Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers.

BACKGROUND: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. METHODS: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). RESULTS: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. LIMITATIONS: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. CONCLUSIONS: Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear

Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Abstract: Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry

Assessment of cognitive scales to examine memory, executive function and language in individuals with Down syndrome: implications of a 6-month observational study

Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior. Previous pharmacological studies in this population have been limited by a lack of appropriate endpoints that accurately measured change in cognitive and functional abilities. Therefore, the current longitudinal observational study assessed the suitability and reliability of existing cognitive scales to determine which tools would be the most effective in future interventional clinical studies. Subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Clinical Evaluation of Language Fundamentals-Preschool-2 (CELF-P-2), and the Observer Memory Questionnaire-Parent Form (OMQ-PF), Behavior Rating Inventory of Executive Function®–Preschool Version (BRIEF-P) and Leiter International Performance Scale-Revised were assessed. The results reported here have contributed to the optimization of trial design and endpoint selection for the Phase 2 study of a new selective negative allosteric modulator of the GABAA receptor α5-subtype (Basmisanil), and can be applied to other studies in the DS population

Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI® (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD

Patients with autism spectrum disorders display reproducible functional connectivity alterations

Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder(ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchro-nization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance ofthese alterations. Here, we addressed these questions in four large ASD cohorts. Using rs-fMRI, we identified func-tional connectivity alterations associated with ASD. We tested for associations of these imaging phenotypes withclinical and demographic factors such as age, sex, medication status, and clinical symptom severity. Our resultsshowed reproducible patterns of ASD-associated functional hyper- and hypoconnectivity. Hypoconnectivity wasprimarily restricted to sensory-motor regions, whereas hyperconnectivity hubs were predominately located inprefrontal and parietal cortices. Shifts in cortico-cortical between-network connectivity from outside to withinthe identified regions were shown to be a key driver of these abnormalities. This reproducible pathophysiologicalphenotype was partially associated with core ASD symptoms related to communication and daily living skills andwas not affected by age, sex, or medication status. Although the large effect sizes in standardized cohorts areencouraging with respect to potential application as a treatment and for patient stratification, the moderate linkto clinical symptoms and the large overlap with healthy controls currently limit the usability of identified altera-tions as diagnostic or efficacy readout

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABA\u3csub\u3eA\u3c/sub\u3e-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. Methods: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12–13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. Results: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. Conclusions: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. Trial registration: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789

Altered connectivity between cerebellum, visual and sensory-motor networks in autism spectrum disorder: results from the EU-AIMS Longitudinal European Autism Project

BACKGROUND:Resting-state functional magnetic resonance imaging–based studies on functional connectivity inautism spectrum disorder (ASD) have generated inconsistent results. Interpretation offindings is further hamperedby small samples and a focus on a limited number of networks, with networks underlying sensory processingbeing largely underexamined. We aimed to comprehensively characterize ASD-related alterations within andbetween 20 well-characterized resting-state networks using baseline data from the EU-AIMS (European AutismInterventions—A Multicentre Study for Developing New Medications) Longitudinal European Autism Project.METHODS:Resting-state functional magnetic resonance imaging data was available for 265 individuals with ASD(7.5–30.3 years; 73.2% male) and 218 typically developing individuals (6.9–29.8 years; 64.2% male), all with IQ.70.We compared functional connectivity within 20 networks—obtained using independent component analysis—between the ASD and typically developing groups, and related functional connectivity within these networks tocontinuous (overall) autism trait severity scores derived from the Social Responsiveness Scale Second Editionacross all participants. Furthermore, we investigated case-control differences and autism trait–related alterations inbetween-network connectivity.RESULTS:Higher autism traits were associated with increased connectivity within salience, medial motor, andorbitofrontal networks. However, we did not replicate previously reported case-control differences within thesenetworks. The between-network analysis did reveal case-control differences showing on average 1) decreasedconnectivity of the visual association network with somatosensory, medial, and lateral motor networks, and 2)increased connectivity of the cerebellum with these sensory and motor networks in ASD compared with typicallydeveloping subjects.CONCLUSIONS:We demonstrate ASD-related alterations in within- and between-network connectivity. Thebetween-network alterations broadly affect connectivity between cerebellum, visual, and sensory-motor networks,potentially underlying impairments in multisensory and visual-motor integration frequently observed in ASD