypothesis-driven examinations of specific brain regions and/or longitudinal studies to assess brain development in autism.

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