The BRAIN Foundation

Synchrony Symposium 2023 Highlights

Synchrony 2023 was an in-person event, held this year on Oct 20-22 at the Asilomar Conference Grounds, Pacific Grove, California.

Synchrony covered many of the most cutting-edge topics in basic science and clinical research, with the speaker line up featuring leading academics, clinical practitioners, pharmaceutical industry leaders, venture partners and emerging biotech companies.

Some of the highlights included:

TALK BY A NOBEL LAUREATE – Mario Capecchi PhD, shared his amazing life’s journey – from a homeless street urchin at the age of 4 in wartime Italy to winning the Nobel Prize Winner in Medicine/Physiology in 2007.

KEYNOTE BY David Fajgenbaum, MD, MBA, MSc, co-founder of Every Cure and author of the best-seller ‘Chasing My Cure’. In 2010 David was diagnosed with Castleman Disease, which he was told was incurable. He nearly died five times, yet he didn’t give up – using his own samples, records and research he eventually discovered a new use for an existing drug. Now in remission for 8 years, he is on a mission to scale his approach and find cures for diseases that currently have none.

CLINICAL PEARLS SESSION and CME credits for physicians

CLINICAL & RESEARCH ROUNDTABLES – topics ranging from repurposed drugs to Transcranial Magnetic Stimulation, from biomarkers to organiods

ACTION PLAN – to get to standard of care for seizure management & neuropsychiatric exacerbations in autism

INDUSTRY TRACK – biotech and venture partners presented updates on therapeutics under development for FDAapproval

RESEARCHERS COURSE designed to inform, inspire and offer a springboard for young and upcoming researchers

MENTOR-MENTEE SESSIONS to foster cross-field interaction with leading experts, clinicians and researchers

Recordings of Synchrony 2023 presentations now available to watch here 🎥

▶️ Update on the clinical trials of microbiota transplant therapy MTT for autism
▶️ Update on clinical trials of photobiomodulation light therapy for autism
▶️ Update on transcranial magnetic stimulation TMS for autism
▶️ Talk on exploring heterogeneity to advance precision medicine in autism
▶️ Keynote by David Fajgenbaum, MD, MBA, MSc, the author of the best-seller ‘Chasing My Cure’

And many others!

NEW: Earn CME credits by watching Synchrony videos!

We are delighted to now share The Pathways link for the video library (enduring content). Learners who have viewed the videos can use this link to launch into a separate portal (the accredited activity) to reflect on what they learned to earn credits. With this solution, they can use this link multiple times (to reflect on all the videos and various concepts that inspired their learning!).

This experience offers pathways to continuing education opportunities Dentists, Nurses, Nurse Practitioners, Pharmacists, Physician Associates, Physicians, Licensed Clinical Social Workers and other members of the healthcare team.

And many more 🎥

Synchrony 2023 Roundtables

CHAIRS: John Gaitanis MD, Director of Child Neurology, Brown Medical School, Pediatric Neurologist, Epileptologist, Hasbro Children’s Hospital and Richard Frye MD, PhD
Behavioral Child Neurologist, Neurodevelopmental Precision Medicine

PANEL: Jennifer Frankovich MD MS, Clinical Professor, Dept of Pediatrics, Stanford Children’s Health, Lucile Packard Children’s Hospital, Stanford University; Harumi Jyonouchi MD, Allergist- Immunologist, St. Peter’s University Hospital; Arthur Krigsman MD, Pediatric Gastroenterologist, Private Practice, New York

COMING SOON

CHAIR: Lindsay M. Oberman PhD, Director, Developmental Clinical Neurophysiology and Neurostimulation Research Program, National Institute of Mental Health, NIH

PANEL: Kim Hollingsworth Taylor, CEO, Clearly Present Foundation, Peter Enticott, PhD, Associate Dean, Research, Faculty of Health, Deakin University, Manpreet Kaur Singh, MD, MS, Associate Professor of Psychiatry and Behavioral Sciences, Stanford University, Nolan Williams, MD, Associate Professor of Psychiatry and Behavioral Sciences, Director, Stanford Interventional Psychiatry Clinical Research, Director, Stanford Brain Stimulation Laboratory, Co-Founder, Magnus Medical Inc., Ernest Pedapati, MD, MS, FAAP, Assistant Professor, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Isabella (Crys) Borsellino, Patient Experience, Student, UCSD, Developmental Psychology, Melissa Kirkovski, PhD, Research Fellow – iHES, College of Sport, Health, & Engineering, Victoria University

COMING SOON

CHAIR: Alysson Muotri, PhD, Director, Stem Cell Program, UCSD, Professor, Departments of Pediatrics and Cellular & Molecular Medicine, UC, San Diego

PANEL: Giorgia Quadrato PhD, Assistant Professor of Stem Cell, Biology, Keck School of Medicine, University of Southern California; Alex Shcheglovitov, PhD, Assistant Professor, Neurobiology, University of Utah; Kristen Brennand PhD, Elizabeth Mears and House Jameson Professor of Psychiatry and Professor of Genetics, Yale University School of Medicine

ALEX SHCHEGLOVITOV, PHD
TITLE: Single neural rosette-derived organoids as a tool for modeling human brain development and disease
ABSTRACT: Human brain development is unique, and we still have much to learn about the cellular and molecular mechanisms that underlie the specification and function of various cell types in the human brain. Moreover, it remains largely unknown how different cells and mechanisms are affected in neurodevelopmental disorders. We recently developed a new method for generating human telencephalic organoids from stem cell-derived single neural rosettes (SNR) and investigated the properties of cells in these organoids in health and disease (Wang, Chiola, et al., Nat Communication 2022). During my presentation, I will elaborate on our methodologies for generating SNR-derived organoids and discuss how we use these organoids for modeling neurodevelopmental disorders caused by specific genetic abnormalities.

