Gastrointestinal (GI) pathology is prevalent in autism spectrum disorder (ASD), with ASD-associated enterocolitis characterized as a distinct inflammatory condition. In this Synchrony 2024 presentation, Arthur Krigsman, MD, evaluates treatment outcomes in 143 ASD children (aged 2–18 years) with biopsy-confirmed enterocolitis. Ileocolonoscopy revealed chronic inflammation (e.g., lymphoid nodular hyperplasia, colitis) in 92% of cases, distinguishing it from classic inflammatory bowel diseases. Patients received anti-inflammatory therapy (e.g., sulfasalazine, mesalamine) and dietary interventions, resulting in significant GI symptom improvement (e.g., reduced diarrhea, abdominal pain) in 85% of cases within 6–12 months (p < 0.01), as assessed by clinical follow-up and parental reports. Concurrently, 67% of responders demonstrated behavioral enhancements, including decreased irritability and improved social engagement, measured by the Autism Treatment Evaluation Checklist (ATEC) (mean score reduction: 35 ± 8 to 22 ± 6, p < 0.05). Histological follow-up in a subset (n = 30) confirmed reduced mucosal inflammation post-treatment (p < 0.05), while non-responders (15%) showed persistent symptoms, often tied to treatment non-adherence. These findings suggest that addressing enterocolitis in ASD may yield dual GI and neurobehavioral benefits, supporting a gut-brain axis hypothesis. Prospective, controlled trials are warranted to validate these observations and standardize therapeutic protocols.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) are neuroimmune disorders characterized by sudden-onset obsessive-compulsive disorder (OCD), anxiety, and motor abnormalities, often following infectious triggers. In this 2024 update delivered at the Synchrony symposium, Jennifer Frankovich, MD, MS, presents advancements in understanding the pathophysiology, clinical management, and long-term outcomes of PANS/PANDAS, drawing from the Stanford Immune Behavioral Health Clinic’s cohort of 251 patients (2012–2024). Data reveal a 28.3% incidence of subsequent autoimmune conditions by age 14 (p < 0.001), with enthesitis-related arthritis (56% Achilles enthesitis) and inflammatory back pain (64%) predominant, suggesting a systemic inflammatory overlap. Immunological findings during flares show elevated striatal cholinergic interneuron antibody binding (p < 0.05) and increased blood-brain barrier permeability (p < 0.01), both normalizing in remission. Treatment with immunomodulatory therapies (e.g., IVIG, naproxen) reduced flare frequency by 60% in 50 patients over 24 months (p < 0.01), with OCD severity decreasing (Pediatric OCD Rating Scale: 28 ± 5 to 12 ± 3, p < 0.001). The PANS Illuminate project integrates multi-omics (transcriptomics, proteomics) to identify remission predictors, while genetic analyses highlight HLA associations with immune dysregulation. Wearable technology tracks autonomic responses (e.g., heart rate variability), revealing flare signatures. These findings underscore a gut-brain-immune axis in PANS/PANDAS, advocating for rheumatologic-psychiatric collaboration.

TCF7L2-related neurodevelopmental disorder (TRND) is an autosomal dominant condition arising from de novo variants in the TCF7L2 gene, a critical transcription factor in the Wnt signaling pathway, implicated in neurodevelopment and cellular regulation. In this presentation at Synchrony 2024, Sally Nijim from Every Cure elucidates the clinical phenotype and therapeutic potential of TRND, drawing from a cohort of 11 genetically confirmed cases. Patients exhibit a spectrum of neurodevelopmental challenges, including developmental delays (100%), autism spectrum disorder (36%), mild to moderate intellectual disability (45%), and myopia (50%), alongside variable dysmorphic features and orthopedic anomalies. Longitudinal data indicate that while early motor and speech delays are universal, intellectual outcomes range from normal to impaired, suggesting variable expressivity. Molecular analyses reveal disrupted Wnt signaling due to loss-of-function and missense mutations clustering near the high-mobility group box domain, impairing transcriptional regulation critical for brain development. Leveraging Every Cure’s drug repurposing platform, preliminary in silico screening identified candidate compounds, including folinic acid, which showed modest symptom improvement in a pilot study of 5 TRND patients with autism features (ATEC score reduction: 10 ± 3, p < 0.05). These findings highlight TRND’s heterogeneous presentation and propose a framework for precision therapeutics, with ongoing trials exploring Wnt pathway modulators to mitigate neurodevelopmental deficits.

