1. Bicker F, Nardi L, Maier J, Vasic V, Schmeisser MJ. Criss-crossing autism spectrum disorder and adult neurogenesis. Journal of neurochemistry. 2021; 159(3): 452-78.

Autism spectrum disorder (ASD) comprises a group of multifactorial neurodevelopmental disorders primarily characterized by deficits in social interaction and repetitive behavior. Although the onset is typically in early childhood, ASD poses a lifelong challenge for both patients and caretakers. Adult neurogenesis (AN) is the process by which new functional neurons are created from neural stem cells existing in the post-natal brain. The entire event is based on a sequence of cellular processes, such as proliferation, specification of cell fate, maturation, and ultimately, synaptic integration into the existing neural circuits. Hence, AN is implicated in structural and functional brain plasticity throughout life. Accumulating evidence shows that impaired AN may underlie some of the abnormal behavioral phenotypes seen in ASD. In this review, we approach the interconnections between the molecular pathways related to AN and ASD. We also discuss existing therapeutic approaches targeting such pathways both in preclinical and clinical studies. A deeper understanding of how ASD and AN reciprocally affect one another could reveal important converging pathways leading to the emergence of psychiatric disorders.

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2. Cañigueral R, Palmer J, Ashwood KL, Azadi B, Asherson P, Bolton PF, McLoughlin G, Tye C. Alpha oscillatory activity during attentional control in children with Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and ASD+ADHD. Journal of child psychology and psychiatry, and allied disciplines. 2021.

BACKGROUND: Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) share impairments in top-down and bottom-up modulation of attention. However, it is not yet well understood if co-occurrence of ASD and ADHD reflects a distinct or additive profile of attention deficits. We aimed to characterise alpha oscillatory activity (stimulus-locked alpha desynchronisation and prestimulus alpha) as an index of integration of top-down and bottom-up attentional processes in ASD and ADHD. METHODS: Children with ASD, ADHD, comorbid ASD+ADHD, and typically-developing children completed a fixed-choice reaction-time task (‘Fast task’) while neurophysiological activity was recorded. Outcome measures were derived from source-decomposed neurophysiological data. Main measures of interest were prestimulus alpha power and alpha desynchronisation (difference between poststimulus and prestimulus alpha). Poststimulus activity linked to attention allocation (P1, P3), attentional control (N2), and cognitive control (theta synchronisation, 100-600 ms) was also examined. ANOVA was used to test differences across diagnostics groups on these measures. Spearman’s correlations were used to investigate the relationship between attentional control processes (alpha oscillations), central executive functions (theta synchronisation), early visual processing (P1), and behavioural performance. RESULTS: Children with ADHD (ADHD and ASD+ADHD) showed attenuated alpha desynchronisation, indicating poor integration of top-down and bottom-up attentional processes. Children with ADHD showed reduced N2 and P3 amplitudes, while children with ASD (ASD and ASD+ADHD) showed greater N2 amplitude, indicating atypical attentional control and attention allocation across ASD and ADHD. In the ASD group, prestimulus alpha and theta synchronisation were negatively correlated, and alpha desynchronisation and theta synchronisation were positively correlated, suggesting an atypical association between attentional control processes and executive functions. CONCLUSIONS: ASD and ADHD are associated with disorder-specific impairments, while children with ASD+ADHD overall presented an additive profile with attentional deficits of both disorders. Importantly, these findings may inform the improvement of transdiagnostic procedures and optimisation of personalised intervention approaches.

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3. Chee ZJ, de Vries M. Language Matters: The Autism-Spectrum Quotient in English, Mandarin and Bahasa Malaysia. Journal of autism and developmental disorders. 2021.

The autism-spectrum quotient (AQ) measures autistic traits and has been studied in different countries, sometimes with the English version, and sometimes with translated versions. However, the language of the questionnaire might influence non-native English speakers’ answering tendency. In the current study we compared the responses on the AQ of multilingual Malaysians (96 participants filled out the AQ in English and Mandarin, and 79 participants filled out English and Bahasa Malaysia). Participants scored higher on the English AQ compared to the Mandarin AQ, whereas there was no difference between the English and Bahasa Malaysia AQ score. Analysis of the response style suggests the same person might display discrepant response styles in different languages, which seems to be related to language proficiency.

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4. Conson M, Siciliano M, Trojano L, Zoccolotti P, Zappullo I, Baiano C, Caputo G, Russo A, Santangelo G. Figure Disembedding: The Gottschaldt’s Hidden Figure Test in Children with Typical Development and Autism. Journal of autism and developmental disorders. 2021.

In two studies, we used the Gottschaldt’s Hidden Figure Test (GHFT) for assessing figure disembedding ability in children aged 7-11. Study 1 demonstrated in a large sample of typically developing children that GHFT accuracy and time scores differed across age groups, without sex and socioeconomic differences. Thus, we provided normative data only taking into account children’s age. In Study 2, GHFT normative values were used to assess children with autism, who were also compared with a closely age-matched group of typical controls. Children with autism achieved time scores at or above the 50th centile and significantly differed from the controls for time score. The GHFT seems a valuable tool for defining the cognitive profile of children with autism.

