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1.
Mol Autism ; 12(1): 19, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648569

RESUMO

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.

2.
J Autism Dev Disord ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33559019

RESUMO

Pivotal Response Treatment (PRT) is promising for children with Autism Spectrum Disorder (ASD), but more methodologically robust designed studies are needed. In this randomized controlled trial, forty-four children with ASD, aged 9-15 years, were randomly allocated to PRT (n = 22) or treatment-as-usual (TAU; n = 22). Measurements were obtained after 12- and 20-weeks treatment, and 2-month follow-up. PRT resulted in significant greater improvements on parent-rated social-communicative skills after 12 weeks treatment (p = .004, partial η2 = 0.22), compared to TAU. Furthermore, larger gains in PRT compared to TAU were observed on blindly rated global functioning, and parent-rated adaptive socialization skills and attention problems. Implications for clinical practice and suggestions for future research are discussed.

3.
Hum Brain Mapp ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570244

RESUMO

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

4.
Psychiatry Res ; 298: 113795, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33582524

RESUMO

Reversal learning deficits following reward and punishment processing are observed across disruptive behaviors (DB) and attention-deficit/hyperactivity disorder (ADHD), and have been associated with callous-unemotional (CU) traits. However, it remains unknown to what extent these altered reinforcement sensitivities are linked to the co-occurrence of oppositional traits, ADHD symptoms, and CU traits. Reward and punishment sensitivity and perseverative behavior were therefore derived from a probabilistic reversal learning task to investigate reinforcement sensitivity in participants with DB (n=183, ODD=62, CD=10, combined=57, age-range 8-18), ADHD (n=144, age-range 11-28), and controls (n=191, age-range 8-26). The SNAP-IV and Conners rating scales were used to assess oppositional and ADHD traits. The Inventory of CU traits was used to assess CU traits. Decreased reward sensitivity was associated with ADHD symptom severity (p=0.018) if corrected for oppositional symptoms. ADHD symptomatology interacted with oppositional behavior on perseveration (p=0.019), with the former aggravating the effect of oppositional behavior on perseveration and vice versa. Within a pooled sample, reversal learning alterations were associated with the severity of ADHD symptoms, underpinned by hyposensitivity to reward and increased perseveration. These results show ADHD traits, as opposed to oppositional behavior and CU traits, is associated with decreased reward-based learning in adolescents and adults.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33549739

RESUMO

BACKGROUND: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. METHODS: We reviewed studies with more than 2,000 participants or meta-analyses from five or more studies or 2,000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. RESULTS: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 79 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 362 people who have read this document and agree with its contents. CONCLUSIONS: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

6.
Hum Brain Mapp ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33595143

RESUMO

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

7.
Mol Psychiatry ; 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33456050

RESUMO

Genomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494). Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.

8.
J Clin Psychopharmacol ; 41(1): 13-18, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33347017

RESUMO

BACKGROUND: Antipsychotics are frequently prescribed to children and adolescents for nonpsychotic indications. Guidelines recommend regularly assessing treatment response and adverse effects and the ongoing need for their use. We aimed to assess adherence to recommendations of available guidelines regarding monitoring antipsychotic use and to test the influence of children's age, sex, intelligence quotient, and diagnosis on adherence. METHODS: We reviewed 426 medical records from 26 centers within 3 large Dutch child and adolescent psychiatry organizations, excluding children with schizophrenia, psychosis, mania, or an intelligence quotient below 70. We investigated whether there was regular assessment of treatment response, adverse events (physical and laboratory), and at least annual discussion of the need of continued use. RESULTS: On average, treatment response was assessed in 69.3% of the recommended treatment periods, height in 25.6%, weight in 30.6%, blood pressure in 20.6%, evaluation of adverse events in 19.4%, and cardiometabolic measures in 13.7%; discontinuation and/or continued need was discussed at least annually in 36.2%. Extrapyramidal and prolactin-related adverse effects, waist circumference, glucose, and lipids were rarely investigated. Higher age was associated with lower rates of assessment of treatment response. Most antipsychotics were prescribed long-term. In those children with sufficient documentation of the course of treatment, 57.7% was still using an antipsychotic 3 years after initiation. CONCLUSIONS: Our findings indicate insufficient adherence to guideline recommendations for monitoring antipsychotic use in children and adolescents, as well as long duration of use in the majority of children. Especially, older children are at higher risk of receiving suboptimal care.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33184474