Despite recent advances in understanding the connection between the gut microbiota and the brain, there remains a wide knowledge gap in how gut inflammation impacts brain development. Microbiota-derived metabolite signaling from the gut to the brain is required for normal development of microglia, the brain’s resident immune cells. Disruption of the microbiota-brain communication has been linked to impaired behaviours and Autism Spectrum Disorder. We hypothesized that intestinal inflammation in early life would negatively affect neurodevelopment through dysregulation of microbiota communication to brain microglia. To test this hypothesis, we developed a novel pediatric model of Inflammatory bowel disease (IBD). IBD is an incurable condition affecting millions of people worldwide, characterized by chronic intestinal inflammation, and has comorbid symptoms of anxiety, depression and cognitive impairment. Significantly, 25% of IBD patients are diagnosed during childhood and children with ASD are more likely to develop IBD. We developed a chemical model of pediatric chronic IBD by treating juvenile mice with dextran sodium sulfate (DSS) in drinking water. DSS-treated mice displayed increased intestinal inflammation, altered microbiota and decreases in circulating metabolites. We also found that alterations in gut microbiota have long-term impacts on female microglia and male sex-specific behaviours and testosterone regulation, consistent with delayed puberty observed in male IBD patients. Our research expands our understanding of microbiota-microglia communication underlying development. This is an exciting target for personalized medicine as microbiome manipulations could be feasible for early intervention to reverse these deficits.

Folate metabolism plays a critical role in neurodevelopment, with disruptions linked to autism spectrum disorder (ASD) and cerebral folate deficiency (CFD). In this Synchrony 2024 presentation, Edward Quadros, PhD, explores the metabolic basis for levofolinate (5-methyltetrahydrofolate) treatment in ASD, emphasizing folate receptor alpha autoantibodies (FRAA) as a key pathogenic factor. In a study of 102 ASD children (aged 3–12 years), 63% tested positive for FRAA, impairing folate transport across the blood-brain barrier and reducing cerebrospinal fluid (CSF) folate levels (mean: 19 ± 5 nM vs. 60 ± 10 nM in controls, p < 0.001). Levofolinate calcium, administered orally at 1–2 mg/kg/day, bypasses FRAA blockade by utilizing alternative uptake mechanisms, restoring CSF folate in 70% of treated patients (n = 40, mean post-treatment: 55 ± 8 nM, p < 0.01) within 6 months. Clinically, 58% of responders showed improved verbal communication and reduced irritability (Aberrant Behavior Checklist scores decreased: 32 ± 7 to 20 ± 5, p < 0.05), correlating with normalized CSF folate and methionine levels. Non-responders (42%) exhibited persistent FRAA titers or comorbidities (e.g., mitochondrial dysfunction), suggesting heterogeneity in treatment efficacy. Quadros highlights levofolinate’s stability and bioavailability over folinic acid, proposing it as a targeted intervention for FRAA-positive ASD subsets. These findings underscore a metabolic-neurobehavioral link in ASD and advocate for FRAA screening to guide therapy, with ongoing trials needed to optimize dosing and assess long-term outcomes.

Dr. Shannon Rose, an Associate Professor at the Department of Health Promotion and Disease Prevention at the University of Tennessee, presented her research on autoantibodies and cytokine biomarker discovery in patients with autism and neurodevelopmental disorders. The goal of their research was to identify specific patterns of autoantibodies and immune markers associated with different subtypes of NDDs. Autoantibody analyses of 250 antigens and 44 cytokines are conducted in plasma and two autoantibodies and a cytokine called eotaxin have been narrowed down to play an important role. The important cytokine they found, eotaxin, has been shown to be elevated in hospitalized COVID patients. The study underscores the insights into the role of the immune system in ASD and other NDDs.

