Federico Bolognani

Cerebellar anatomical alterations and attention to eyes in autism

The cerebellum is implicated in social cognition and is likely to be involved in the pathophysiology of autism spectrum disorder (ASD). The goal of our study was to explore cerebellar morphology in adults with ASD and its relationship to eye contact, as measured by fixation time allocated on the eye region using an eye-tracking device. Two-hundred ninety-four subjects with ASD and controls were included in our study and underwent a structural magnetic resonance imaging scan. Global segmentation and cortical parcellation of the cerebellum were performed. A sub-sample of 59 subjects underwent an eye tracking protocol in order to measure the fixation time allocated to the eye region. We did not observe any difference in global cerebellar volumes between ASD patients and controls; however, regional analyses found a decrease of the volume of the right anterior cerebellum in subjects with ASD compared to controls. There were significant correlations between fixation time on eyes and the volumes of the vermis and Crus I. Our results suggest that cerebellar morphology may be related to eye avoidance and reduced social attention. Eye tracking may be a promising neuro-anatomically based stratifying biomarker of ASD.

Adaptive behavior in autism: Minimal clinically important differences on the Vineland-II

Autism Spectrum Disorder (ASD) is associated with persistent impairments in adaptive abilities across multiple domains. These social, personal, and communicative impairments become increasingly pronounced with development, and are present regardless of IQ. The Vineland Adaptive Behavior Scales, Second Edition (Vineland‐II) is the most commonly used instrument for quantifying these impairments, but minimal clinically important differences (MCIDs) on Vineland‐II scores have not been rigorously established in ASD. We pooled data from several consortia/registries (EU‐AIMS LEAP study, ABIDE‐I, ABIDE‐II, INFOR, Simons Simplex Collection and Autism Treatment Network [ATN]) and clinical investigations and trials (Stanford, Yale, Roche) resulting in a data set of over 9,000 individuals with ASD. Two approaches were used to estimate MCIDs: distribution‐based methods and anchor‐based methods. Distribution‐based MCID [d‐MCID] estimates included the standard error of the measurement, as well as one‐fifth and one‐half of the covariate‐adjusted standard deviation (both cross‐sectionally and longitudinally). Anchor‐based MCID [a‐MCID] estimates include the slope of linear regression of clinician ratings of severity on the Vineland‐II score, the slope of linear regression of clinician ratings of longitudinal improvement category on Vineland‐II change, the Vineland‐II change score maximally differentiating clinical impressions of minimal versus no improvement, and equipercentile equating. Across strata, the Vineland‐II Adaptive Behavior Composite standardized score MCID estimates range from 2.01 to 3.2 for distribution‐based methods, and from 2.42 to 3.75 for sample‐size‐weighted anchor‐based methods. Lower Vineland‐II standardized score MCID estimates were observed for younger and more cognitively impaired populations. These MCID estimates enable users of Vineland‐II to assess both the statistical and clinical significance of any observed change. Autism Res 2018, 11: 270–283.

Psychiatric comorbidities and use of psychotropic medications in people with autism spectrum disorder in the United States

This study investigated psychotropic medication usage in two large, cohorts of people with autism spectrum disorder (ASD) throughout the calendar year 2014. The cohorts referred to individuals with commercial (employer‐sponsored) and Medicaid insurance in the United States. We aimed to understand prescribing patterns of such medications across a wide age‐range and in the presence/absence of other clinical and non‐clinical characteristics, including psychiatric comorbidities. We described the prevalence and length of prescriptions by age, psychiatric comorbidity and overall. We also fitted multivariable logistic regression models to describe the relationship between treatments and subject characteristics simultaneously. Eighty percent of the identified population was male, although gender did not impact the odds of receiving medication. Medication use was strongly associated with age, increasing most rapidly before adulthood; generally plateauing thereafter. All psychiatric comorbidities studied also individually increased the chances of medication use, with epilepsy and ADHD having the highest associations in both the commercial (OR > 7) and Medicaid (OR around 12) cohorts. Those in non‐capitated insurance plans, in foster care and white individuals also had increased odds of prescriptions. Overall, slightly more Medicaid enrollees received any psychotropic treatment (commercial: 64%, Medicaid: 69%). Nonetheless in both cohorts, a large proportion of individuals received treatment even without a diagnosis of any other psychiatric comorbidity (commercial: 31%, Medicaid: 33%). In summary, this report sheds new light on the latest patterns of psychiatric comorbidity profile and psycho‐pharmacological treatment patterns in ASD Autism Res 2017, 10: 2037–2047.