KRISTIN BRENNAND, PHD
TITLE: Studying the genomics of brain disorders using stem cells
ABSTRACT: Each person’s distinct genetics and environment predispose them to some phenotypes and confers resilience to others. How do all the individual variants across the genetic landscape combine to yield larger phenotypic impacts in aggregate? How does genetic variation govern the penetrance of deleterious mutations, variable expressivity, and pleiotropy? What is the role of the environment across the lifespan? Understanding how these elements interact will advance our knowledge of human development, aging, health, and disease. Our functional genomics approach integrates human induced pluripotent stem cell models with CRISPR-based genome engineering to introduce and reverse genetic variation, yielding precision models that can be combined with genetic and pharmacological screens. With this approach, we demonstrated that diverse risk variants share downstream convergent impacts, and that when added together, their combinatorial perturbations yield novel non-additive outcomes that cannot yet be predicted by individual manipulations alone. We seek to understand the genetic regulation of phenotype, and how it is impacted by developmental, cellular, and environmental contexts. Thus, rather than just characterize the impact of trait-associated variants, we seek to uncover modifiers that alter it. For example, we study how genotype-phenotype relationships vary across people and dynamic conditions. Our goal is to decipher the frameworks that buffer genetic risk, in order to confer biological resilience and promote healthy development. We are uniquely positioned to answer critical questions: How does the environment impact genetic regulation? Why are there marked sex effects across many human traits and diseases? What are the molecular mechanisms of resilience, whereby individuals with high genetic risk show no clinical manifestation of disease? Understanding the basic biology governing the complex interplay between genetic variants and the environment will springboard the development of novel, personalized approaches to improve health and prevent disease.

CHAIR: Sarkis MazmanianPhD, Soux Professor, Caltech

PANEL: James Adams,PhD, President’s Professor, Arizona State University; Stephen Walker, Professor, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine

COMING SOON
PANEL: Karen Parker, Professor and Associate Chair of the Department of Psychiatry and Behavioral Sciences, Stanford University; John Slattery, Chief Executive Officer, BIORosa technologies
COMING SOON
CHAIR: David C. Fajgenbaum MD, MBA, MSc, FCPP, Associate Professor, University of Pennsylvania

PANEL: Richard Frye MD, PhD Behavioral Child Neurologist, Neurodevelopmental Precision Medicine, Arthur Krigsman MD, Pediatric Gastroenterologist, Private Practice, New York, Harumi Jyonouchi MD, Allergist- Immunologist, St. Peter’s University Hospital, John Gaitanis MD, Director of Child Neurology, Brown Medical School, Pediatric Neurologist, Epileptologist, Hasbro Children’s Hospital; Ben Marlow MD, Consultant Paediatrician, Colchester General Hospital

COMING SOON
Synchrony was amazing. The talks were incredibly inspiring, and my students and I have absolutely benefited from attending Synchrony.
Crystal Engineer PhD, University of Texas at Dallas

Synchrony 2023 Clinical Pearls from Specialists

JOHN GAITANIS, MD
Director of Child Neurology, Brown Medical School, Pediatric Neurologist, Epileptologist, Hasbro Children’s Hospital
Autism epilepsy and Aggression: The Second Regression Syndrome

A case is presented of a 17 year old boy with responsive nerve stimulation (RNS) who underwent a treatment course of IVIG for severe OCD and Tourette’s syndrome. The RNS leads were placed in the centromedian nucleus of the thalamus bilaterally. The effect of IVIG treatment on RNS detections is reviewed and compared to his treatment response.

JENNIFER FRANKOVICH, MD MS
Clinical Professor, Lucile Packard Children’s Hospital, Stanford University
Invasive Brain Monitoring in a case of PANDAS treated with IVIG
COMING SOON
RICHARD FRYE, MD PHD
Behavioral Child Neurologist, Neurodevelopmental Precision Medicine
Follow the Data: Finding The Pearls in Research
Answering a scientific question is difficult and experiments do not usually turn out as predicted. To make breakthroughs in science we must follow the data towards the story it is trying to tell us rather than following our a priori biases. I provide an example of my work on mitochondrial dysfunction in Autism Spectrum Disorder which provided unexpected results leading to a potential new understanding of the role of mitochondrial function in neurodevelopmental disorders.

