Faculty Bibliography
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101
Assessment of Neuroanatomical Endophenotypes of Autism Spectrum Disorder and Association With Characteristics of Individuals With Schizophrenia and the General Population
IMPORTANCE:Autism spectrum disorder (ASD) is associated with significant clinical, neuroanatomical, and genetic heterogeneity that limits precision diagnostics and treatment. OBJECTIVE:To assess distinct neuroanatomical dimensions of ASD using novel semisupervised machine learning methods and to test whether the dimensions can serve as endophenotypes also in non-ASD populations. DESIGN, SETTING, AND PARTICIPANTS:This cross-sectional study used imaging data from the publicly available Autism Brain Imaging Data Exchange (ABIDE) repositories as the discovery cohort. The ABIDE sample included individuals diagnosed with ASD aged between 16 and 64 years and age- and sex-match typically developing individuals. Validation cohorts included individuals with schizophrenia from the Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging (PHENOM) consortium and individuals from the UK Biobank to represent the general population. The multisite discovery cohort included 16 internationally distributed imaging sites. Analyses were performed between March 2021 and March 2022. MAIN OUTCOMES AND MEASURES:The trained semisupervised heterogeneity through discriminative analysis models were tested for reproducibility using extensive cross-validations. It was then applied to individuals from the PHENOM and the UK Biobank. It was hypothesized that neuroanatomical dimensions of ASD would display distinct clinical and genetic profiles and would be prominent also in non-ASD populations. RESULTS:Heterogeneity through discriminative analysis models trained on T1-weighted brain magnetic resonance images of 307 individuals with ASD (mean [SD] age, 25.4 [9.8] years; 273 [88.9%] male) and 362 typically developing control individuals (mean [SD] age, 25.8 [8.9] years; 309 [85.4%] male) revealed that a 3-dimensional scheme was optimal to capture the ASD neuroanatomy. The first dimension (A1: aginglike) was associated with smaller brain volume, lower cognitive function, and aging-related genetic variants (FOXO3; Z = 4.65; P = 1.62 × 10-6). The second dimension (A2: schizophrenialike) was characterized by enlarged subcortical volumes, antipsychotic medication use (Cohen d = 0.65; false discovery rate-adjusted P = .048), partially overlapping genetic, neuroanatomical characteristics to schizophrenia (n = 307), and significant genetic heritability estimates in the general population (n = 14 786; mean [SD] h2, 0.71 [0.04]; P < 1 × 10-4). The third dimension (A3: typical ASD) was distinguished by enlarged cortical volumes, high nonverbal cognitive performance, and biological pathways implicating brain development and abnormal apoptosis (mean [SD] β, 0.83 [0.02]; P = 4.22 × 10-6). CONCLUSIONS AND RELEVANCE:This cross-sectional study discovered 3-dimensional endophenotypic representation that may elucidate the heterogeneous neurobiological underpinnings of ASD to support precision diagnostics. The significant correspondence between A2 and schizophrenia indicates a possibility of identifying common biological mechanisms across the 2 mental health diagnoses.
PMID: 37017948
ISSN: 2168-6238
CID: 5542382
Author Correction: Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets
PMID: 34880244
ISSN: 2041-1723
CID: 5152722
Predicting multiscan MRI outcomes in children with neurodevelopmental conditions following MRI simulator training
Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.
PMCID:8517836
PMID: 34649041
ISSN: 1878-9307
CID: 5068032
The utility of parent-report screening tools in differentiating autism versus attention-deficit/hyperactivity disorder in school-age children
LAY ABSTRACT/UNASSIGNED:. They also underscore the need to assess multiple sources of information for increased accuracy.
PMID: 34219504
ISSN: 1461-7005
CID: 4930132
Towards robust and replicable sex differences in the intrinsic brain function of autism
BACKGROUND:Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data. METHODS:We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research. RESULTS:Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples-EU-AIMS LEAP. LIMITATIONS:Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability. CONCLUSIONS:Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.
PMCID:7923310
PMID: 33648569
ISSN: 2040-2392
CID: 4837712
Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups
OBJECTIVE:Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data. METHODS:-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures). RESULTS:No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood. CONCLUSIONS:The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.
