Dr. Karen Parker: The Causes & Treatments for Autism

Dr. Karen Parker (00:00:00)

• Dr. Karen Parker leads the social neurosciences research program at Stanford.
• Her research focuses on the biological basis of social functioning throughout life.
• The research heavily concentrates on autism spectrum disorders.
• Discussion includes biological causes of autism and new research findings on its origins and treatments.

Autism, Frequency, Diagnosis (00:06:25)

• There is increased awareness and improved detection of autism, leading to earlier diagnoses.
• Current U.S. rates are 1 in 36 children diagnosed with autism.
• Autism shows male predominance, with 3-4 boys diagnosed for every one girl.
• CDC tracks prevalence of autism through 11 monitoring sites in the U.S.
• Diagnosis is based on observed behaviors, focusing on persistent social interaction challenges and restricted repetitive behavior.
• Autism can accompany anxiety, sensory challenges, seizure disorders, and sleep disorders.

Early Interventions; Heritability & Autistic Traits (00:10:41)

• Upon diagnosis, children can receive a variety of behavioral interventions.
• High autism heritability suggests the potential for baby sibling studies to identify at-risk children for early intervention.
• Autistic traits are continuously distributed in the general population, with the prevalence of certain traits higher among individuals in STEM fields, though not necessarily diagnosable autism.
• Autistic traits measurement tools include the social responsiveness scale (U.S.) and the Autism quotient (England).

Autistic Spectrums; Studying Autism (00:13:00)

• Autism is conceptualized as a spectrum, traditionally viewed as ranging from severe to mild in symptom expression.
• The severity spectrum is noted by experiences with severely autistic individuals at the Deo School, where some parents opt for full-time specialized care for their children.
• At the other end, individuals identifying as autistic may be high-functioning, able to drive, maintain relationships, and manage life well, demonstrating neurodiversity.
• It is suggested that there might not be a single spectrum but multiple dimensions of autism, including severity, stereotyped behaviors, and focused interests, making it a complex multi-dimensional condition.
• Biological understanding of autism is crucial for effective categorization and treatment. It is highly heritable, with 40-80% attributed to genetics, primarily polygenic with common variants affecting the spectrum's presentation.
• The discussion touches on the challenges of diagnosing and treating brain disorders like autism without a clear understanding of its biological basis.
• Autism may involve altered genes or proteins at neuron synapses, and while it is commonly accepted as a brain disorder, questions arise about potential systemic influences beyond the brain.
• Conducting studies on autism in humans can be difficult due to the challenges in obtaining brain tissue samples, cerebral spinal fluid, or performing brain scans, especially in children with autism.
• Modeling autism in animals is challenging because traditional mouse models may not have the necessary traits to accurately reflect human conditions, affecting drug development.
• The failure in translating animal model successes to human clinical trials can be due to poorly selected animal models, highlighting the need for more sophisticated models for the study of autism. Non-human primate models are viewed as a promising approach to improve this translation due to their closer similarity to humans.

Environment, Risk Factors & In Utero Development (00:21:29)

• Genes and the environment interact to influence the frequency and presentation of autism.
• Environmental risk factors for autism may include advanced parental age, prematurity, and maternal illness during pregnancy.
• Early prenatal ultrasounds have been hypothesized to potentially affect neuronal migration, potentially correlating with autism incidence, but conclusive links have not been established.
• Multiple hypotheses on environmental influences, such as parental occupation, food toxicity, and vaccines, have not resulted in a consensus on major risk factors.
• Genetic background diversity complicates identifying environmental risk impacts in large epidemiological studies.
• Stratified trials considering genetic composition could be beneficial in understanding gene-environment interactions.
• Neurogenetic syndromes like fragile X show high autism penetrance, suggesting that treatment responses may vary based on specific genetic conditions.
• The relationship between co-occurring conditions (e.g., cardiac issues in Timothy syndrome) and autism is complex, sometimes leading to questioning whether "autism" is an umbrella term for multiple distinct disorders.
• The lack of a clear biological definition of autism complicates the classification and understanding of the disorder and its subtypes.

Oxytocin, Vasopressin, Social Behavior & Parent-Child Bonding (00:31:26)

• Oxytocin and vasopressin are chemically similar neuropeptides, each only differing by two amino acids, and are ancient, highly evolutionarily conserved.
• Both influence social behavior across species, particularly mammals, and are produced in many species, including humans and house cats.
• These neuropeptides bind to four different receptors, making their specific effects and locations in the brain complex to determine.
• Originally discovered for their peripheral effects (outside the brain), oxytocin plays roles in uterine contractions and milk release during lactation, while vasopressin is involved in urine regulation and blood pressure.
• Historical research in animals such as sheep and goats revealed that oxytocin co-released into the brain during delivery and lactation is critical for maternal bonding.
• The effect of oxytocin on mother-infant bonding is species-specific and can be influenced by evolutionary history; in humans and other primates, extended family groups and adoption practices impact the bonding process, indicating that the mechanism for bonding in primates is not yet fully understood.
• There is a strong interest in oxytocin and vasopressin research due to their implications in disorders characterized by social connectedness issues such as autism and drug abuse.