HARUMI JYONOUCHI, MD
Allergist- Immunologist, St. Peter’s University Hospital
Autism Spectrum Disorder Inflammatory Subtype and Long COVID

In the analysis of innate immunity in autism spectrum disorders (ASD) subjects, we recognized noticeable changes in innate immunity in those suffering from long-term sequelae of coronavirus disease-2019 (COVID-19), now referred as to long COVID, along with overlapping behavioral symptoms. The current study addresses whether there exist any denominating changes in innate immunity in ASD and non-ASD subjects suffering from long COVID and how these changes are associated with neuropsychiatric symptoms. As for monocyte cytokine profiles, both ASD and non-ASD subjects with long COVID revealed higher production of inflammatory (TNF-α, IL-1ß, IL-12p40, and IL-23) and counter-regulatory (IL-10 and sTNFRII) cytokines under cultures mimicking viral stimuli, than non-ASD controls. These changes in monocyte cytokine profies predict subsequent Th1/Th17 skewed T-cell responses. Non-ASD/long COVID patients revealed high Aberrant Behavior Checklist (ABC) scores in the subscales of irritability and hyperactivity: these changes were also seen in ASD/long COVID subjects. ASD/non-long COVID patients tended to have higher scores in the ABC subscale of stereotypy. Long COVID appears to have significant effects on behavioral symptoms in both ASD and non-ASD subjects, which may be associated with inflammation skewed changes in innate immunity. Partly funded by the Brain Foundation.
synchrony symposium on latest autism research and science attracts lead world experts in the field
synchrony symposium on latest autism research and science attracts lead world experts in the field
synchrony symposium on latest autism research and science attracts lead world experts in the field
synchrony conference autism research event with top experts in ASD
synchrony symposium on latest autism research and science attracts lead world experts in the field
synchrony symposium on latest autism research and science attracts lead world experts in the field

roundtable
discussions

clinical
pearls

researchers’
‘mini’ course

one-on-one
mentoring

research
presentations

industry
updates

Selected panel of Brain Principal Investigator Talks

CHANDRA MENENDEZ, PHD
Postdoctoral Fellow, University of Oklahoma
Infectious Sequelae Associated Anti-Neuronal and Anti-Microbial
Autoantibodies in Autism Spectrum Disorder and PANDAS: Unraveling
Neuroimmune Mechanisms and Comorbidities
The detection of brain-targeted autoantibodies in children with Autism Spectrum Disorder (ASD) opens the inquiry into autoimmune encephalopathy (AE). Emerging evidence and effectiveness of therapies like Intravenous Immunoglobulin (IVIG) indicate potential immune dysfunction in a subset of children with ASD.

Given the overlapping neuropsychiatric symptoms and the presence of anti-neuronal autoantibodies in both ASD and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS), our study explored shared mechanisms to identify AE PANDAS subtypes in ASD.

Our investigation into the cross-reactive anti-neuronal and anti-microbial autoantibody responses associated with streptococcal and other childhood infections in ASD and PANDAS revealed that sera from both groups exhibited autoreactive anti-neuronal IgG against dopamine receptors, brain tubulin, and activated calcium/calmodulin-dependent protein kinase II (CaMKII) in human neuronal cells. The autoantibody-mediated dopamine receptor and CaMKII activation was mitigated by absorbing ASD and PANDAS sera with microbial polysaccharides or neuronal antigens. Abnormal antibody responses to streptococcal carbohydrate N-acetyl-beta-D-glucosamine were elevated in
both PANDAS and ASD subsets, alongside observed deficiencies in other microbial polysaccharide antibodies, defining potential immunoglobulin deficiencies and cross-reactivities in these diseases.

Further, we demonstrated shared gene expression signatures and enriched pathways mediated by ASD and PANDAS sera, suggesting similarities and differences in these neurological and psychiatric disorders, and the role of infection. Our findings suggest that molecular mimicry and immune cross-reactivity between host and pathogen contribute to the pathogenesis of infection-mediated autoimmune sequelae, resulting in
the emergence of tic and OCD behaviors in ASD and PANDAS.

STEVE WALKER, PHD
Professor, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine
Developing an evidence-based framework to quantify pathologic status in ASD-associated enterocolitis
This talk provided a methodological outline and progress update on our Brain Foundation-funded project to evaluate colonic tissue from children with ASD-associated enterocolitis and non-ASD controls. The goal of the project is to determine whether the histologic findings in GI tissue from ASD children with enterocolitis is consistent with an IBD-like pathology seen with Crohn’s disease and ulcerative colitis in typically developing children. In this brief update we will describe the study design, the use of AI-assisted identification and quantification of stained cells, and initial findings from four groups of ASD and non-ASD patient samples.

