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Neuroscience and Biobehavioral Reviews Jun 2024Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive... (Review)
Review
Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive deficits that overlap between young autistic individuals and elderlies with dementia raise an important question: does compromised cognitive ability and brain structure during early development drive autistic adults to be more vulnerable to pathological aging conditions, or does it protect them from further decline? To answer this question, we have synthesized current theoretical models of aging in ASD and conducted a systematic literature review (Jan 1, 1980 - Feb 29, 2024) and meta-analysis to summarize empirical studies on cognitive and brain deviations in middle-to-old aged autistic adults. We explored findings that support different aging theories in ASD and addressed study limitations and future directions. This review sheds light on the poorly understood consequences of aging question raised by the autism community to pave the way for future studies to identify sensitive and reliable measures that best predict the onset, progression, and prognosis of pathological aging in ASD.
PubMed: 38944227
DOI: 10.1016/j.neubiorev.2024.105782 -
Social Science & Medicine (1982) Jun 2024While parents' and professionals' perceptions regarding children with autism spectrum disorder (ASD) have been studied extensively, limited data regarding the...
INTRODUCTION
While parents' and professionals' perceptions regarding children with autism spectrum disorder (ASD) have been studied extensively, limited data regarding the perspectives of children with ASD on their needs and the challenges they face are available. The study aimed to examine how children with ASD understand their condition and the aims of the interventions they undergo.
METHODS
Nineteen children and adolescents (ages 5.7-14.2 years) formally diagnosed with ASD, with borderline to high intelligence (range 70-140), and able to converse verbally were interviewed in person at a child development clinic. A qualitative approach was used to capture children's perceptions of their strengths and challenges and their understanding of a novel ASD treatment. The interview included direct and projective open-ended questions on each topic. Interpretive content analysis was used to evaluate the children's answers. Medical data were extracted from medical records. The children's parents completed questionnaires on their children's disability levels, awareness of ASD diagnosis, and sociodemographic details.
FINDINGS
Children spoke of their embodied sensations and feelings and discussed "normality" vs. "disability." They varied in their awareness of their diagnosis/symptoms, and only one boy named his diagnosis and described its consequences in detail. Most children lacked an understanding of the educational and therapeutic aspects of the goals set for them.
DISCUSSION AND CONCLUSIONS
Children with ASD are aware of their unique emotional and behavioral challenges. Nevertheless, they are frequently excluded from the process of patient information provision and lack an understanding of the goals of interventions. Findings suggest the need to explore developmentally and emotionally adaptive ways to involve children with ASD in discussions of their condition and possible interventions.
PubMed: 38943777
DOI: 10.1016/j.socscimed.2024.117066 -
Brain : a Journal of Neurology Jun 2024The histone methyltransferase ASH1L plays a crucial role in regulating gene expression across various organ systems during development, yet its role in brain development...
The histone methyltransferase ASH1L plays a crucial role in regulating gene expression across various organ systems during development, yet its role in brain development remains largely unexplored. Over 130 individuals with autism harbour heterozygous loss-of-function ASH1L variants, and population studies confirm it as a high-risk autism gene. Previous studies on Ash1 l deficient mice have reported autistic-like behaviours and provided insights into the underlying neuropathophysiology. In this study, we used mice with a cre-inducible deletion of Ash1 l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). Our investigation evaluated the impact of Ash1 l loss-of-function on survival and craniofacial skeletal development. Using a tamoxifen-inducible cre strain, we targeted Ash1 l knockout early in cortical development (Emx1-Cre-ERT2; e10.5). Immunohistochemistry was utilized to assess cortical lamination, while EdU incorporation aided in birthdating cortical neurons. Additionally, single-cell RNA sequencing was employed to compare cortical cell populations and identify genes with differential expression. At e18.5, the proportion of homozygous Ash1 l germline knockout embryos appeared normal; however, no live Ash1 l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: n = 41, P = 0.00095). Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017). In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype, P = 0.0001) and were distributed through the cortical plate. Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2 (e13.5 injection: n = 4/genotype, P = 0.0126). Single cell RNA sequencing revealed significant differences in gene expression between control and mutant upper layer neurons, leading to distinct clustering. Pseudotime analysis indicated that the mutant cluster followed an altered cell differentiation trajectory. This study underscores the essential role of Ash1 l in postnatal survival and normal craniofacial development. In the cortex, ASH1L exerts broad effects on gene expression and is indispensable for determining the fate of upper layer cortical neurons. These findings provide valuable insights into the potential mechanisms of ASH1L neuropathology, shedding light on its significance in neurodevelopmental disorders like autism.