Dr. Naveen Nagarajan presented his research on calcium transients in microglia regulating autism specific behaviors. The neural network and microglia cell ecosystem are often in communication to attain optimal brain function and health. The influence of Hoxb8 microglia cells on neurons in patients with ASD and OCD is not well understood. Dr. Nagarajan shows how artificially induced ASD-specific repetitive behavior in mice can trigger Hoxb8-linenage microglia to showcase calcium transients. The Hoxb8 microglia increase their calcium levels when grooming occurs and is sustained until the cessation of grooming behavior. The study results showcase how grooming behaviors can elicit morphological and function programming of microglia to endow them with an acute calcium-dependent response program and the capacity to cross talk with the neighboring neurons. A loss of function mutation for the Hoxb8 microglia can disrupt the calcium regulating capacity and thereby cause a loss of control in regulating grooming behavior. The studies findings underscore how Hoxb8 microglia is a key mediator of neuronal-microglia cross-talk via behavior locked calcium regulation. This calcium regulation can serve as a node for therapeutic interventions in ASD and OCD behaviors.

Autism spectrum disorder (ASD) exhibits significant sex-dependent differences in prevalence and symptomatology, yet the underlying neurobiological mechanisms remain poorly understood. This presentation investigates the role of dopamine-driven serotonin plasticity in an ASD model, focusing on sex-specific neurochemical alterations. Using preclinical models, we demonstrate that dopamine-serotonin interactions in key brain regions, such as the striatum and prefrontal cortex, exhibit distinct patterns in males and females, contributing to divergent behavioral phenotypes associated with ASD. Our findings reveal that dopamine modulates serotonin transporter function and synaptic plasticity differently across sexes, potentially explaining higher ASD prevalence in males and variations in social, repetitive, and sensory behaviors. Pharmacological and genetic interventions targeting these neurotransmitter systems show promise in normalizing aberrant plasticity, offering insights into sex-tailored therapeutic strategies. These results highlight the critical need for sex-specific approaches in ASD research and treatment, advancing our understanding of its neurobiological heterogeneity and informing precision medicine for affected individuals.

Dr. Adam Naples from Yale School of Medicine presented his research on characterizing dynamics of auditory sensitivities. Auditory sensitivity is a common and disruptive symptom for individuals with autism spectrum disorder (ASD), with 70% reporting heightened sensitivity that intensifies with stress and anxiety. While these sensitivities significantly impact daily life, their underlying mechanisms are poorly understood, and effective treatments are lacking. Self-reports suggest that auditory sensitivity fluctuates in response to stress, indicating that it may reflect a variable perception rather than a fixed over- or under-sensitivity. Here, the study presents pioneering research to characterize this variability in auditory sensitivity through two novel approaches. First, the study co-registers EEG and pupil diameter to capture real-time interactions between arousal and brain responses to sound stimuli, revealing moment-to-moment changes in auditory processing. Second, the study utilizes an innovative online psychophysics task to track day-to-day shifts in auditory sensitivity. This combined data provides the first detailed profile of how auditory perception varies within individuals with ASD, linking sensory experiences to the dynamic interplay of brain activity and arousal.

Dwight German, PhD, from University of Texas Southwestern Medical Center, presented research on a promising blood biomarker panel for diagnosing autism spectrum disorder (ASD) in boys, achieving 83% sensitivity and 85% specificity. His study analyzed serum samples from 76 boys with ASD and 78 typically developing (TD) boys, using proteomic analysis to examine over 1,100 proteins. A set of 12 proteins, identified through machine learning, showed significant differences between ASD and TD groups, with an area under the curve (AUC) of 87% for identifying ASD. Four of these proteins correlated with ASD severity, suggesting potential use in both diagnosis and severity assessment. Ongoing validation with new samples aims to confirm these proteins as reliable biomarkers for ASD in boys.

In all the CNV mice we identified changes in mitochondrial bioenergetics in the hippocampus, startle habituation deficits, cognitive deficits, and reduced social interactions. In preliminary studies, chronic treatment with the mild mitochondrial complex I inhibitor CP2 known for its ability to increase mitochondrial biogenesis, reversed behavioral deficits in mice with 4 copies of Gldc. Our long-term plan is to identify neuronal population or ensemble activities in prefrontal cortex which might be useful as biomarkers to evaluate novel pharmacological treatment strategies with drugs that may be repurposed for NDD treatment, including the PGC1α activator, bezafibrate, which increases mitochondrial biogenesis, and the mitochondrial complex I inhibitor metformin.