JENNIFER FRANKOVICH, MD MS
Clinical Professor, Lucile Packard Children’s Hospital, Stanford University
Talk title: coming soon

COMING SOON

Synchrony 2023 Research Talks

NAVEEN NAGARAJAN, PHD
Postdoctoral scientist, University of Utah
Calcium transients in microglia drive repetitive form of autistic behaviors
The disruption of Hoxb8 in mice or genetic ablation of the Hoxb8 cell lineage, a subset of microglia, is causative for chronic anxiety and pathological over-grooming, a symptomatic phenotype found in Autistic children and patients. Further, optogenetic stimulation of Hoxb8 microglia in specific regions of the brain induces elevated anxiety, Autism specific repetitive grooming or both. Conversely, do microglia in specific regions of the brain respond to induced grooming or anxiety type of Autistic phenotype in mice? Herein, using fluorescent based calcium reporters, detected by in vivo microendoscopic imaging with single cell resolution, we show that induction of repetitive grooming or anxiety based Autistic phenotype in mice does indeed drive production of calcium transients within microglia in specific regions of the brain. In response to induced grooming, Hoxb8 microglia within the DMS and mPFC exhibit calcium transients reflective of the Autism-specific repetitive grooming pattern. On the other hand, induction of anxiety via the visual cortex results in generating calcium transients in Hoxb8 microglia residing within the vCA1 region of the hippocampus. Multiple grooming bouts induce multiple calcium transients locked to the repetitive grooming pattern. Microglial induced calcium transients within either the DMS or mPFC in response to induced grooming are not produced in Hoxb8 mutant mice! This defect appears to result from the inability of Hoxb8 mutant microglia to control their intracellular levels of free calcium concentrations. This failure may also account for Hoxb8 mutant mice exhibiting chronic anxiety and pathological Autistic-specific repetitive overgrooming. The results of induced calcium transient in normal mice, combined with the optogenetic results, provides the means for interrogating microglial/neuronal cross communication from opposite poles, from Hoxb8 microglia-optogenetic stimulation to generate autism-specific behavioral outputs and from the induced autistic behaviors in mice back to individual microglial responses with the production of calcium transients.

ADRIEN ESHRAGI, MD MSc FACS
Professor of Otolaryngology, Neurosurgery, Pediatrics and Biomedical Engineering, University of Miami
Augmenting mGluR5 activity ameliorates behavior deficits in a transgenic rat model of Autism Spectrum Disorder

COMING SOON
LIOR BRIMBERG, PHD
Assistant Professor, Feinstein Institutes for Medical Research
Captopril, an Angiotensin-Converting Enzyme (ACE) Inhibitor, attenuates Microglial Activation and Improves Social Behavior in a Mouse Model of Autism Spectrum Disorder
As the primary brain immune cells, microglia are critical for maintaining a healthy brain and are recognized as important sculptors of neuronal development. Exposure in utero to maternal brain reactive antibodies may perturb microglia programing leading to neurodevelopmental disorder. We have shown that exposure in utero to anti-Caspr2 IgG (originally cloned from a mother of a child with Autism Spectrum Disorder, ASD) leads to ASD like phenotypes in male but not female offspring. In this model, mice exposed in utero to anti-Caspr2 IgG (“Anti-Caspr2”) show increase neuroinflammation in the hippocampus as measured by microPET, compared to mice exposed in utero to control IgG (“Control”). Our studies confirm increase in microglial reactivity with altered synaptic pruning in the hippocampus of adult Anti-Caspr2 male mice compared to Control. Treatment with ACE inhibitors, Captopril, (BBB-permeable), but not enalapril (BBB-impermeable), or saline suppress microglial reactivity, ameliorate the synaptic pruning and social deficit in Anti-Caspr2 males, compared to Anti-Caspr2 males treated with enalapril or vehicle. scRNA-sequencing of hippocampal microglia from Anti-Caspr2 and Control mice treated with saline or captopril revealed a subtype of microglia responsive to captopril in Anti-Caspr2 likely modulating neuronal-microglial interaction. Overall, our work suggests potential benefits of using microglia-modulating therapeutics in ASD.
JESSICA HELLINGS, PHD
Professor of Psychiatry, University of Missouri-Kansas City
Low Dose Loxapine Resembles an Atypical Antipsychotic with a More Favorable Metabolic Profile Warranting Clinical Trials in ASD
Background: Only risperidone and aripiprazole are FDA-approved for irritability in autism spectrum disorders (ASD). Both cause serious metabolic side effects. Other treatment options are urgently needed.

Objectives/Methods: Loxapine 5-15mg daily resembles an atypical antipsychotic on PET studies. Preliminary evidence suggests a superior metabolic profile. We synthesize published evidence.

Results: PET scan studies demonstrated low dose loxapine blocks 5-HT2 and D2 receptors equipotently in vivo; loxapine action resembled atypical antipsychotic actions on dopamine and acetylcholine release in the nucleus accumbens and prefrontal cortex. Loxapine but NOT other antipsychotics produced neural sprouting in human pluripotent stem cells. A prospective open trial of low dose loxapine add-on for irritability in ASD found significant improvement, little or no weight gain, and increases in serum BDNF. A retrospective study of long-term low- dose loxapine in ASD found rates of EPS and TD lower than expected for classical antipsychotics. A retrospective chart review of loxapine 5-10mg daily add-on followed by atypical antipsychotic taper found mean 17-month weight LOSS of 5.7kg, mean BMI REDUCTION of 1.9, and mean triglyceride REDUCTION of 33.7mg/dl (p=.02). One subject discontinued insulin; 2 were tapered off metformin by endocrinologists.

Conclusions: Preliminary evidence justifies immediate pursuit of clinical trials of loxapine in ASD.