Oxytocin in Humans; Social Features of Autism, Intranasal Oxytocin (00:43:24)

• Oxytocin is assumed to be involved in human bonding processes, such as mother-infant and romantic partner bonding, based on animal models.
• The term "love hormone" associated with oxytocin is misleading as it oversimplifies its role and ignores other functions.
• Studies on human brain imaging and oxytocin focus on the response to stimuli, particularly its potential to decrease the amygdala's response to fear, suggesting a pro-social effect.
• The role of oxytocin in autism has been explored through giving intranasal oxytocin to autistic individuals, primarily males.
• Early studies indicated oxytocin might improve social cognition and motivation in individuals with high-functioning autism.
• There's a demand to explore how oxytocin would affect females with autism, and further research is necessary.
• Oxytocin is not currently available over the counter and requires a prescription; it is not approved by the FDA to treat core features of autism.
• Autism often has a lifelong impact, though some individuals may outgrow their diagnosis or respond well to interventions like behavioral therapy.

Oxytocin & Autism; Benefit & Risks (00:55:16)

• It is unclear if low levels of natural circulating oxytocin are a consistent feature of autism.
• Measuring oxytocin in the blood may not accurately reflect its levels in the brain; cerebrospinal fluid could be a more relevant measure.
• Some mouse models of social impairment show a reduction of oxytocin in the hypothalamus and blood after certain genes are modified.
• An experiment suggested that applying oxytocin across development could restore normal oxytocin neuron numbers in genetically modified mice.
• A clinical trial at Stanford found that children with lower baseline blood oxytocin levels showed more significant improvement with oxytocin treatment compared to those with higher levels.
• A multi-site phase three oxytocin trial showed no overall benefit, raising questions about the proper measurement and handling of oxytocin levels during testing.
• Oxytocin is generally safe for children, but its effectiveness is questionable without identifying specific subsets who could benefit the most.
• There is urgency among parents of autistic children to find safe treatments, but health professionals are cautious without clear evidence pointing to oxytocin as an effective broad treatment.
• Further research is necessary to determine if a subset of individuals with autism might benefit from oxytocin therapy, but funding and interest in such research could be limited due to previously unsuccessful trials.

Neuroplasticity & Autism; Early Intervention; Challenges of Early Diagnosis (01:06:30)

• Neuroplasticity plays a key role in improving social cognition and behavior in autistic children.
• There is potential in utilizing treatments such as SSRIs, wellbutrin, and psilocybin, not because of their neurotransmitter effects, but due to their neuroplasticity benefits.
• Trials are considered for substances like MDMA and atypical antidepressants in autistic children, to aid in rewiring the brain.
• Autism is heterogeneous, making it challenging to decide who to include in trials and measure treatment outcomes.
• It's suggested that oxytocin could be more effective at younger ages, emphasizing the importance of early intervention.
• Current diagnostic wait times for autism are long, prompting the need for efficient, scalable screening methods such as biomarker panels or eye-gaze tracking technology.
• A more democratic and accessible approach to autism screening could support early identification, particularly beneficial in resource-limited environments.

MDMA & Autism (01:14:30)

• There is interest in researching MDMA or methylene dioxy methamphetamine, known as ecstasy, for autism treatment.
• MDMA causes significant increases in serotonin, aiding neuroplasticity, which might benefit autistic individuals.
• The hesitance in giving children psychedelics challenges the use of MDMA; an alternative chemical compound may be more acceptable.
• There is a comparison to ADHD medications, such as amphetamines, suggesting exploration into chemically similar compounds to MDMA for autism in clinical trials.
• Future research will determine the appropriateness and effectiveness of these interventions in autism treatment.