RESUMO

Attention-Deficit/Hyperactivity Disorder (ADHD) and Substance Use Disorder (SUD) often co-occur and are associated with treatment resistance. Both disorders are characterized by similar reward-processing deficits with decreased striatal responses to reward anticipation, though literature is inconsistent. It is unclear whether substance misuse exaggerates reward-processing deficits observed in ADHD. The aim of this study was to examine substance misuse effects on reward-processing in ADHD. Functional MRI data in a Monetary Incentive Delay (MID) task from a multi-site study were compared across ADHD groups with and without substance misuse (ADHD + SM and ADHD-only, respectively) and healthy controls (n = 40/group, 74 males and 46 females, aged 13.7-25.9 years). Substance misuse was defined as misuse of alcohol, nicotine, or drugs. Groups were matched with presence/absence of parental SUD to avoid interference with SUD trait effects. Compared to ADHD-only and controls, ADHD + SM showed hyperactivation in putamen during reward anticipation. Compared to controls, the ADHD groups showed hypoactivation in motor/sensory cortices and hyperactivation in frontal pole and OFC during reward outcome. ADHD + SM also showed hyperactivation in frontal pole during neutral outcome. Moreover, ADHD + SM patients showed higher callous-unemotional (CU) traits that were positively correlated with putamen responses to reward anticipation. Our results show distinct condition-independent neural activation profile for ADHD + SM compared to ADHD-only and controls. Effects of comorbid substance misuse and variability of its prevalence across ADHD studies might have contributed to inconsistencies in ADHD literature. Contrasted with findings for reward-processing in SUD literature, results potentially suggest distinct underlying mechanisms for SUD subgroups with different characteristics, like antisocial/psychopathic traits.

10.
Transl Psychiatry ; 10(1): 384, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159037

RESUMO

Autism is a complex neurodevelopmental condition with substantial phenotypic, biological, and etiologic heterogeneity. It remains a challenge to identify biomarkers to stratify autism into replicable cognitive or biological subtypes. Here, we aim to introduce a novel methodological framework for parsing neuroanatomical subtypes within a large cohort of individuals with autism. We used cortical thickness (CT) in a large and well-characterized sample of 316 participants with autism (88 female, age mean: 17.2 ± 5.7) and 206 with neurotypical development (79 female, age mean: 17.5 ± 6.1) aged 6-31 years across six sites from the EU-AIMS multi-center Longitudinal European Autism Project. Five biologically based putative subtypes were derived using normative modeling of CT and spectral clustering. Three of these clusters showed relatively widespread decreased CT and two showed relatively increased CT. These subtypes showed morphometric differences from one another, providing a potential explanation for inconsistent case-control findings in autism, and loaded differentially and more strongly onto symptoms and polygenic risk, indicating a dilution of clinical effects across heterogeneous cohorts. Our results provide an important step towards parsing the heterogeneous neurobiology of autism.

11.
Neuropharmacology ; 184: 108370, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33137342

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention and/or hyperactivity and impulsivity. ADHD is highly prevalent in childhood and often persists into adulthood. Both genetic variants and environmental factors play a role in the onset and persistence of ADHD, and epigenetic changes, such as DNA methylation are considered as a link for their interplay. To investigate this, we studied DNA methylation in 37 candidate genes by performing targeted bisulfite sequencing of DNA isolated from whole blood of N = 88 individuals diagnosed with adult ADHD and N = 91 unaffected individuals (mean age 34.2 years). Differentially methylated sites were assessed by generalized linear models testing ADHD status and ADHD symptoms, accounting for a methylation-based smoking score, age, sex, and blood cell count. DNA methylation of single sites within DRD4 and KLDR1 was associated with adult ADHD status, and multiple DNA methylation sites within TARBP1 were associated with ADHD symptoms in adulthood and childhood. Awaiting replication, findings of this pilot study point to TARBP1 as a new candidate gene for ADHD symptoms. Our work also stresses the need for research to further examine the effects of environmental factors, such as nicotine exposure, on epigenetic modifications associated with psychiatric traits.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33147348