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5. Erten F. Lycopene ameliorates propionic acid-induced autism spectrum disorders by inhibiting inflammation and oxidative stress in rats. Journal of food biochemistry. 2021; 45(10): e13922.

This study was conducted to study lycopene efficacy in brain-behavior, pro-inflammatory and apoptotic markers, and antioxidant levels in a rodent model. Rats were administered with propionic acid (PPA) (500 mg/kg BW) to induce autism-like disorders, then treated with different lycopene (L) concentrations (5, 10, 20 mg kg(-1) day(-1) ) for 35 days. The groups were: (i);control, (ii);PPA, (iii);PPA + L5, (iv);PPA + L10, and (v);PPA + L20. In this study, serum and brain malondialdehyde (MDA) levels decreased with lycopene supplements compared to the PPA group, similarly to the brain levels of inflammatory factors (IL-1α, IL-8, NF-κB, TNF-α; p < .05). Besides, brain levels of anti-apoptotic Bcl-2 decreased, whereas pro-apoptotic Bax, antioxidant Nrf2, and HO-1 levels in brain increased compared with PPA (p < .05). This study showed that lycopene might have therapeutic value to improve the dysfunctions in learning and memory in a dose-dependent way, along with the antioxidant, anti-inflammatory, and antiapoptotic molecular responses in a rat model of ASD-like disorders. PRACTICAL APPLICATIONS: This study suggested that lycopene can reduce propionic acid (PPA)-induced learning and memory impairment and oxidative damage by participating in multiple biological activities such as antioxidant, and anti-inflammatory effects. Lycopene protects serum and brain tissues against PPA induced oxidative damage in rats. These effects may be realized through up-regulation of the brain Nrf2/HO-1 pathway and down-regulation of the IL-1α, IL-8, TNF-α, and NF-κB levels. Lycopene may also contribute to memory and learning function, apoptotic/antiapoptotic modulation, and antioxidant and possible therapeutic efficacy in PPA-induced- Autism spectrum disorder cases.

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6. Faja S, Clarkson T, Gilbert R, Vaidyanathan A, Greco G, Rueda MR, Combita LM, Driscoll K. A preliminary randomized, controlled trial of executive function training for children with autism spectrum disorder. Autism : the international journal of research and practice. 2022; 26(2): 346-60.

Executive function, which is a set of thinking skills that includes stopping unwanted responses, being flexible, and remembering information needed to solve problems, is a challenge for many children on the autism spectrum. This study tested whether executive function could be improved with a computerized executive function training program under the guidance of a coach who reinforced the use of executive function skills. Seventy children with autism spectrum disorder from age 7 to 11 years of age participated in the study. They were randomly assigned to receive training or to a waiting group. The tests most likely to determine whether the training may be effective were chosen from a larger battery before the study started and included one task measuring brain responses, two measures of executive function in the lab, and a parent questionnaire. Changes in social functioning and repetitive behaviors were also explored. All children assigned to training completed the program and families generally reported the experience was positive. Brain responses of the training group changed following training, but not within the waiting group during a similar time period. Children who received training did not exhibit behavioral changes during the two the lab-based tasks. Parent report on questionnaires indicated that neither group showed a significant change in their broad use of executive function in other settings. Yet, children who received training were reported to have fewer restricted and repetitive behaviors following training. These initial findings suggest that short executive function training activities are feasible and may improve some functioning of school-aged children on the autism spectrum.

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7. Fyfe I. Early-onset dementia in autism spectrum disorder. Nature reviews Neurology. 2021; 17(10): 595.

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8. Guilbaud J, Vuattoux D, Bezzan G, Malchair A. [Autism spectrum disorder : ethiopathogenesis and benefits of early diagnosis]. Revue medicale de Liege. 2021; 76(9): 672-6.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that manifests in altered or reduced social behaviours, social communication disorders, and repetitive behaviours and/or restricted interests. The etiology of ASD is complex and multifactorial. The etiopathogenesis of the disorder is multiple, including brain abnormalities, visual contact and early interaction disorders. These signs are often the focus of parental concerns. In addition, since ASD is neurodevelopmental, all signs are not always present simultaneously. Indeed, they appear progressively, until the age of 3 years, at which the diagnosis can usually be made. Nevertheless, in more complex cases, this diagnosis may be considered later. The first signs of ASD (before 24 months) will be addressed because they are crucial for an early diagnosis. Their knowledge allows the establishment of a follow-up as well as its quick specific care. Indeed, by acting during a developmental period when brain plasticity is high, early intervention allows to modify the evolution of symptoms, and later on to limit secondary handicaps.

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9. Scheffer IE, Hulihan J, Messenheimer J, Ali S, Keenan N, Griesser J, Gutterman DL, Sebree T, Sadleir LG. Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial. JAMA network open. 2021; 4(9): e2123930.