Vasopressin, Social Interaction; Voles & Parenthood (01:17:05)

• Vasopressin is chemically similar to oxytocin and is manufactured in the human brain and body.
• It's produced in the hypothalamus and released throughout the brain, with receptors found in multiple regions.
• Vasopressin was found to be critical for male social behavior through studies conducted in the early to mid-1990s.
• Experiments with Prairie voles showed that vasopressin induced pair bonding and paternal care; these voles typically form monogamous relationships and engage in paternal behaviors.
• In contrast, Montane voles were presented as a more asocial species, with males not providing parental care.
• In Prairie voles, vasopressin or antagonists could induce bond formation with a mate, even without mating, by living together for a short time.
• A researcher's graduate work with Meadow voles, which are sensitive to light, showed that shorter daylight triggered parental behavior in males.
• Through direct administration of vasopressin into the brains of voles, previously negligent fathers exhibited attentive parental behaviors, suggesting that brain circuitry for those behaviors is present but latent.
• The dramatic impact of vasopressin exemplifies the ability of peptides to act as switches, activating existing brain circuitry.

The summary provides key information about vasopressin's role in brain functioning and social behavior, particularly in voles, which serves as a model for understanding similar mechanisms in humans. It highlights both evolutionary aspects of bonding and parental care, as well as the neuroendocrinological basis for these behaviors.

Human Social Connection, Oxytocin Levels & Autism (01:27:07)

• Dr. Karen Parker was inspired to pursue autism research while at Stanford, influenced by clinicians and noticing the clinical relevance of her work on stress.
• Dedicated parents were actively lobbying for increased funding for autism research due to it being considerably underfunded, given rising prevalence rates.
• Autism Speaks was formed from these parent grassroots organizations and substantial funding was provided by donors like Jim Simons with possible personal connections to autism.
• Dr. Parker was encouraged by her department chair to explore the biological basis of autism, leading her to consider the role of neuropeptides like oxytocin and vasopressin in social impairments associated with autism.
• Her research clarified that blood oxytocin is not a distinct biomarker for autism, but lower levels correlate with social difficulties in children with autism, their unaffected siblings, and control children.
• The focus shifted from using oxytocin levels to differentiate individuals with autism to identifying subgroups who may benefit from neuropeptide-based treatments.
• Her approach moves away from the broad and complex diagnosis of autism, concentrating instead on specific challenges in social cognition and behavior.
• Dr. Parker's research suggests oxytocin has a wider role in human sociality, beyond just those diagnosed with autism, and could have healing potential when used as a modulator in therapies.

Primate Model of Social Impairment (01:33:45)

• Discussed the significance of vasopressin in relation to autism and social functioning.
• Dr. Karen Parker began researching vasopressin through a primate model of social impairments, particularly interested in biomarker discovery in cerebral spinal fluid rather than blood.

Preclinical Animal Models, Mouse & Primates (01:42:47)

• Highlighted the limitations in animal models, particularly rodent models, that fail in translating treatments to humans due to differences in brain complexity.
• Noted that certain drugs tested safe in rodents caused significant harm in humans, and such consequences might have been avoided by testing in primates.
• Emphasized the need for careful justification in selecting animal models for research, with a nod toward stem cell and organoid work as alternatives or complements.
• Stressed the importance of choosing appropriate animal models for cognitive disorders, citing the close relationship between primate and human social behaviors as a key reason for using primates in autism research.

Primates, Biomarkers & Social Connection; Vasopressin (01:47:11)

• Monkeys with behaviors similar to human autism were studied to find biomarkers indicating social affiliation.
• A variety of neurotransmitter systems was tested to differentiate low social monkeys from high social ones with 93% accuracy using blood, CSF, and a machine-learning algorithm.
• Cerebral spinal fluid (CSF) levels of vasopressin, but not blood vasopressin levels, were key in identifying social capacity.
• The findings were replicated in another monkey cohort to validate the biomarker's consistency and correlation with grooming behavior, a key social bonding activity.
• Low CSF vasopressin levels were linked to less time spent grooming in monkeys, showcasing the possibility of translating these findings to human studies since vasopressin levels were a stable marker within individuals.
• Allopathic grooming was discussed as a vital behavior for establishing trust and relationships within primate societies and compared with human concepts of personal space and consent.
• Despite the parallels, it was emphasized that monkeys do not have autism, leading to questions about the applicability of these findings to human autism.

Vasopressin Levels & Autism, Children & In Utero (01:52:20)

• Research aimed to assess vasopressin levels in cerebral spinal fluid (CSF) to find a potential biomarker for autism, since blood levels did not show differences.
• Studies in monkeys showed profound differences in spinal fluid but not in blood levels of vasopressin between socially high and low individuals.
• CSF was obtained from children with clinical indications for lumbar puncture and also consented for extra samples for research.
• Despite difficulty obtaining funding and ethical approvals, CSF samples from children with and without autism were finally collected.
• A study with a small cohort demonstrated CSF vasopressin levels could nearly perfectly classify children with and without autism.
• The findings showed lower CSF vasopressin levels in individuals with autism, regardless of biological sex, and correlated with social symptom severity but not restricted repetitive behaviors.
• Efforts to replicate the results included collaborating with a professor who had collected CSF from infants at the NIH. The study confirmed the initial findings and included a sample of girls for the first time.
• A study with a colleague who had "Liquid Gold" - banked neonatal CSF samples - allowed researching vasopressin levels' role in autism causality using past samples linked to electronic medical records.
• Proposed that early intervention with vasopressin replacement therapy could potentially alter developmental trajectories in infants predisposed to autism.

