Additive interaction between birth asphyxia and febrile seizures on autism spectrum disorder: a population-based study.

BACKGROUND: Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder that can significantly impact an individual's ability to socially integrate and adapt. It's crucial to identify key factors associated with ASD. Recent studies link both birth asphyxia (BA) and febrile seizures (FS) separately to higher ASD prevalence. However, investigations into the interplay of BA and FS and its relationship with ASD are yet to be conducted. The present study mainly focuses on exploring the interactive effect between BA and FS in the context of ASD. METHODS: Utilizing a multi-stage stratified cluster sampling, we initially recruited 84,934 Shanghai children aged 3-12 years old from June 2014 to June 2015, ultimately including 74,251 post-exclusion criteria. A logistic regression model was conducted to estimate the interaction effect after controlling for pertinent covariates. The attributable proportion (AP), the relative excess risk due to interaction (RERI), the synergy index (SI), and multiplicative-scale interaction were computed to determine the interaction effect. RESULTS: Among a total of 74,251 children, 192 (0.26%) were diagnosed with ASD. The adjusted odds ratio for ASD in children with BA alone was 3.82 (95% confidence interval [CI] 2.42-6.02), for FS alone 3.06 (95%CI 1.48-6.31), and for comorbid BA and FS 21.18 (95%CI 9.10-49.30), versus children without BA or FS. The additive interaction between BA and FS showed statistical significance (P < 0.001), whereas the multiplicative interaction was statistically insignificant (P > 0.05). LIMITATIONS: This study can only demonstrate the relationship between the interaction of BA and FS with ASD but cannot prove causation. Animal brain experimentation is necessary to unravel its neural mechanisms. A larger sample size, ongoing monitoring, and detailed FS classification are needed for confirming BA-FS interaction in ASD. CONCLUSION: In this extensive cross-sectional study, both BA and FS were significantly linked to ASD. The coexistence of these factors was associated with an additive increase in ASD prevalence, surpassing the cumulative risk of each individual factor.

Oxytocin, GABA, and dopamine interplay in autism.

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms.

Awareness of Autism Spectrum Disorder Among Population of Kazakhstan.

BACKGROUND: In recent years, an abundance of research has substantiated the escalating prevalence of Autism Spectrum Disorder (ASD) on a global scale. The aim to assess the level of awareness regarding ASD among the Kazakhstan population, as well as their readiness to offer help to individuals affected by ASD. METHODS: A cross-sectional study was conducted encompassing individuals aged 18 years and above, using both the Russian and Kazakh languages. The survey was administered through Google Forms during April to June 2023. The link to survey was disseminated through WhatsApp chats of different social groups, including primary care specialists (general practitioners and nurses), and educators from primary and secondary schools from all 17 regions of Kazakhstan, spanning urban and rural areas. 410 participants took part in the survey in total. Statistical significance will be defined as p-values < 0.05. RESULTS: Individuals aged 25 and above, who are both educated and employed, exhibit a greater awareness of ASD compared to other demographic groups. A low proportion of respondents (18.3%) demonstrated familiarity with the key symptoms of ASD as well as on its causes. Furthermore, it's noteworthy that the primary resource for acquiring information about ASD was the internet for both of these regions. CONCLUSION: Low awareness on ASD symptoms and treatment methods was identified in both areas. There is a need to develop activities to increase the public awareness on ASD, including knowledge on early symptoms of ASD and facilities that address the needs of people on the ASD and their families.

Pathogenic gating pore current conducted by autism-related mutations in the NaV1.2 brain sodium channel.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ/KV7 potassium channel cause gating pore currents (Igp) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A/NaV1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of NaV1.2 caused Igp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective Igp. These potentially pathogenic Igp were exacerbated by the absence of the extracellular Mg2+ and Ca2+. In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward Igp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.

Beyond the Diagnosis: Evaluation of Quality-of-Life Measures and Family Functioning in SLC6A1-Related Neurodevelopmental Disorder.