EVDOKIA ANAGNOSTOU, PHD
Assistant Director, Bloorview Research Institute, Child Neurologist and Senior Clinician Scientist, Holland Bloorview Kids Rehabilitation Hospital, Associate Professor, Department of Pediatrics, University of Toronto
Exploring heterogeneity in neurodevelopment to advance precision health in Autism and related conditions
COMING SOON
CRYSTAL ENGINEER PHD
Assistant Professor, University of Texas
Vagus nerve stimulation as a potential adjuvant to behavioral therapy for autism and other neurodevelopmental disorders
Individuals with neurodevelopmental disorders, including autism spectrum disorder, often exhibit impaired auditory processing. Despite behavioral interventions, individuals frequently continue to experience deficits. To address this pressing issue, we investigated the potential of vagus nerve stimulation (VNS) combined with auditory training to reverse auditory processing deficits in rodent models. Our study focused on two rodent models: heterozygous Mecp2 rats (modeling Rett syndrome) and rats prenatally exposed to valproic acid (modeling autism spectrum disorders). VNS releases neuromodulators important for plasticity, including acetylcholine, norepinephrine, and serotonin, which enhance plasticity and neural responses in the auditory pathway when delivered concurrent with sound presentation. Following 20 days of VNS-sound pairing intervention, both auditory cortical and subcortical response strength and response latency to sounds were restored. Moreover, neural response patterns in VNS-sound paired rats enabled more accurate sound identification compared to rats receiving sham therapy. Our findings highlight the effectiveness of VNS-sound pairing in enhancing auditory processing in rodent models of neurodevelopmental disorders with degraded auditory function. These studies provide insight into the ability of novel plasticity-based therapies to be effective in treating auditory processing impairments in individuals with neurodevelopmental disorders that result in part from a degraded neural representation of sounds.

NING QUAN, PHD
Director, Program in Neuroimmunology and Glial Biology, Professor, Stiles-Nicholson Brain Institute, Florida Atlantic University
Neuronal IL-1R1 contributes to Early Life Stress-Induced Long-Lasting Social Interaction Deficits

Early life stress (ELS) is one of the common environmental factors that changes neurodevelopmental trajectory. ELS is strongly associated with neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Increased cytokine production is one of the common responses to ELS. The proinflammatory cytokine interleukin-1 (IL-1) acting through its receptor interleukin-1 receptor-1 (IL-1R1) has critical roles in non-inflammatory neuroimmune activities (such as in maintaining the homeostasis of the central nervous system and regulating neural circuit functions) and neuroinflammation.

Our recent publication showed that neuronal IL- 1R1 (nIL-1R1) is important for cognition and social interaction in adult mice. The role of nIL-1R1 in neurodevelopment and related cognitive and affective functions is not known.

Here, we investigated the spatiotemporal expression patterns of nIL-1R1 during neurodevelopment and asked how nIL-1R1 might modulate neurodevelopment. We found that nIL-1R1 expression is very dynamic during brain development and changes dramatically in various brain regions including dentate gyrus of hippocampus (DG), dorsal raphe nucleus (DRN), ventral posteromedial (VPM), and posterolateral thalamic nuclei (VPL). These dynamic changes occurred in brain regions related to neurocircuits involved in the memory, sensory, and mood-regulation functions of the brain in a temporal spatial specific manner.

We assessed ELS- induced social interaction changes and found that nIL-1R1 is necessary for mediating maternal separation (MS, a well-established ELS paradigm) induced deficits in social interaction and social recognition later in life. Molecular analysis revealed a nIL-1R1-dependent acceleration of neuronal maturation in DG, somatosensory cortex, and frontal cortex in the early sensitive period after MS. In addition, we found that -FosB accumulated in granule neurons that express nIL-1R1 in DG after MS whereas this accumulation was not observed in controls. Our behavioral analysis suggests that nIL-1R1 is necessary for MS-induced deficits in social interaction and social recognition later in life.

These findings suggest that: 1) nIL-1R1 is tightly regulated during brain development correlating with its critical role in the control of neuronal maturation by non-neuroinflammatory neuro-immune activities, and 2) nIL-1R1 modulates the ELS-induced stress responses in DG which leads to long-lasting social interaction abnormalities by changing neuronal activity and/or plasticity in the DG

Great conference. I am very excited about the work being done on Microbiome in particular!

Stefanie Cross-Wilson, parent to a child with autism

Synchrony 2023 Researcher Mini Course

MARIO CAPECCHI, PHD
Nobel Laureate (2007), Biophysicist, Distinguished Professor of Human Genetics, University of Utah
The making of a scientist, an unlikely journey