RESUMO

Disruptive behavior during childhood and adolescence is heterogeneous and associated with several psychiatric disorders. The identification of more homogeneous subgroups might help identify different underlying pathways and tailor treatment strategies. Children and adolescents (aged 8-18) with disruptive behaviors (N = 121) and healthy controls (N = 100) were included in a European multi-center cognition and brain imaging study. They were assessed via a battery of standardized semi-structured interviews and questionnaires. K-means cluster-model analysis was carried out to identify subgroups within the group with disruptive behaviors, based on clinical symptom profiles, callous-unemotional (CU) traits, and proactive and reactive aggression. The resulting subgroups were then compared to healthy controls with regard to these clinical variables. Three distinct subgroups were found within the group with disruptive behaviors. The High CU Traits subgroup presented elevated scores for CU traits, proactive aggression and conduct disorder (CD) symptoms, as well as a higher proportion of comorbidities (CD + oppositional defiant disorder + attention deficit hyperactivity disorder (ADHD). The ADHD and Affective Dysregulation subgroup showed elevated scores for internalizing and ADHD symptoms, as well as a higher proportion of females. The Low Severity subgroup had relatively low levels of psychopathology and aggressive behavior compared to the other two subgroups. The High CU Traits subgroup displayed more antisocial behaviors than the Low Severity subgroup, but did not differ when compared to the ADHD and Affective Dysregulation subgroup. All three subgroups differed significantly from the healthy controls in all the variables analyzed. The present study extends previous findings on subgrouping children and adolescents with disruptive behaviors using a multidimensional approach and describes levels of anxiety, affective problems, ADHD, proactive aggression and CU traits as key factors that differentiate conclusively between subgroups.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33054990

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity. ADHD has been related to differences in white matter (WM) microstructure. However, much remains unclear regarding the nature of these WM differences and which clinical aspects of ADHD they reflect. We systematically investigated whether fractional anisotropy (FA) is associated with current and/or lifetime categorical diagnosis, impairment in daily life, and continuous ADHD symptom measures. METHODS: Diffusion-weighted imaging data were obtained from 654 participants (322 unaffected, 258 affected, 74 subthreshold; 7-29 years of age). We applied automated global probabilistic tractography on 18 major WM pathways. Linear mixed-effects regression models were used to examine associations of clinical measures with overall brain and tract-specific FA. RESULTS: There were significant interactions of tract with all ADHD variables on FA. There were no significant associations of FA with current or lifetime diagnosis, nor with impairment. Lower FA in the right cingulum angular bundle was associated with higher hyperactivity-impulsivity symptom severity (pfamilywise error = .045). There were no significant effects for other tracts. CONCLUSIONS: This is the first time global probabilistic tractography has been applied to an ADHD dataset of this size. We found no evidence for altered FA in association with ADHD diagnosis. Our findings indicate that associations of FA with ADHD are not uniformly distributed across WM tracts. Continuous symptom measures of ADHD may be more sensitive to FA than diagnostic categories. The right cingulum angular bundle in particular may play a role in symptoms of hyperactivity and impulsivity.

14.
PLoS Biol ; 18(10): e3000908, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33108370

RESUMO

Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development [TD] N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33097470

RESUMO

BACKGROUND: Autism spectrum disorder ("autism") is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, but its potential as a neural stratification marker has not been widely examined. METHODS: In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS (European Autism Interventions-A Multicentre Study for Developing New Medications) Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical control subjects as well as a replication dataset from ABIDE (Autism Brain Imaging Data Exchange) (513 individuals with autism, 691 neurotypical subjects) using a promising approach that moves beyond mean group comparisons. We derived gray matter voxelwise laterality values for each subject and modeled individual deviations from the normative pattern of brain laterality across age using normative modeling. RESULTS: Individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language, motor, and visuospatial regions, associated with symptom severity. Language delay explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged, with individuals with autism with language delay showing more pronounced rightward deviations than individuals with autism without language delay. CONCLUSIONS: Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism and indicate that atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.

16.
Mol Autism ; 11(1): 86, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126911

RESUMO

BACKGROUND: Voxel-based morphometry (VBM) studies in autism spectrum disorder (autism) have yielded diverging results. This might partly be attributed to structural alterations being associating with the combined influence of several regions rather than with a single region. Further, these structural covariation differences may relate to continuous measures of autism rather than with categorical case-control contrasts. The current study aimed to identify structural covariation alterations in autism, and assessed canonical correlations between brain covariation patterns and core autism symptoms. METHODS: We studied 347 individuals with autism and 252 typically developing individuals, aged between 6 and 30 years, who have been deeply phenotyped in the Longitudinal European Autism Project. All participants' VBM maps were decomposed into spatially independent components using independent component analysis. A generalized linear model (GLM) was used to examine case-control differences. Next, canonical correlation analysis (CCA) was performed to separately explore the integrated effects between all the brain sources of gray matter variation and two sets of core autism symptoms. RESULTS: GLM analyses showed significant case-control differences for two independent components. The first component was primarily associated with decreased density of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and increased density of caudate nucleus in the autism group relative to typically developing individuals. The second component was related to decreased densities of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to typically developing individuals. The CCA results showed significant correlations between components that involved variation of thalamus, putamen, precentral gyrus, frontal, parietal, and occipital lobes, and the cerebellum, and repetitive, rigid and stereotyped behaviors and abnormal sensory behaviors in autism individuals. LIMITATIONS: Only 55.9% of the participants with autism had complete questionnaire data on continuous parent-reported symptom measures. CONCLUSIONS: Covaried areas associated with autism diagnosis and/or symptoms are scattered across the whole brain and include the limbic system, basal ganglia, thalamus, cerebellum, precentral gyrus, and parts of the frontal, parietal, and occipital lobes. Some of these areas potentially subserve social-communicative behavior, whereas others may underpin sensory processing and integration, and motor behavior.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33080250