BACKGROUND: SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is a rare genetic disorder linked to autism spectrum disorder, epilepsy, and developmental delay. In preparation for future clinical trials, understanding how the disorder impacts patients and their families is critically important. Quality-of-life (QoL) measures capture the overall disease experience of patients. This study presents QOL findings from our SLC6A1-NDD clinical trial readiness study and the Simons Searchlight SLC6A1-NDD registry. METHODS: We compiled QoL data from participants with SLC6A1-NDD enrolled in our clinical trial readiness study (n = 20) and the Simons Searchlight registry (n = 32). We assessed the distribution of scores on the Quality-of-Life Inventory-Disability (QI Disability), Quality of Life of Childhood Epilepsy (QOLCE-55), and Pediatric Quality of Life Inventory Family Impact Module (PedsQL-FIM) administered to caregivers. RESULTS: In our cohort of 52 participants, the mean QI Disability total score was 73 ± 12.3, the QOLCE-55 mean total score was 49 ± 17.1, and the mean total PedsQL score was 51 ± 17.6. Longitudinal QoL scores for a subset of participants (n = 7) demonstrated a reduction in the Family Relationship domain of PedsQL-FIM (Δ-10.0, P = 0.035). Bootstrap resampling of total scores displays nonoverlapping 95% confidence intervals for the 10th, 50th, and 90th percentiles on all three measures. CONCLUSIONS: This is the first study to investigate QoL measures for SLC6A1-NDD. Findings suggest that scores within the 10th percentile's confidence interval could be clinically significant, referring to QI-Disability scores of <61, QOLCE-55 scores of <46, and PedsQL-FIM scores of <42. Future validation studies are needed.

Gender and Autism Program: A novel clinical service model for gender-diverse/transgender autistic youth and young adults.

Objective: Situated in Children's National Hospital (CNH)'s Neuropsychology Division, the Gender and Autism Program (GAP) is the first clinical service dedicated to the needs of autistic gender-diverse/transgender youth. This study describes GAP clinical assessment profiles and presents a multi-perspective programmatic review of GAP evaluation services. Method: Seventy-five consecutive gender- and neuropsychologically-informed GAP evaluations were analyzed, including demographics, gender and autism characterization, and primary domains evaluated. Three program-based Delphi studies were conducted and identify: clinician priorities and challenges in providing care, program administrator lessons learned and ongoing barriers, and considerations adapting this model for a rural academic medical center. Results: Nearly two-thirds of referrals were transfeminine. Most youth had existing autism diagnoses; of those undiagnosed, three-quarters were found to be autistic. Five goals of evaluations were identified: Mental health was always assessed, and most evaluations also assessed gender-related needs in the context of autism neurodiversity. Neuropsychological characterization of strengths and challenges informed personalized accommodations to support youth gender-related self-advocacy. Clinicians emphasized frequent youth safety concerns. Administrators emphasized the need for specialized training for working with families. Components for adaptation of the GAP in a rural academic medical center were identified. Conclusions: Since its founding, the GAP has proven a sustainable neuropsychology-based service with consistent referral flow and insurance authorizations. Capturing staff perspectives through rigorous Delphi methods, and addressing the GAP's feasibility and replicability, this study provides a road map for replicating this service. We also highlight GAP training of specialist clinicians, fundamental to addressing the desperate shortage of providers in this field.

Depressive symptoms and activity engagement in autistic adolescents and those with other developmental disabilities.

BACKGROUND: Autistic adults and those with other developmental disabilities (DD) have increased depressive symptoms and decreased activity engagement when compared to those with no DD. Few studies explore activities related to depressive symptoms in autistic people and those with other DD during adolescence. OBJECTIVE: The objectives of this analysis were to describe depressive symptoms and activity engagement among autistic adolescents and those with other DD and no DD and explore types of activities associated with depressive symptoms, stratified by study group. METHODS: Parents of adolescents completed a multi-site case-control study of autism and other DD when their child was 2-5 years of age and a follow-up survey when their child was 12-16 years of age. Questions asked about the adolescent's current diagnoses, depressive symptoms (i.e., diagnosis, medication use, or symptoms), and engagement in club, social, sport, vocational, volunteer, and other organized activities. RESULTS: Autistic adolescents (N = 238) and those with other DD (N = 222) were significantly more likely to have depressive symptoms than adolescents with no DD (N = 406), (31.9 %, 30.6 %, and 15.0 % respectively). Lower percentages of autistic adolescents participated in activities than peers with other DD, who had lower percentages than peers with no DD. Participation in sports was associated with lower likelihood of depressive symptoms in all groups. CONCLUSIONS: Autistic adolescents and those with other DD are at increased risk for depressive symptoms and reduced activity engagement. Participation in sports may be especially important for adolescent mental health regardless of disability status. Implications for public health education and intervention are discussed.

Preparing to "Live a Life of Possibilities": Experiences of Healthcare Providers Readying Autistic Adolescents and Their Families for Independent Driving.