PMID: 32539527
ISSN: 1535-7228
CID: 4484542
A systematic review of the role of parent characteristics in parent-mediated interventions for children with autism spectrum disorder
Parent-mediated interventions (PMI) are increasingly being used to target skill deficits in children with Autism Spectrum Disorder (ASD). Evidence documenting the benefits of PMI is accumulating, however, little is known about whether parent characteristics impact children's treatment outcomes. We reviewed the PMI literature using PRISMA guidelines to address this gap. We identified 115 PMI studies published between 1987 and September 2018; of these, only 11 examined the contributions of baseline parent/caregiver characteristics on children's outcomes. These studies vary widely in regard to the interventions employed and outcome measures explored. Early intervention programs were the most common form of treatment and stress was the most frequently targeted parent/caregiver characteristic. Results indicated that stress, socioeconomic status, and the broad autism phenotype may be related to children's outcomes, with varying effects depending on the specific treatment and outcome examined. These results underscore the need for systematic research on the role of parent baseline characteristics in PMI. A deeper understanding of the relationship between parent/caregiver variables and child outcomes may inform treatment selection and elucidate key mechanisms of therapeutic change. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
PSYCH:2019-01017-001
ISSN: 1573-3580
CID: 4901052
Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets
Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen's d = -0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.
PMCID:6823355
PMID: 31673008
ISSN: 2041-1723
CID: 4220682
Multidimensional Neuroanatomical Subtyping of Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with multiple biological etiologies and highly variable symptoms. Using a novel analytical framework that integrates cortex-wide MRI markers of vertical (i.e., thickness, tissue contrast) and horizontal (i.e., surface area, geodesic distance) cortical organization, we could show that a large multi-centric cohort of individuals with ASD falls into 3 distinctive anatomical subtypes (ASD-I: cortical thickening, increased surface area, tissue blurring; ASD-II: cortical thinning, decreased distance; ASD-III: increased distance). Bootstrap analysis indicated a high consistency of these biotypes across thousands of simulations, while analysis of behavioral phenotypes and resting-state fMRI showed differential symptom load (i.e., Autism Diagnostic Observation Schedule; ADOS) and instrinsic connectivity anomalies in communication and social-cognition networks. Notably, subtyping improved supervised learning approaches predicting ADOS score in single subjects, with significantly increased performance compared to a subtype-blind approach. The existence of different subtypes may reconcile previous results so far not converging on a consistent pattern of anatomical anomalies in autism, and possibly relate the presence of diverging corticogenic and maturational anomalies. The high accuracy for symptom severity prediction indicates benefits of MRI biotyping for personalized diagnostics and may guide the development of targeted therapeutic strategies.
PMID: 28968847
ISSN: 1460-2199
CID: 3277522
Is Increased Response Time Variability Related to Deficient Emotional Self-Regulation in Children With ADHD?
OBJECTIVE:Elevated response time intrasubject variability (RT-ISV) characterizes ADHD. Deficient emotional self-regulation (DESR), defined by summating Child Behavior Checklist Anxious/Depressed, Aggressive, and Attention subscale scores, has been associated with worse outcome in ADHD. To determine if DESR is differentially associated with elevated RT-ISV, we examined RT-ISV in children with ADHD with and without DESR and in typically developing children (TDC). METHOD/METHODS:We contrasted RT-ISV during a 6-min Eriksen Flanker Task in 31 children with ADHD without DESR, 34 with ADHD with DESR, and 65 TDC. RESULTS:Regardless of DESR, children with ADHD showed significantly greater RT-ISV than TDC ( p < .001). The ADHD subgroups, defined by presence or absence of DESR, did not differ from each other. CONCLUSION/CONCLUSIONS:Increased RT-ISV characterizes ADHD regardless of comorbid DESR. Alongside similar findings in children and adults with ADHD, these results suggest that RT-ISV is related to cognitive rather than emotional dysregulation in ADHD.
PMID: 30047295
ISSN: 1557-1246
CID: 3216502
