1. Bäckström A, Johansson AM, Rudolfsson T, Rönnqvist L, von Hofsten C, Rosander K, Domellöf E. Motor planning and movement execution during goal-directed sequential manual movements in 6-year-old children with autism spectrum disorder: A kinematic analysis. Research in developmental disabilities. 2021; 115: 104014.

BACKGROUND: Atypical motor functioning is prevalent in children with autism spectrum disorder (ASD). Knowledge of the underlying kinematic properties of these problems is sparse. AIMS: To investigate characteristics of manual motor planning and performance difficulties/diversity in children with ASD by detailed kinematic measurements. Further, associations between movement parameters and cognitive functions were explored. METHODS AND PROCEDURES: Six-year-old children with ASD (N = 12) and typically developing (TD) peers (N = 12) performed a sequential manual task comprising grasping and fitting a semi-circular peg into a goal-slot. The goal-slot orientation was manipulated to impose different motor planning constraints. Movements were recorded by an optoelectronic system. OUTCOMES AND RESULTS: The ASD-group displayed less efficient motor planning than the TD-group, evident in the reach-to-grasp and transport kinematics and less proactive adjustments of the peg to the goal-slot orientations. The intra-individual variation of movement kinematics was higher in the ASD-group compared to the TD-group. Further, in the ASD-group, movement performance associated negatively with cognitive functions. CONCLUSIONS AND IMPLICATIONS: Planning and execution of sequential manual movements proved challenging for children with ASD, likely contributing to problems in everyday actions. Detailed kinematic investigations contribute to the generation of specific knowledge about the nature of atypical motor performance/diversity in ASD. This is of potential clinical relevance.

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2. Baribeau D, Anagnostou E. Novel treatments for autism spectrum disorder based on genomics and systems biology. Pharmacology & therapeutics. 2022; 230: 107939.

BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with a complex underlying genetic architecture. There are currently no known pharmacologic treatments for the core ASD symptoms of social deficits and restricted/ repetitive behavior. However, there are dozens of clinical trials currently underway that are testing the impact of novel and existing agents on core and associated symptoms in ASD. METHODS: We present a narrative synthesis of the historical and contemporary challenges to drug discovery in ASD. We then provide an overview of novel treatments currently under investigation from a genomics and systems biology perspective. RESULTS: Data driven network and cluster analyses suggest alterations in transcriptional regulation, chromatin remodelling, synaptic transmission, neuropeptide signalling, and/or immunological mechanisms may contribute to or underlie the development of ASD. Agents and upcoming trials targeting each of the above listed systems are reviewed. CONCLUSION: Identifying effective pharmacologic treatments for the core and associated symptom domains in ASD will require further collaboration and innovation in the areas of outcome measurement, biomarker research, and genomics, as well as systematic efforts to identify and treat subgroups of individuals with ASD who may be differentially responsive to specific treatments.

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3. Fyke W, Premoli M, Echeverry Alzate V, López-Moreno JA, Lemaire-Mayo V, Crusio WE, Marsicano G, Wöhr M, Pietropaolo S. Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1854-72.

Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains.

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4. Ortgies T, Rullmann M, Ziegelhöfer D, Bläser A, Thome UH. The role of early-onset-sepsis in the neurodevelopment of very low birth weight infants. BMC pediatrics. 2021; 21(1): 289.

AIMS: The study investigated a putative association between early-onset-sepsis (EOS) and poor neurodevelopmental outcomes at 2 years corrected age in very low birth weight infants. METHODS: This was a single-center cohort study on infants weighing less than 1500 g with a gestational age below 35 weeks at birth born between 2008 and 2011. Neurodevelopmental outcomes were assessed at follow-up with the Bayley Scales of Infant Development-II. EOS was defined as either culture-proven EOS or clinical EOS using blood culture, CrP levels, and clinical symptoms and treatment. Neurodevelopmental impairment (NDI) was defined as one or more of the following: Mental Developmental Index (MDI) and/or Psychomotor Developmental Index (PDI) scores lower than 70; presence of cerebral palsy. RESULTS: Of 405 eligible newborns in the study period 166 were included. Two had culture-proven and 29 clinical EOS. Median MDI scores in patients with EOS were 96 (IQR: 86-106) and in the control group 94 (84-106, p = 0.77). PDI scores in patients with EOS were 96 (86-106) and in the control group 99,5 (92-103, p = 0.03). Of infected patients 7/31 (24%) showed NDI as defined, whereas only 11/135 (8%) showed NDI in the control group (OR 3.3, p = 0.03). Multiple regression analyses identified chorioamnionitis and poor CRIB-Scores as individual risk factors for MDI or PDI values < 70. CONCLUSION: In our study, EOS among VLBW-infants significantly impaired the neurodevelopment at 2 years corrected age. As shown in previous reports infection continues to be a problem and strategies for a reduction need further improvement.