Autistic adolescents and their families may experience barriers to transportation, including independent driving, which is critical to supporting quality of life and engagement in social, educational, and employment opportunities. Healthcare providers may feel unprepared to provide guidance to autistic adolescents, although they are among the professionals families turn to for guidance. This study describes providers' experiences supporting autistic adolescents and families in the decision to pursue licensure and identifies barriers experienced in providing support. We conducted interviews with 15 healthcare providers focused on how they support autistic adolescents and their families in navigating topics related to independence, driving, and transportation. Key themes identified included: importance of understanding adolescents' perspectives and motivations, approaches to readying caregivers for children to pursue driving, and role of providers in fostering agreement between adolescents and caregivers. Results reflect healthcare providers as intermediaries between autistic adolescents and caregivers making the decision to pursue licensure and bring families to consensus. Our findings emphasize the importance of healthcare providers, in collaboration with community-based providers, in supporting autistic adolescents and their families considering licensure. Improving conversations between providers and families provides opportunity to better support quality of life among autistic adolescents and their caregivers navigating the transition to independence.

The impact of spectral basis set composition on estimated levels of cingulate glutamate and its associations with different personality traits.

BACKGROUND: 1H-MRS is increasingly used in basic and clinical research to explain brain function and alterations respectively. In psychosis research it is now one of the main tools to investigate imbalances in the glutamatergic system. Interestingly, however, the findings are extremely variable even within patients of similar disease states. One reason may be the variability in analysis strategies, despite suggestions for standardization. Therefore, our study aimed to investigate the extent to which the basis set configuration- which metabolites are included in the basis set used for analysis- would affect the spectral fit and estimated glutamate (Glu) concentrations in the anterior cingulate cortex (ACC), and whether any changes in levels of glutamate would be associated with psychotic-like experiences and autistic traits. METHODS: To ensure comparability, we utilized five different exemplar basis sets, used in research, and two different analysis tools, r-based spant applying the ABfit method and Osprey using the LCModel. RESULTS: Our findings revealed that the types of metabolites included in the basis set significantly affected the glutamate concentration. We observed that three basis sets led to more consistent results across different concentration types (i.e., absolute Glu in mol/kg, Glx (glutamate + glutamine), Glu/tCr), spectral fit and quality measurements. Interestingly, all three basis sets included phosphocreatine. Importantly, our findings also revealed that glutamate levels were differently associated with both schizotypal and autistic traits depending on basis set configuration and analysis tool, with the same three basis sets showing more consistent results. CONCLUSIONS: Our study highlights that scientific results may be significantly altered depending on the choices of metabolites included in the basis set, and with that emphasizes the importance of carefully selecting the configuration of the basis set to ensure accurate and consistent results, when using MR spectroscopy. Overall, our study points out the need for standardized analysis pipelines and reporting.

Comparison of the efficacy of parent-mediated NDBIs on developmental skills in children with ASD and fidelity in parents: a systematic review and network meta-analysis.

BACKGROUND: Recently, studies on behavioral interventions for autism have gained popularity. Naturalistic Developmental Behavior Interventions (NDBIs) are among the most effective, evidence-based, and widely used behavior interventions for autism. However, no research has been conducted on which of the several NDBI methods is most effective for parents and children with autism spectrum disorders. Therefore, we conducted a network meta-analysis to compare the specific effects of each type of parental-mediated NDBI on children's developmental skills and parent fidelity. METHODS: PubMed, Embase, Cochrane Library, Medline, Web of Science, China National Knowledge Infrastructure (CNKI), CINAHL, and Wanfang databases were searched from inception to August 30, 2023. A total of 32 randomized controlled trial studies that examined the efficacy of different NDBIs were included. RESULTS: Parents of children with ASD who received Pivotal Response Treatment (PRT) reported significant improvements in their children's social skills (SUCRA, 74.1%), language skills (SUCRA, 88.3%), and parenting fidelity (SUCRA, 99.5%). Moreover, parents who received Early Start Denver Model (ESDM) reported significant improvements in their children's language (SMD = 0.41, 95% CI: 0.04, 0.79) and motor skills (SMD = 0.44, 95% CI: 0.09, 0.79). In terms of the efficacy of improving parent fidelity, the results showed that the Improving Parents as Communication Teachers (ImPACT) intervention significantly improved parent fidelity when compared with the treatment-as-usual group (TAU) (SMD = 0.90, 95% CI: 0.39, 1.42) and the parental education intervention (PEI) (SMD = 1.10, 95% CI:0.28, 1.91).There was a difference in parent fidelity among parents who received PRT(SMD = 3.53, 95% CI: 2.26, 4.79) or ESDM(SMD = 1.42, 95% CI: 0.76, 2.09) training compared with PEI. CONCLUSION: In conclusion, this study revealed that parents can achieve high fidelity with the ImPACT intervention, and it can serve as an early first step for children newly diagnosed with ASD. It also showed that parent-mediated ESDM is effective in improving language and motor skills for children with ASD and can be used as part of the second stage of parent training. Parent-mediated PRT can also be used as a third stage of parent training with sufficient training intensity to further improve language, social, and motor skills.