Dr. Adrien Eshraghi, from the University of Miami, presented research on the role of peroxynitrite-induced redox signaling in autism spectrum disorder (ASD), focusing on oxidative stress and its impact on neuronal health. His study highlights peroxynitrite as a potent oxidant that modifies proteins, such as Heat shock protein 90 (Hsp90), through nitration, leading to neuronal death and behavioral abnormalities associated with ASD. Using the Cntnap2 knock-out rat model, his team observed elevated levels of nitrated proteins and neuronal nitric oxide synthase (nNOS), implicating excessive peroxynitrite production in ASD pathology. Notably, treatment with an NOS inhibitor and a peroxynitrite scavenger reduced nitrated protein levels and improved behavioral symptoms in these models. This research suggests that targeting redox signaling could be a promising therapeutic strategy to alleviate ASD symptoms, potentially improving the quality of life for individuals with ASD and their families.

To this end, we present a library of nanoscale near-infrared fluorescent nanosensors for dopamine, serotonin, and oxytocin, where the nanosensors are developed from polymers pinned to the surface of single wall carbon nanotubes (SWNT) in which the surface-adsorbed polymer is the recognition moiety and the carbon nanotube the fluorescence transduction element. Excitonic transitions in functionalized SWNT yield up to ΔF/F = 4500% near-infrared fluorescence emission in the presence of dopamine (Beyene et al. Science Advances 2019), ΔF/F = 200% for serotonin (Jeong et al. Science Advances 2019), and ΔF/F = 120% for oxytocin (Mun et al. PNAS 2024). We next demonstrate imaging of evoked dopamine release in acute striatal slices, and show altered dopamine reuptake kinetics when brain tissue is exposed to dopamine receptor agonist and antagonist drugs. We characterize our findings in the context of their utility for high spatial and temporal neuromodulator imaging in the brain to study non-reproductive social behavior in voles, with implications for understanding neurochemical signaling in social autism spectrum disorders.

Dr. Robert Naviaux, from UCSD School of Medicine, presented research on mitochondrial and metabolic development in autism spectrum disorder (ASD), focusing on an abnormal persistence of newborn-like excitatory signaling in children with ASD. Typically, GABA signaling in the brain shifts from excitatory at birth to inhibitory by age 1-2, a process that many children with ASD do not undergo, resulting in an imbalance between excitatory and inhibitory (E-I) signaling. Naviaux’s study found that children with ASD retain this newborn excitatory purine network, making them hypersensitive to ATP signaling and environmental stimuli. This metabolic anomaly underscores the potential for antipurinergic drugs, such as suramin, to restore normal E-I balance by addressing ATP hypersensitivity, thereby offering a targeted approach to alleviate core ASD symptoms. Naviaux highlighted the unique metabolic roles of mitochondria, which vary across tissues and are central to developmental changes in signaling that influence neurodevelopment and behavior.

Dr. Susan Daniels the National Autism Coordinator in the U.S. The Department of Health and Human Services presented about the role of federal autism coordination in shaping national autism research priorities. Autism has had a broad array of research, services and policy issues throughout the years which is the main topic the Office of National Autism Coordination and other entities are tackling. There are multiple stakeholders in federal autism coordination aside from those individuals either diagnosed with ASD or that have family with ASD. Some of these include clinicians/researchers, Congress, state and local agencies, and the White House. Federal departments such as the CDC, NIH, FEMA, USGS are all partnering with them to coordinate activities related to autism. An autism collaboration, accountability, research, education and services (CARES act) was authorized in 2019. The goal of the act was to foster communication/collaboration among federal agencies and support autism research, services, and policies.

Expert discussion panel with Gopala Anumachipalli PhD, Assistant Professor, Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Laura Gwilliams PhD, Assistant Professor of Psychology and, by courtesy, of Linguistics, Stanford Psychology, Wu Tsai Neurosciences Institute and Stanford Data Science, Stanford University, CA

In this Synchrony 2024 session a panel of physicians with field expertise from neurology, immunology, gastroenterology and other fields reviewed and discussed complex cases of autism and medical comorbidities submitted by members of the audience