COMING SOON
SARKIS MAZMANIAN, PHD
Luis and Nelly Soux Professor, Caltech
The Gut Microbiome Impacts Symptoms in Shank3 Mice
We show that manipulation of gut microbiome in Shank3 KO mice alters some core behaviors and gastrointestinal phenotypes, suggesting that non-genetic factors are implicated in this model. These results suggest that some of the outcomes in Shank3 KO mice are due to gene-environment (ie., microbiome) interactions.
NICOLE ZURCHER PHD
Assistant Professor of Radiology, Harvard Medical School, Massachusetts General Hospital
Simultaneous PET-MRI reveals choroid plexus alterations in autism spectrum disorder
A rapidly growing number of studies have demonstrated that the choroid plexus, a structure that acts as a gateway for immune cells to enter the brain, plays a key role in mediating immune processes in psychiatric disorders. Our preliminary data show striking alterations in choroid plexus in vivo in adults with autism spectrum disorder (ASD), both in terms of volume and levels of translocator protein (TSPO), a mitochondrial protein involved in immune mechanisms. In addition, our preliminary data show a correlation between choroid plexus volume and autism symptom severity. In the brain, TSPO was elevated in females with ASD compared to age-and sex-matched controls and lower in males with ASD compared to age-and sex-matched controls. Translocator protein is involved in several biological processes and altered TSPO levels could reflect alterations in immune mechanisms or mitochondrial function. To date, only a handful out of over seventy PET studies in ASD have specifically assessed females with ASD, by either studying them as a separate group or investigating group-by-sex interaction effects. As such, this study adds essential knowledge to in vivo molecular markers in the brain of both females and males with ASD and highlights strong sex-specific alterations in TSPO levels.
ALYSSON MUOTRI PHD
Director, Stem Cell Program, UCSD, Professor, Departments of Pediatrics and Cellular & Molecular Medicine, UC, San Diego
Title: coming soon
COMING SOON
RICHARD FRYE MD, PHD
Behavioral Child Neurologist, Neurodevelopmental Precision Medicine
Neuroinflammatory Patterns in Autism Spectrum Disorder Patients with and without Seizures
Epilepsy is an important comorbidity associated with autism spectrum disorder (ASD) which can have significant consequences. To determine whether neuroinflammation could be associated with seizures in ASD we reviewed the Cunningham panel in 89 consecutive patients. Patients were divided into groups depending on whether they manifest clinical seizures or abnormal EEGs. Individuals without clinical seizures and normal EEGs tended to have normal Cunningham panel or simultaneous elevations in anti-tubulin and Cam Kinase II.

Individuals with childhood onset seizures without genetic abnormalities tended to have normal Cunningham panels or isolated elevations in anti-tubulin but not Cam Kinase II. Individuals with adolescent onset seizures, childhood onset seizures with genetic abnormalities or subclinical epileptiform discharges tended to have isolated elevations in Cam Kinase II without other autoantibodies elevated.

This study suggests that there are subgroups of children with ASD that have distinct patterns of neuroinflammation markers which fall into subgroups. One of these groups demonstrates elevation in CamKinase II without an identified autoantibody. This suggests that there are yet to be discovered autoantibodies or other inflammatory proteins that are driving Cam Kinase II elevations in this subgroup. Identifying these such proteins can help in the treatment of difficult to control seizures in ASD.

RANDY BLAKELY PHD
Executive Director , Stiles-Nicholson Brain Institute and Florida Atlantic University College of Medicine
Serotonin autism and the immune system
Serotonin is a powerful neuromodulator, released in the brain by widely projecting neural circuits that regulate, among others mood, habit, reward, anxiety, and social behavior. The targets of serotonin also include major peripheral processes that range from vasoconstriction and blood clotting to intestinal and placenta function. Our lab first identified the gene encoding the antidepressant-sensitive serotonin transporter (SERT, 5-HTT, SLC6A4), and over the past three decades, have progressively elucidated mechanisms that normally regulate the surface trafficking and activity of SERT protein, as well as human mutations that perturb, or mimic, these processes. Key pathways identified in this effort involve the convergent actions of the protein kinases PKG and p38a MAPK. The well-known role played by latter kinase in innate immune signaling led us to elucidate mechanisms through the major inflammatory cytokine IL-1B, regulates SERT. In conjunction with this effort, we found that in vivo expression in mice of a mutant SERT that exhibits excess p38a MAPK drives reversible changes in CNS physiology, behavior and gut function. Following a review of the major findings in these studies, I will discuss recent, unpublished findings that IL-1b modulates serotonin signaling through somatic and axonal IL-1 receptors mediated by p38a MAPK signaling, with consequent changes in a distributed pattern of forebrain circuit activity that can be normalized using genetic and pharmacological approaches.
JEREMY VEENSTRA- VANDERWEELE MD
Child and Adult Psychiatrist, Columbia University
Trials and tribulations: testing new interventions in autism spectrum disorder
COMING SOON
KAREN J. PARKER PHD
Professor and Associate Chair of the Department of Psychiatry and Behavioral Sciences, Stanford University
Developing valid animal models for streamlined translation and clinical impact for autism
The biological underpinnings of autism spectrum disorder (ASD) remain poorly understood. Consequently, there are currently no disease-modifying medications that effectively treat ASD’s core behavioral symptoms. Scientific progress in detecting and treating ASD has been impeded, in part, by overreliance on model systems that fundamentally lack crucial features for modeling ASD. This minicourse will detail considerations for selecting appropriate model systems, gold-standard criteria for validating them, and best practice guidelines. An example from the speaker’s own research program on social functioning – spanning model conception to model validation to successful clinical translation – will briefly be highlighted. This approach to model development stands to advance our understanding of ASD in a manner not readily achievable with many existing models, and can readily be adapted to investigate other core and associated features of this clinically heterogeneous disorder, thereby streamlining translation and amplifying clinical impact for ASD more broadly.
STUART LIPTON MD, PHD
Professor – Step Family Endowed Chair; Founding Co-director, Neurodegeneration New Medicines Center, Department of Molecular Medicine, Scripps Research Institute
Talk title coming soon
COMING SOON
This is a really important conference for moving quality of life of autism folks forward. Thank you so much to the Brain Foundation leadership for doing this!
Christina Bogert, parent to a child with autism