Navigating Multiple Challenges: Malnutrition and Nephrotoxic Drug Effects in a Non-verbal Child With Autism Spectrum Disorder Requiring Dialysis.

Acute kidney injury (AKI) is a common medication adverse event, particularly in patients with pre-existing medical conditions taking nephrotoxic medications. However, little is known about the differences in the risk of nephrotoxic medication-related complications in children with autism spectrum disorder (ASD) compared to the general pediatric population. A nine-year-old non-verbal boy with ASD was hospitalized for scrotal cellulitis requiring vancomycin and piperacillin/tazobactam due to a lack of clinical response to cephalosporins. His history is significant for being an extremely selective eater, and his appetite decreased over four months prior to presentation. Poorly controlled scrotal pain, despite acetaminophen use, was suspected based on his facial expressions and maternal assessment, especially considering his non-verbal status. Consequently, a non-steroidal anti-inflammatory drug was initiated. The hospital course was complicated by the development of a scrotal abscess, minimal enteral intake, hypoalbuminemia-induced intravascular dehydration, oliguria, and generalized edema. His creatinine increased to 5.11 mg/dL from 0.51 mg/dL despite early discontinuation of nephrotoxic medications and fluid resuscitation, which led to hemodialysis due to worsening AKI. Subsequently, urinary output and edema improved. Creatinine improved to <1 mg/dL with careful creatinine monitoring and concomitant furosemide and albumin infusion in the pediatric intensive care unit. Children with comorbidities, such as malnutrition, who require nephrotoxic medications, need extra attention. Implementing clinical decision support tools or quality improvement programs can promote the prevention of nephrotoxic medication exposure and decrease the incidence of AKI. An alert within an electronic health record system for multiple nephrotoxic drugs and daily multidisciplinary huddles during patient-centered rounds could help reduce and eliminate adverse events. In particular, for non-verbal patients or those with limited communication skills, such as children with ASD, rigorous and close monitoring of vital signs, physical condition, pain, medication intake, and lab results, in addition to a nephrotoxic medication screening and notification system, should be key to optimizing patient care.

Undiagnosed Autism Spectrum Disorder in a Child With Chronic Pain: A Case Report.

The literature acknowledges the presence of psychiatric comorbidities in pediatric chronic pain populations. Few studies have focused on comorbidity with autism spectrum disorders. We describe the case of a 10-year-old patient at the onset of his care by the chronic pain team. This boy had been experiencing refractory multifocal chronic pain for three years and had undergone multiple medical examinations that had not identified the cause of the pain or provided sufficient pain relief. During our consultations, the behavioral peculiarities (averted gaze, inhibition), the atypical description of this boy's pain (pain in the hair), and sensory peculiarities (intolerance to noise) led us to suspect an autism spectrum disorder. A multidisciplinary approach, including a thorough developmental history and evaluation by an autism resource center, confirmed this suspicion. The diagnosis of an underlying autism spectrum disorder allowed us to guide our management by integrating the specific sensory aspects of this boy. Concurrently, we facilitated the family's better understanding of the young boy's issues and addressed his social and communication difficulties. Through multidisciplinary care and the integration of these various aspects, our patient's clinical situation improved. Multidisciplinary management is essential in chronic pain teams.

Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α.

Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.

Activator of KAT3 histone acetyltransferase family ameliorates a neurodevelopmental disorder phenotype in the syntaxin 1A ablated mouse model.

Syntaxin-1A (stx1a) repression causes a neurodevelopmental disorder phenotype, low latent inhibition (LI) behavior, by disrupting 5-hydroxytryptaminergic (5-HTergic) systems. Herein, we discovered that lysine acetyltransferase (KAT) 3B increases stx1a neuronal transcription and TTK21, a KAT3 activator, induces stx1a transcription and 5-HT release in vitro. Furthermore, glucose-derived CSP-TTK21 could restore decreased stx1a expression, 5-HTergic systems in the brain, and low LI in stx1a (+/-) mice by crossing the blood-brain barrier, whereas the KAT3 inhibitor suppresses stx1a expression, 5-HTergic systems, and LI behaviors in wild-type mice. Finally, in wild-type and stx1a (-/-) mice treated with IKK inhibitors and CSP-TTK21, respectively, we show that KAT3 activator-induced LI improvement is a direct consequence of KAT3B-stx1a pathway, not a side effect. In conclusion, KAT3B can positively regulate stx1a transcription in neurons, and increasing neuronal stx1a expression and 5-HTergic systems by a KAT3 activator consequently improves the low LI behavior in the stx1a ablation mouse model.

