Hardiansyah I, Nyström P, Taylor MJ, Bölte S, Ronald A, Falck-Ytter T.

Commun Biol. 2023 Mar 28;6(1):339. doi: 10.1038/s42003-023-04707-3.

ABSTRACT

Autism is a heritable and common neurodevelopmental condition, with behavioural symptoms typically emerging around age 2 to 3 years. Differences in basic perceptual processes have been documented in autistic children and adults. Specifically, data from many experiments suggest links between autism and alterations in global visual motion processing (i.e., when individual motion information is integrated to perceive an overall coherent pattern). Yet, no study has investigated whether a distinctive organization of global motion processing precede the emergence of autistic symptoms in early childhood. Here, using a validated infant electroencephalography (EEG) experimental paradigm, we first establish the normative activation profiles for global form, global motion, local form, and local motion in the visual cortex based on data from two samples of 5-month-old infants (total n = 473). Further, in a sample of 5-month-olds at elevated likelihood of autism (n = 52), we show that a different topographical organization of global motion processing is associated with autistic symptoms in toddlerhood. These findings advance the understanding of neural organization of infants’ basic visual processing, and its role in the development of autism.

PMID:36977757 | PMC:PMC10050234 | DOI:10.1038/s42003-023-04707-3

Ilioska I, Oldehinkel M, Llera A, Chopra S, Looden T, Chauvin R, Van Rooij D, Floris DL, Tillmann J, Moessnang C, Banaschewski T, Holt RJ, Loth E, Charman T, Murphy DGM, Ecker C, Mennes M, Beckmann CF, Fornito A, Buitelaar JK.

Biol Psychiatry. 2022 Dec 23:S0006-3223(22)01852-2. doi: 10.1016/j.biopsych.2022.12.018. Online ahead of print.

ABSTRACT

BACKGROUND: Neuroimaging studies of functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age and/or sex dependent.

METHODS: The study included resting-state functional magnetic resonance imaging and clinical data from the EU-AIMS LEAP (European Autism Interventions Longitudinal European Autism Project) and the ABIDE (Autism Brain Imaging Data Exchange) 1 and 2 initiatives of 1824 (796 with autism) participants with an age range of 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis.

RESULTS: Autism was associated with a brainwide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior, and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant.

CONCLUSIONS: The FC alterations observed, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the default mode network and subcortex with the rest of the brain, do not appear to be age or sex dependent and correlate with clinical dimensions of social difficulties, restrictive and repetitive behaviors, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the main symptom domains of the condition.

PMID:36925414 | DOI:10.1016/j.biopsych.2022.12.018

Loth E

Front Psychiatry. 2023 Feb 22;14:1085445. doi: 10.3389/fpsyt.2023.1085445. eCollection 2023.

ABSTRACT

Over the past decade, precision medicine has become one of the most influential approaches in biomedical research to improve early detection, diagnosis, and prognosis of clinical conditions and develop mechanism-based therapies tailored to individual characteristics using biomarkers. This perspective article first reviews the origins and concept of precision medicine approaches to autism and summarises recent findings from the first “generation” of biomarker studies. Multi-disciplinary research initiatives created substantially larger, comprehensively characterised cohorts, shifted the focus from group-comparisons to individual variability and subgroups, increased methodological rigour and advanced analytic innovations. However, although several candidate markers with probabilistic value have been identified, separate efforts to divide autism by molecular, brain structural/functional or cognitive markers have not identified a validated diagnostic subgroup. Conversely, studies of specific monogenic subgroups revealed substantial variability in biology and behaviour. The second part discusses both conceptual and methodological factors in these findings. It is argued that the predominant reductionist approach, which seeks to parse complex issues into simpler, more tractable units, let us to neglect the interactions between brain and body, and divorce individuals from their social environment. The third part draws on insights from systems biology, developmental psychology and neurodiversity approaches to outline an integrative approach that considers the dynamic interaction between biological (brain, body) and social mechanisms (stress, stigma) to understanding the origins of autistic features in particular conditions and contexts. This requires 1) closer collaboration with autistic people to increase face validity of concepts and methodologies; (2) development of measures/technologies that enable repeat assessment of social and biological factors in different (naturalistic) conditions and contexts, (3) new analytic methods to study (simulate) these interactions (including emergent properties), and (4) cross-condition designs to understand which mechanisms are transdiagnostic or specific for particular autistic sub-populations. Tailored support may entail both creating more favourable conditions in the social environment and interventions for some autistic people to increase well-being.

PMID:36911126 | PMC:PMC9992810 | DOI:10.3389/fpsyt.2023.1085445

Vitrac A, Leblond CS, Rolland T, Cliquet F, Mathieu A, Maruani A, Delorme R, Schön M, Grabrucker AM, van Ravenswaaij-Arts C, Phelan K, Tabet AC, Bourgeron T.

Eur J Med Genet. 2023 May;66(5):104732. doi: 10.1016/j.ejmg.2023.104732. Epub 2023 Feb 21.

ABSTRACT

SHANK3-related Phelan-McDermid syndrome (PMS) is caused by a loss of the distal part of chromosome 22, including SHANK3, or by a pathological SHANK3 variant. There is an important genetic and phenotypic diversity among patients who can present with developmental delay, language impairments, autism, epilepsy, and other symptoms. SHANK3, encoding a synaptic scaffolding protein, is deleted in the majority of patients with PMS and is considered a major gene involved in the neurological impairments of the patients. However, differences in deletion size can influence clinical features, and in some rare cases, deletions at the 22q13 locus in individuals with SHANK3-unrelated PMS do not encompass SHANK3. These individuals with SHANK3-unrelated PMS still display a PMS-like phenotype. This suggests the participation of other 22q13 genes in the pathogenesis of PMS. Here, we review the biological function and potential implication in PMS symptoms of 110 genes located in the 22q13 region, focusing on 35 genes with evidence for association with neurodevelopmental disorders, including 13 genes for epilepsy and 11 genes for microcephaly and/or macrocephaly. Our review is restricted to the 22q13 region, but future large-scale studies using whole genome sequencing and deep-phenotyping are warranted to develop predictive models of clinical trajectories and to target specific medical and educational care for each individual with PMS.

PMID:36822569 | DOI:10.1016/j.ejmg.2023.104732

Ahmad M, Stirmlinger N, Jan I, Stifel U, Lee S, Weingandt M, Kelp U, Bockmann J, Ignatius A, Böckers TM, Tuckermann J.

JBMR Plus. 2022 Dec 15;7(2):e10711. doi: 10.1002/jbm4.10711. eCollection 2023 Feb.

ABSTRACT

Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2 ^-/-) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)-derived osteoblasts from a loss-of-function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

PMID:36751416 | PMC:PMC9893268 | DOI:10.1002/jbm4.10711