Synchrony 2023 Invited Talks

RICHARD FRYE MD, PHD,
Behavioral Child Neurologist, Neurodevelopmental Precision Medicine
Transgenerational Inherited (non-genetic?) metabolic disorders
Autism spectrum disorder (ASD) has a high heritability which has been assumed to be of genetic origin, but genetic studies have repeatedly been unable to confirm inherited genetic disorders as a major cause of ASD. Indeed, when genetic abnormalities are found they are usually de novo.

Recent research is providing evidence of metabolic disorders associated with a majority of children with ASD, including abnormalities in folate, mitochondrial and transmethylation/transsulfuration metabolism. All of these disorders have evidence of transgenerational inheritance without a clear genetic component. These pathways are highly influenced by environmental factors and are prime pathways to study to understand environmental x genetic (probably polygenic) interaction that contribute to ASD.

Studying these abnormalities from the top down (physiological abnormalities) rather than from the bottom up (genetic changes) may help uncover the complicated combination of factors which result in ASD and other neurodevelopmental disorders.

JOHN GAITANIS MD
Director of Child Neurology, Brown Medical School, Pediatric Neurologist, Epileptologist, Hasbro Children’s Hospital
EEG: Past, Present and Future: Implications for Autism

COMING SOON
LINDSAY OBERMAN, PHD
Director, Developmental Clinical Neurophysiology and Neurostimulation Research Program, National Institute of Mental Health, NIH
Transcranial Magnetic Stimulation and Autism
COMING SOON
MARIO CAPECCHI PHD
Nobel Laureate (2007), Biophysicist, Distinguished Professor of Human Genetics, University of Utah
Defective Hoxb8 Microglia are Causative for both Chronic Anxiety and OCSD-like Behavior in Mice
We have shown in mice there are two cell lineages that give rise to microglia with distinct
ontogenies; Hoxb8 microglia and non-Hoxb8 microglia. Disruption of Hoxb8 or ablation of the Hoxb8 cell lineage gives rise to both chronic anxiety and OCSD-like behavior (trichotillomania, compulsive pathological overgrooming leading to lesions at the sites of overgrooming). There is a strong sex bias for both behavioral pathologies, with females showing much more aggressive disease. By cell transplantation of purified, cell sorted Hoxb8 microglia progenitors derived from Wt or Hoxb8 mutant mice we were able to demonstrate causation of defective Hoxb8 microglia for both behavioral pathologies. More recently we have demonstrated that optogenetic activation of Hoxb8 microglia in specific regions of the brain induces higher levels of anxiety, grooming or both. Further, these experiments have demonstrated that Hoxb8 microglia function to reduce anxiety and grooming (function as brakes) whereas non-Hoxb8 microglia function to increase these behaviors (function as an accelerator). Now we know why mammals have two populations of microglia.
DORIS TRAUNER MD
Distinguished professor of neurosciences and pediatrics, UC San Diego
A Clinical Trial of Cannabidiol for Autism: What We’ve found and What I’ve Learned
This is a preliminary report from a double-blind placebo-controlled crossover clinical trial of CBD to treat severe problem behaviors in boys with autism. CBD appears to be safe and well tolerated by boys with severe manifestations of autism. There was a prominent placebo effect that reduced the ability to determine the effectiveness of CBD. Results suggest that CBD may be effective in reducing anxiety, repetitive and self-injurious behaviors. The study underscores the importance of a placebo-controlled and blinded study and highlights the need for further well-controlled studies with a larger cohort, varying doses of CBD, and inclusion of both males and females.

STEPHEN WALKER, PHD
Professor, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine
ARTHUR KRIGSMAN, MD
Pediatric Gastroenterologist, Private Practice, New York
Significant improvements (gastrointestinal, behavioral, cognitive) following standard-of-care treatment in children with ASD-associated enterocolitis: A longitudinal assessment

Significant improvements (gastrointestinal, behavioral, cognitive) following standard-of-care treatment in children with ASD-associated enterocolitis: A longitudinal assessment. This talk will describe exciting findings of our recently completed Brain Foundation-sponsored Treatment Study. In this study, 25 children diagnosed with ASD-associated enterocolitis were followed for one year during their standard-of-care treatment by a single pediatric gastroenterologist (Dr. Arthur Krigsman). Questionnaires designed to evaluate GI status (bowel movement symptoms and externalizing behaviors specific to ASD) and ASD behavior and cognition (VABS, ABC, and SRS) were collected at baseline and over the course of 12 months during treatment to assess longitudinal changes. Although there was some individual variability in response to treatment throughout the year, for this group of 25 children statistically significant improvements were apparent in both GI and ASD symptoms starting at 3 months and persisting out to 12 months.
DAVID FAJGENBAUM MD, MBA, MSC, FCPP
Associate Professor, University of Pennsylvania
From Chasing My Cure to Every Cure
COMING SOON