The relationship between subjective difficulty in interoceptive processing and accuracy of heartbeat perception in autistic individuals.

Most autistic people experience difficulties in sensory processing, including interoceptive processing. For example, they often report subjective difficulties in the interoceptive processing of interoceptive input, such as difficulty in interpreting bodily signals, including hunger, thirst, and fatigue. However, whether these subjective interoceptive difficulties are from underlying problems in interoceptive accuracy remains unclear. This study investigated the relationship between subjective interoceptive difficulty and behavioral interoceptive accuracy in autistic adults and a control group. Subjective interoceptive accuracy was measured using an interoceptive sensitivity questionnaire, and behavioral interoceptive accuracy was measured using a heartbeat counting task. The results showed no significant relationship between subjective interoceptive difficulty and behavioral interoceptive accuracy in the autistic or control groups. This suggests that subjective interoceptive difficulty and behavioral interoceptive accuracy reflect different aspects of interoceptive processing. One possible interpretation is that autistic adults can identify individual local sensory inputs, such as heartbeats, however, they have difficulty integrating multiple inputs and recognizing internal body states such as hunger and fatigue.

Effect of Osteopathic Manipulation in an Autism Spectrum Child With Speech Impairment and Attention Deficit: A Case Report.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by challenges in communication, social interaction, and repetitive behaviors. Children with ASD often experience comorbidities such as speech impairment and attention deficit, which can significantly impact their quality of life and ability to engage in daily activities. This case report aims to investigate the potential benefits of osteopathic manipulation in addressing speech impairment and attention deficit in a child diagnosed with ASD. A four-year-old male child diagnosed with ASD, presenting with speech impairment and attention deficit, received a series of osteopathic manipulation sessions over a period of 12 weeks. The treatment protocol was tailored to address musculoskeletal dysfunctions, cranial restrictions, somatic dysfunctions, and digestive system dysfunctions identified through osteopathic assessment. Following the osteopathic manipulation sessions, improvements were observed in the child's speech fluency and attention span. The child demonstrated increased engagement in communication activities and showed enhanced focus during therapy sessions. Additionally, improvements were noted in the child's overall behavior and social interaction skills. This case report suggests that osteopathic manipulation may be a beneficial adjunctive therapy for children with ASD experiencing speech impairment and attention deficit. Further research with larger sample sizes and controlled study designs is warranted to validate these findings and elucidate the mechanisms underlying the observed improvements. Osteopathic manipulation holds promise as a non-invasive, holistic approach to addressing various aspects of ASD, contributing to the multidisciplinary management of this complex condition.

Effectiveness of multimodal participant recruitment in SPARK, a large, online longitudinal research study of autism.

Background: SPARK launched in 2016 to build a US cohort of autistic individuals and their family members. Enrollment includes online consent to share data and optional consent to provide saliva for genomic analysis. SPARK's recruitment strategies include social media and support of a nation-wide network of clinical sites. This study evaluates SPARK's recruitment strategies to enroll a core study population. Methods: Individuals who joined between January 31, 2018, and May 29, 2019 were included in the analysis. Data include sociodemographic characteristics, clinical site referral, the website URL used to join, how the participant heard about SPARK, enrollment completion (online registration, study consents, and returning saliva sample), and completion of the baseline questionnaire. Logistic regressions were performed to evaluate the odds of core participant status (completing enrollment and baseline questionnaire) by recruitment strategy. Results: In total, 31,715 individuals joined during the study period, including 40% through a clinical site. Overall, 88% completed online registration, 46% returned saliva, and 38% were core participants. Those referred by a clinical site were almost twice as likely to be core participants. Those who directly visited the SPARK website or performed a Google search were more likely to be core participants than those who joined through social media. Discussion: Being a core participant may be associated with the "personal" connection and support provided by a clinical site and/or site staff, as well as greater motivation to seek research opportunities. Findings from this study underscore the value of adopting a multimodal recruitment approach that combines social media and a physical presence.

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates.

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was partially reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals' USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions.

The 'PSILAUT' protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin.

BACKGROUND: The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function. We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin - principally, but not exclusively, 5HT2A receptor pathways-function differently in autistic and non-autistic adults. METHODS: The 'PSILAUT' "shiftability" study is a case-control study autistic and non-autistic adults. How neural responses 'shift' in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order. RESULTS: This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function. CONCLUSIONS: This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches. TRIAL REGISTRATION: NCT05651126.