PubMed: 38943682
DOI: 10.1093/brain/awae218 -
Autism Research : Official Journal of... Jun 2024This study aimed to document the safety and efficacy of a single infusion of autologous umbilical cord blood (UCB) in 20 autistic children aged 24-72 months. A...
Autologous umbilical cord blood infusion for the treatment of autism in young children: A within-subjects open label study on safety (assessed via caregiver report) and efficacy.
This study aimed to document the safety and efficacy of a single infusion of autologous umbilical cord blood (UCB) in 20 autistic children aged 24-72 months. A pre-post treatment within-subjects open label design was used. At T = 0, 6, 12, and 18 months, participants underwent detailed and structured safety evaluations (via caregiver report), Vineland Adaptive Behavior Scale (Vineland-3), Stanford Binet Intelligence Scale (SB-5), Expressive One-Word Picture Vocabulary Test, Brief Observation of Social Communication Change (BOSCC), Pervasive Developmental Disorder-Behavior Inventory, Repetitive Behavior Scale-Revised, Sensory Experience Questionnaire (SEQ-2.1), Child Behavior Checklist, Clinical Global Impression-Severity and Improvement (CGI-I) Scales, and eye-gaze tracking. UCB infusion was conducted at T = 6 months, hence, 0-6 months was the control period, and 6-18 months the follow-up period. Of 20 children recruited, 19 completed the study and 1 was withdrawn due to UCB not meeting quality control criteria for infusion. There were 15 males and 4 females with an overall mean (SD) age of 4.15 (0.62) years. Mean (SD) cell dose administered was 38.16 (9.82) million cells/kg. None suffered serious adverse events although there were mild behavioral side effects and one unit grew coagulase negative staphylococcus from a post-thaw sample. There were no significant differences in Vineland-3, SB-5, BOSCC, and SEQ-2.1 scores at T = 12 and T = 18 months. Twelve participants had T = 18 CGI-I scores of 2-3 (minimally to much improved), seven participants had scores of 4 (no change). Autologous UCB infusion in autistic children is generally safe but not without risks, including that of infection. In this within-subjects study, some children showed global symptom improvements while others showed no change. Stem cell therapies for autism should only be conducted under strict clinical trial conditions with clear risk discussions.
PubMed: 38943428
DOI: 10.1002/aur.3187 -
Technology and Health Care : Official... Jun 2024Brain variations are responsible for developmental impairments, including autism spectrum disorder (ASD). EEG signals efficiently detect neurological conditions by...
BACKGROUND
Brain variations are responsible for developmental impairments, including autism spectrum disorder (ASD). EEG signals efficiently detect neurological conditions by revealing crucial information about brain function abnormalities.
OBJECTIVE
This study aims to utilize EEG data collected from both autistic and typically developing children to investigate the potential of a Graph Convolutional Neural Network (GCNN) in predicting ASD based on neurological abnormalities revealed through EEG signals.
METHODS
In this study, EEG data were gathered from eight autistic children and eight typically developing children diagnosed using the Childhood Autism Rating Scale at the Central Institute of Psychiatry, Ranchi. EEG recording was done using a HydroCel GSN with 257 channels, and 71 channels with 10-10 international equivalents were utilized. Electrodes were divided into 12 brain regions. A GCNN was introduced for ASD prediction, preceded by autoregressive and spectral feature extraction.
RESULTS
The anterior-frontal brain region, crucial for cognitive functions like emotion, memory, and social interaction, proved most predictive of ASD, achieving 87.07% accuracy. This underscores the suitability of the GCNN method for EEG-based ASD detection.
CONCLUSION
The detailed dataset collected enhances understanding of the neurological basis of ASD, benefiting healthcare practitioners involved in ASD diagnosis.
PubMed: 38943414
DOI: 10.3233/THC-240550 -
Molecular Brain Jun 2024The cerebellum plays an important role in cognitive and social functioning. Childhood damage in the cerebellum increases the risk of autism spectrum disorder. Cerebellar...