Synchrony 2023 Industry Updates

JOHN SLATTERY
Chief Executive Officer, BIORosa technologies
An update from BioROSA’s Metabolic Autism Prediction (MAP) study

Research conducted over the past few decades have consistently shown dysfunctional metabolic signals involving redox metabolism in patients diagnosed with Autism Spectrum Disorder (ASD). To date there have been no double-blind case/control studies that seek to determine if abnormalities in 1-carbon folate metabolism, cellular methylation, and redox abnormalities are predictive of all forms of ASD compared to other types of developmental concerns (DD) that present early in life. BioROSA Technologies recently completed the first multicenter prospective double-blind case/control trial in which 163 children aged 18-60 months were enrolled. All children had a fasting blood draw and underwent diagnostic evaluation for ASD using DSM-5 criteria for diagnosis. All children had an assessment that included the Autism Diagnostic Observation Schedule (ADOS), Mullen Scales of Early Learning (MSEL), Vineland Adaptive Behavior Scales (VABS), and a full medical history and physical exam. The primary endpoint for the trial was to determine if metabolic biomarkers using a machine learning algorithm could accurately differentiate ASD from DD with accuracy >/= 80%. BioROSA test performance has demonstrated a positive signal in the MAP pilot trial. Details will be discussed.

FRED SAMUELS
Chief Executive Officer, Cell El
Can Serum Protein Biomarkers Identify Children at High Risk
for Autism Spectrum Disorder?
COMING SOON
XIAOMING ZHANG
Senior Vice President of Pharmaceutical Development, Eumentis Therapeutics
& RANDALL MARSHALL
Chief Medical Officer, Eumentis Therapeutics
EM-113 for autism spectrum disorder patients with elevated glutamate in the anterior cingulate cortex by MR Spectroscopy
There are currently no approved medications for treating the core symptoms of ASD, in part because the disorder is highly heterogeneous with respect to symptom severity, comorbidity, and underlying neurobiology. To address this critical gap, there is a pressing need for the development of a predictive biomarker to identify patients who are most likely to respond to a particular medicine. Such a precision medicine approach holds the promise of enhancing the probability of success in pivotal clinical trials and ultimately developing an effective medicine for treating individuals with ASD. The pregenual ACC plays an important role in social information processing and has been shown to be abnormally activated in intellectually capable ASD patients. Via the 505(b)2 regulatory pathway, EuMentis’ is developing a unique dosing regimen of memantine to treat a subgroup of ASD patients with elevated glutamate levels in the pregenual anterior cingulate cortex (ACC), based on a recent placebo-
controlled trial from MGH showing memantine is highly effective for improving social deficits in this subgroup of children (Gagan Joshi MD, MGH). Prior large, controlled trials’ failure with memantine were likely due to under-dosing, heterogeneity of ASD patients enrolled, and lack of a precision biomarker.Results from the MGH trial and the EuMentis planned trial will be presented and discussed.
JAMES ADAMS, PHD
President, Gut-Brain Axis Therapeutics
& KHEMLAL NIRMALKAR, PHD
Research Scientist, Biodesign center for Health Through Microbiomes, Arizona State University
Microbiota Transplant Therapy for Adults with Autism
This presentation will cover the results of a major Phase 2 clinical trial of Microbiota Transplant Therapy (MTT) for adults on the autism spectrum. This was a randomized, double-blind, placebo-controlled study for Part 1, and then in Part 2 the placebo group received a similar treatment, and the original treatment group received an extra 8 weeks of microbiota transplant. We found that MTT was generally safe and well-tolerated, and microbiota capsules were better tolerated than placebo capsules. For the primary outcome (autism symptoms), the treatment group improved more than the placebo group (medium effect). For the secondary outcome of daily stool record, the treatment group improved more than the placebo group (medium effect). The microbiome of the treatment group became more similar to the donor, with increases in certain beneficial bacteria. Overall, we believe these positive results demonstrate that MTT is generally safe and effective for treating autism and GI symptoms in adults with autism, and provide important insight into how to improve dosing to potentially improve clinical benefit. We will briefly explain the new company we founded, Gut-Brain Axis Therapeutics Inc, to continue this research.
LUIS DE TABOADA
Chief Technology Officer, JelikaLite
Transcranial Photobiomodulation for treatment of core symptoms of ASD in young children
This presentation showcases the detailed mechanism of action of tPBM, alongwith new findings from analysis of behavioral and brain physiology data gathered from our previous tPBM studies in autism. We discuss reduction in specific symptoms, improvement in speech and changes in EEG as a result of the treatment. This presentation also discusses the novel and unique features incorporated into the device as a result of the two studies discussed above. Furthermore, we provide a detailed description of the Pivotal clinical trial, which Jelikalite initiated in October 2023 to obtain FDA marketing approval through de-novo designation.
MEGHAN DAVIGNON, MD
Medical Director of Pediatric Developmental Disabilities, Kaiser Permanente NCAL
MAUDE
COMING SOON

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