Neuronal RNA-binding protein HuD regulates addiction-related gene expression and behavior

The neuronal RNA‐binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD‐mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuDOE). When this set was further limited to genes in the knowledgebase of addiction‐related genes database (KARG) that contains predicted HuD‐binding sites in their 3′ untranslated regions (3′UTRs), we found that HuD regulates networks that have been associated with addiction‐like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction‐related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild‐type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuDOE and wild‐type mice in CPP and found that HuDOE mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIα and BDNF. These findings suggest HuD involvement in addiction‐related behaviors such as cocaine conditioning and seeking, through increased plasticity‐related gene expression.

Reproducible functional connectivity alterations are associated with autism spectrum disorder

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 synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here we address these questions in the most comprehensive, large-scale effort to date comprising evaluation of four large ASD cohorts. We followed a strict exploration and replication procedure to identify core rs-fMRI functional connectivity (degree centrality) alterations associated with ASD as compared to typically developing (TD) controls (ASD: N=841, TD: N=984). We then tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status and clinical symptom severity. We find reproducible patterns of ASD-associated functional hyper-and hypo-connectivity with hypo-connectivity being primarily restricted to sensory-motor regions and hyperconnectivity hubs being predominately located in prefrontal and parietal cortices. We establish shifts in between-network connectivity from outside to within the identified regions as a key driver of these abnormalities. The magnitude of these alterations is linked to core ASD symptoms related to communication and social interaction and is not affected by age, sex or medication status. The identified brain functional alterations provide a reproducible pathophysiological phenotype underlying the diagnosis of ASD reconciling previous divergent findings. The large effect sizes in standardized cohorts and the link to clinical symptoms emphasize the importance of the identified imaging alterations as potential treatment and stratification biomarkers for ASD.

Increased risk of ADHD in families with ASD

Attention Deficit and Hyperactive Disorder (ADHD) and Autism Spectrum Disorders (ASD) are frequent comorbid neurodevelopmental conditions and the overlap between both disorders remains to be delineated. A more complete understanding of the shared genetic and environmental factors is needed. Using a family-based method, we evaluated the risk of ADHD in a group of relatives with an ASD proband (ASD−) and a group of relatives with an ASD and ADHD proband (ASD+). We enrolled 1245 individuals in the study: 499 probands, their 746 first-degree relatives and 140 controls. We used a multivariate generalized estimating equation (GEE) model, in which the dependent variable was the ADHD diagnosis in the relatives and the independent variable the ASD+ or ASD− in probands. We adjusted for sociodemographic factors (age, sex, IQ) and for the nature of the familial relationship with the affected proband (parent or sibling). Among the probands, there were 287 ASD− and 212 ASD+ individuals. ADHD was more frequent in relatives (19%) than in the control group (7%) (p = 0.001). The risk of ADHD was higher in the ASD+ relatives group than in the ASD− relatives group (GEE model OR 1.58 [95% CI 1.04–2.38], p = 0.032). This result was found in parents (OR 1.96 [95% CI  1.14–3.36], but not in siblings (OR 1.28 [95% CI 0.84–1.94], p = 0.434). Our study provides a representative estimate of the family distribution of ADHD in relatives of ASD probands but supports the modest effect of shared genetic and environmental factors between both disorders.

Development of a patient-centered conceptual model of the impact of living with autism spectrum disorder:

The aim of this study was to generate a patient-centered conceptual model of the impact of living with autism spectrum disorder, which can be used to support the selection of outcome measures for clinical trials. Following an initial literature review to identify preliminary concepts and inform an interview guide, in-depth face-to-face interviews were conducted with adolescents and adults with autism spectrum disorder (IQ ⩾ 70) (n = 10), as well as parents of children, adolescents, and adults with autism spectrum disorder (IQ ⩾ 70) (n = 26). Data were analyzed using established qualitative research methods. The resultant conceptual model contains three interrelated domains reflecting core symptoms of autism spectrum disorder (communication deficits, socialization deficits, and restrictive, repetitive patterns of behavior), three domains reflecting associated symptoms of autism spectrum disorder (physical, cognitive, and emotional/behavioral), and three domains representing the impacts of living with autism spectrum disorder (impacts on activities of daily living, school/work, and social life). Interview respondents also cited social communication deficits as priority targets for new treatments. The conceptual model provides a patient-centered perspective of relevant concepts of autism spectrum disorder from the perspectives of people with autism spectrum disorder and their parents and offers a valuable tool for identifying valid patient-centered outcome measures for future clinical trials.

Social cognition in autism is associated with the neurodevelopment of the posterior superior temporal sulcus

The posterior superior temporal sulcus (pSTS) plays a critical role in the ‘social brain’. Its neurodevelopment and relationship with the social impairment in autism spectrum disorders (ASD) are not well understood. We explored the relationship between social cognition and the neurodevelopment of the pSTS in ASD.