RESUMO

BACKGROUND: Methylphenidate (MPH) is an efficacious treatment for ADHD but concerns have been raised about potential adverse effects of extended treatment on growth. OBJECTIVES: To systematically review the literature, up to December 2018, conducting a meta-analysis of association of long-term (> six months) MPH exposure with height, weight and timing of puberty. RESULTS: Eighteen studies (ADHD n = 4868) were included in the meta-analysis. MPH was associated with consistent statistically significant pre-post difference for both height (SMD = 0.27, 95% CI 0.16-0.38, p < 0.0001) and weight (SMD = 0.33, 95% CI 0.22-0.44, p < 0.0001) Z scores, with prominent impact on weight during the first 12 months and on height within the first 24-30 months. No significant effects of dose, formulation, age and drug-naïve condition as clinical moderators were found. Data on timing of puberty are currently limited. CONCLUSIONS: Long-term treatment with MPH can result in reduction in height and weight. However, effect sizes are small with possible minimal clinical impact. Long-term prospective studies may help to clarify the underlying biological drivers and specific mediators and moderators.

18.
J Psychiatry Neurosci ; 45(6): 190148, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-33009904

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is highly heterogeneous in its etiology and manifestation. The neurobiological processes underlying ASD development are reflected in multiple features, from behaviour and cognition to brain functioning. An integrated analysis of these features may optimize the identification of these processes. METHODS: We examined cognitive and adaptive functioning and ASD symptoms between 8 and 36 months in 161 infants at familial high risk for ASD and 71 low-risk controls; we also examined neural sensitivity to eye gaze at 8 months in a subsample of 140 high-risk and 61 low-risk infants. We used linked independent component analysis to extract patterns of variation across domains and development, and we selected the patterns significantly associated with clinical classification at 36 months. RESULTS: An early process at 8 months, indicating high levels of functioning and low levels of symptoms linked to higher attention to gaze shifts, was reduced in infants who developed ASD. A longitudinal process of increasing functioning and low levels of symptoms was reduced in infants who developed ASD, and another process suggesting a stagnation in cognitive functioning at 24 months was increased in infants who developed ASD. LIMITATIONS: Although the results showed a clear significant trend relating to clinical classification, we found substantial overlap between groups. CONCLUSION: We uncovered underlying processes that acted together early in development and were associated with clinical outcomes. Our results highlighted the complexity of emerging ASD, which goes beyond the borders of clinical categories. Future work should integrate genetic data to investigate the specific genetic risks linked to these processes.

19.
Transl Psychiatry ; 10(1): 342, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033241

RESUMO

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33059383

RESUMO

BACKGROUND: There is an increased interest in 'late-onset' attention-deficit/hyperactivity disorder (ADHD), referring to the onset of clinically significant ADHD symptoms after the age of 12 years. This study aimed to examine whether unaffected siblings with late-onset ADHD could be differentiated from stable unaffected siblings by their neurocognitive functioning in childhood. METHODS: We report findings from a 6-year prospective, longitudinal study of the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study, including individuals with childhood-onset (persistent) ADHD (n = 193), their siblings with late-onset ADHD (n = 34), their stable unaffected siblings (n = 111) and healthy controls (n = 186). At study entry (mean age: 11.3) and follow-up (mean age: 17.01), participants were assessed for ADHD by structured psychiatric interviews and multi-informant questionnaires. Several neurocognitive functions were assessed at baseline and after 6 years, including time reproduction, timing variability (reaction time variability and time production variability), reaction time speed, motor control and working memory; intelligence was taken as a measure of overall neurocognitive functioning. RESULTS: Siblings with late-onset ADHD were similar to individuals with childhood-onset ADHD in showing longer reaction times and/or higher error rates on all neurocognitive measures at baseline and follow-up, when compared to healthy controls. They differed from stable unaffected siblings (who were similar to healthy controls) by greater reaction time variability and timing production variability at baseline. No significant group by time interaction was found for any of the tasks. CONCLUSIONS: For unaffected siblings of individuals with ADHD, reaction time variability and timing production variability may serve as neurocognitive marker for late-onset ADHD.

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