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5. Patel JA, Badiani AA, Nielsen FBH, Assi S, Unadkat V, Patel B, Courtney C, Hallas L. COVID-19 and autism: Uncertainty, distress and feeling forgotten. Public health in practice (Oxford, England). 2020; 1: 100034.

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6. Qiu W, Go KA, Wen Y, Duarte-Guterman P, Eid RS, Galea LAM. Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin. Brain, behavior, and immunity. 2021; 97: 394-409.

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood-brain barrier (BBB). Triozan(TM) is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + Triozan(TM), or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.

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7. Tan Q, Orsso CE, Deehan EC, Kung JY, Tun HM, Wine E, Madsen KL, Zwaigenbaum L, Haqq AM. Probiotics, prebiotics, synbiotics, and fecal microbiota transplantation in the treatment of behavioral symptoms of autism spectrum disorder: A systematic review. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1820-36.

The emerging role of a microbiota-gut-brain axis in autism spectrum disorder (ASD) suggests that modulating gut microbial composition may offer a tractable approach to addressing the lifelong challenges of ASD. The aim of this systematic review was to provide an overview and critically evaluate the current evidence on the efficacy and safety of probiotic, prebiotic, synbiotic, and fecal microbiota transplantation therapies for core and co-occurring behavioral symptoms in individuals with ASD. Comprehensive searches of MEDLINE, EMBASE, Scopus, Web of Science Core Collection, Cochrane Library, and Google Scholar were performed from inception to March 5, 2020, and two update searches were completed on October 25, 2020, and April 22, 2021, respectively. A total of 4306 publications were identified, of which 14 articles met the inclusion criteria. Data were extracted independently by two reviewers using a preconstructed form. Results of probiotic studies do not confirm the supposed beneficial effect of probiotics on ASD, whereas prebiotics and synbiotic combinations appear to be efficacious in selective behavioral symptoms. Evidence of the efficacy of fecal microbiota transplantation in ASD is still scarce but supports further research. Overall, the current evidence base to suggest beneficial effects of these modalities in ASD is limited and inconclusive. More clinical trials are currently looking at the use of microbial-based therapies in ASD. With a robust double-blind randomized controlled protocol to investigate the efficacy, these trials should provide significant and definitive results. LAY SUMMARY: There is a link between altered gut bacteria and autism spectrum disorder. Some people believe that modulating bacterial composition in the gut may help reduce autism symptoms, but evidence from human studies suggesting beneficial effects of probiotic, prebiotic, and combination thereof as well as fecal transplants in autism spectrum disorder is limited and inconclusive. Current data should not encourage use of these modalities. Further clinical studies are needed.

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8. Xu M, Calhoun V, Jiang R, Yan W, Sui J. Brain imaging-based machine learning in autism spectrum disorder: methods and applications. Journal of neuroscience methods. 2021; 361: 109271.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with early childhood onset and high heterogeneity. As the pathogenesis is still elusive, ASD diagnosis is comprised of a constellation of behavioral symptoms. Non-invasive brain imaging techniques, such as magnetic resonance imaging (MRI), provide a valuable objective measurement of the brain. Many efforts have been devoted to developing imaging-based diagnostic tools for ASD based on machine learning (ML) technologies. In this survey, we review recent advances that utilize machine learning approaches to classify individuals with and without ASD. First, we provide a brief overview of neuroimaging-based ASD classification studies, including the analysis of publications and general classification pipeline. Next, representative studies are highlighted and discussed in detail regarding different imaging modalities, methods and sample sizes. Finally, we highlight several common challenges and provide recommendations on future directions. In summary, identifying discriminative biomarkers for ASD diagnosis is challenging, and further establishing more comprehensive datasets and dissecting the individual and group heterogeneity will be critical to achieve better ADS diagnosis performance. Machine learning methods will continue to be developed and are poised to help advance the field in this regard.

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