The cerebellum plays an important role in cognitive and social functioning. Childhood damage in the cerebellum increases the risk of autism spectrum disorder. Cerebellar inflammation induces social avoidance in mice. Oxytocin regulates social relationship and expression pattern of the oxytocin receptor in the brain is related to social behaviors. However, the expression patterns of the oxytocin receptor in the cerebellum remain controversial. Here, we report that the expression patterns of the oxytocin receptor in the cerebellum are highly variable among knock-in transgenic lines. We used Oxtr-Cre knock-in mice combined with a fluorescent reporter line and found that oxytocin receptor expression in Bergmann glia was more variable than that in Purkinje cells. We found that physical damage with inflammation induced the selective upregulation of the oxytocin receptor in Bergmann glia. Our findings indicate high variability in oxytocin receptor expression in the cerebellum and suggest that the oxytocin receptor can affect neural processing in pathological conditions, such as inflammation.
Topics: Receptors, Oxytocin; Animals; Neuroglia; Up-Regulation; Cerebellum; Inflammation; Mice, Transgenic; Mice, Inbred C57BL; Mice; Male; Purkinje Cells
PubMed: 38943193
DOI: 10.1186/s13041-024-01114-5 -
Scientific Reports Jun 2024Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of...
Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish (Danio rerio) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a, c, reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.
Topics: Animals; Zebrafish; Receptor, Muscarinic M1; Allosteric Regulation; CHO Cells; Cricetulus; Acetylcholine; Locomotion; Ligands; Muscarinic Agonists
PubMed: 38942828
DOI: 10.1038/s41598-024-65445-y -
Biochemical Pharmacology Jun 2024GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily... (Review)
Review
GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily of the GPCR superfamily, which is the largest family of membrane protein receptors in the human genome. Studies in recent years have demonstrated that GPR56 is integral to the normal development of the brain and functions as an important player in cortical development, suggesting that GPR56 is involved in many physiological processes. Indeed, aberrant expression of GPR56 has been implicated in multiple neurological and psychiatric disorders, including bilateral frontoparietal polymicrogyria (BFPP), depression and epilepsy. In a recent study, it was found that upregulated expression of GPR56 reduced depressive-like behaviours in an animal model of depression, indicating that GPR56 plays an important role in the antidepressant response. Given the link of GPR56 with the antidepressant response, the function of GPR56 has become a focus of research. Although GPR56 may be a potential target for the development of antidepressants, the underlying molecular mechanisms remain largely unknown. Therefore, in this review, we will summarize the latest findings of GPR56 function in neurological and psychiatric disorders (depression, epilepsy, autism, and BFPP) and emphasize the mechanisms of GPR56 in activation and signalling in those conditions. After reviewing several studies, attributing to its significant biological functions and exceptionally long extracellular N-terminus that interacts with multiple ligands, we draw a conclusion that GPR56 may serve as an important drug target for neuropsychological diseases.
PubMed: 38942087
DOI: 10.1016/j.bcp.2024.116395 -
Cell Genomics Jun 2024Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest...
Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.
PubMed: 38942023
DOI: 10.1016/j.xgen.2024.100589 -
Infant Behavior & Development Jun 2024Autism Spectrum Disorder is a highly heritable condition characterized by sociocommunicative difficulties, frequently entailing language atypicalities that extend to...
Autism Spectrum Disorder is a highly heritable condition characterized by sociocommunicative difficulties, frequently entailing language atypicalities that extend to infants with a familial history of autism. The developmental mechanisms underlying these difficulties remain unknown. Detecting temporal synchrony between the lip movements and the auditory speech of a talking face and selectively attending to the mouth support typical early language acquisition. This preliminary eye-tracking study investigated whether these two fundamental mechanisms atypically function in infant siblings. We longitudinally tracked the trajectories of infants at elevated and low-likelihood for autism in these two abilities at 4, 8, and 12 months (n = 29). We presented two talking faces (synchronous and asynchronous) while recording infants' gaze to the talker's eyes and mouth. We found that infants detected temporal asynchronies in talking faces at 12 months regardless of group. However, compared to their typically developing peers, infants with an elevated likelihood of autism showed reduced attention to the mouth at the end of the first year and no variations in their interest to this area across time. Our findings provide preliminary evidence on a potentially atypical trajectory of reduced mouth-looking in audiovisual speech during the first year in infant siblings, with potential cascading consequences for language development, thus contributing to domain-general accounts of emerging autism.
PubMed: 38941721
DOI: 10.1016/j.infbeh.2024.101973