IMPORTANCE: Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population. OBJECTIVE: To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life. DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period. INTERVENTIONS: Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months. MAIN OUTCOMES AND MEASURES: Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months. RESULTS: Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]). CONCLUSIONS AND RELEVANCE: In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12618000516280.

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10. Schudlo LC, Anagnostou E, Chau T, Doyle-Thomas K. Investigating sensory response to physical discomfort in children with autism spectrum disorder using near-infrared spectroscopy. PloS one. 2021; 16(9): e0257029.

Self-reporting of pain can be difficult in populations with communication challenges or atypical sensory processing, such as children with autism spectrum disorder (ASD). Consequently, pain can go untreated. An objective method to identify discomfort would be valuable to individuals unable to express or recognize their own bodily distress. Near-infrared spectroscopy (NIRS) is a brain-imaging modality that is suited for this application. We evaluated the potential of detecting a cortical response to discomfort in the ASD population using NIRS. Using a continuous-wave spectrometer, prefrontal and parietal measures were collected from 15 males with ASD and 7 typically developing (TD) males 10-15 years of age. Participants were exposed to a noxious cold stimulus by immersing their hands in cold water and tepid water as a baseline task. Across all participants, the magnitude and timing of the cold and tepid water-induced brain responses were significantly different (p < 0.001). The effect of the task on the brain response depended on the study group (group x task: p < 0.001), with the ASD group exhibiting a blunted response to the cold stimulus. Findings suggest that NIRS may serve as a tool for objective pain assessment and atypical sensory processing.

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11. Tóthová C, Link R, Kyzeková P, Nagy O. Serum protein electrophoretic pattern in piglets during the early postnatal period. Scientific reports. 2021; 11(1): 17539.

The pattern of serum proteins, the typical features of the electrophoretogram in newborn piglets and during their postnatal development is not completely described. Therefore, the aim of this study was to characterize the changes in serum protein electrophoretic pattern and features of the electrophoretograms during the early postnatal period. Significant changes during the monitored period were found in all evaluated parameters (P < 0.001). The most marked changes were observed mainly in the period before weaning. The concentrations of total proteins, albumin and γ-globulins were before colostrum intake low, γ-globulins represented the smallest proportion of protein fractions. The proportion of α(1)-globulins was after birth a dominant protein fraction. Significant increase of total proteins, α(2)-, β- and γ-globulins and decrease of α(1)-globulins was found 2 days after colostrum intake. The albumin and A/G values increased after birth gradually until weaning. After weaning a significant changes were found in absolute concentrations of total protein and albumin, and in relative values of β-globulin fractions. Presented results showed marked developmental alterations in the serum protein pattern in piglets along with the age. The study also brings new knowledge in the field of description of typical features of electrophoretograms in the observed period of piglet's life.

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12. VanSickle EA, Michael J, Bachmann AS, Rajasekaran S, Prokop JW, Kuzniecky R, Hofstede FC, Steindl K, Rauch A, Lipson MH, Bupp CP. Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome. American journal of medical genetics Part A. 2021; 185(11): 3485-93.

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

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13. Villanueva EB, Tresse E, Liu Y, Duarte JN, Jimenez-Duran G, Ejlerskov P, Kretz O, Loreth D, Goldmann T, Prinz M, Issazadeh-Navikas S. Neuronal TNFα, Not α-Syn, Underlies PDD-Like Disease Progression in IFNβ-KO Mice. Annals of neurology. 2021; 90(5): 789-807.

OBJECTIVE: Parkinson’s disease (PD) manifests in motor dysfunction, non-motor symptoms, and eventual dementia (PDD). Neuropathological hallmarks include nigrostriatal neurodegeneration, Lewy body (LB) pathology, and neuroinflammation. Alpha-synuclein (α-syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as α-syn pathology is often comorbid with amyloid-beta (Aβ) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether α-syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of α-syn would affect PDD manifestation. METHODS: IFN-β knockout (Ifnb(-/-) ) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with α-syn(+) LBs. We generated Ifnb/Snca double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild-type (Wt), Ifnb(-/-) , and Snca(-/-) mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling. RESULTS: Ifnb/Snca DKO mice developed all clinical PDD-like behavioral manifestations induced by IFN-β loss. Independently of α-syn expression, lack of IFN-β alone induced Aβ plaques, pTau tangles, and LB-like Aβ(+) /pTau(+) inclusion bodies and neuroinflammation. IFN-β loss caused significant elevated glial and neuronal TNF-α and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN-β signaling or blocking TNFR1 rescued caspase 3/t-BID-mediated neuronal-death through upregulation of c-FLIP(S) and lowered intraneuronal Aβ and pTau accumulation. INTERPRETATION: These findings increase our understanding of PD pathology and suggest that targeting α-syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-α/TNFR1 or IFN-β/IFNAR signaling, may attenuate disease. ANN NEUROL 2021;90:789-807.

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