Cerebral Spinal Fluid (CSF) & Vasopressin; Urination; Alternative Therapies (02:03:06)

• Infants who later received an autism diagnosis had lower CSF vasopressin levels at a young age, indicating a potential biomarker for autism risk.
• Oxytocin levels did not show a difference between infants with and without a subsequent autism diagnosis.
• CSF is considered the kitchen sink of the brain, containing nutrients and chemicals from the brain, which is why a spinal tap is useful for measurement.
• The hypothesis is that there may be a deficiency in vasopressin production in individuals with autism.
• Plans to study postmortem human brain tissue, including hypothalamic tissue where vasopressin is made, to understand the production issues and gene expression levels.
• Raising vasopressin levels in the brain may unlock certain behaviors and can be a potential treatment for a subset of children with autism.
• There could be a link between low vasopressin and excessive urination or bedwetting in children with autism, but more epidemiological studies are needed to connect these physiological features.
• Alternative therapies, like acupuncture, that release vasopressin naturally or studies on intranasal vasopressin administration, may offer treatment options, pending safety and efficacy trials.
• Past subcultures have combined vasopressin with other substances for different effects, but the rationale and outcomes are unclear.
• Emphasis on the need for secure and safe clinical trials before using vasopressin-based treatments.

Intranasal Vasopressin, Children, Autism & Social Responsiveness (02:10:32)

• Dr. Karen Parker discusses a controlled clinical trial on vasopressin treatment in children with autism.
• The study was designed to avoid uncontrolled self-administration due to potential severe adverse effects.
• Vasopressin dosage was controlled and administered twice daily for four weeks to children aged 6 to 12.
• The primary outcome measure was the Social Responsiveness Scale (SRS), used in past research and FDA-approved for the study.
• SRS measures social behaviors and other features of autism quantitatively.
• The study showed that vasopressin-treated children exhibited increased social abilities according to parent reports, clinician evaluations, and child performance on laboratory tests.
• It is unclear whether the social improvements are the result of short-term effects or long-term neuroplasticity, as additional research and funding would be needed to determine this.
• Some treated children also displayed reduced anxiety and repetitive behaviors, suggesting vasopressin's effects may extend beyond social behavior.
• Dr. Parker notes that personal experimentation with substances like antidepressants is not uncommon in medical research; however, she has not done so with vasopressin.
• The impact of vasopressin may differ between neurotypical individuals and those with autism, with the latter potentially showing more noticeable changes upon administration.

Vasopressin & Social Connection, Mechanism & Future Studies (02:19:15)

• In a small pilot trial, some children with autism showed improved social interactions after receiving vasopressin, while others did not respond significantly.
• Anecdotes include a child who became more gregarious after the trial, chatting with people in a grocery store, which his father had never witnessed before.
• Vasopressin was delivered via nasal spray, a method that directly affects the brain through the nasal passages, but this approach raises questions about the mechanism of action.
• Researchers are unsure if vasopressin increases social motivation, shifts attention to social cues, or affects sensory processing.
• The next research step should involve imaging studies to identify which brain circuits are affected by vasopressin.
• There is urgency among parents for effective autism treatments since there are limited options available.
• Despite not fully understanding the mechanism, there is a push to continue researching and testing vasopressin for safety and efficacy, given its potential to improve lives ethically and scientifically.

Gut Microbiome & Vasopressin; Scientific Funding (02:26:35)

• Studies in mouse models of autism show that fecal transplants can rescue social deficits, implying a connection between the gut microbiome and social behavior.
• In mice, social function normalization and increased blood oxytocin levels were associated with probiotic treatment, suggesting a microbiota impact on neurotransmission.
• A mouse study found that increased gut microbiota diversity through probiotics upregulated gene expression and oxytocin and vasopressin action in the hypothalamus.
• The vagus nerve, connecting the gut to the hypothalamus, when severed, stops the aforementioned improvement in social behavior, indicating its necessity for this mechanism.
• Fecal transplants make more sense in light of these findings, suggesting a neural and somewhat causal link between the microbiome and oxytocin/vasopressin production.
• Discussion on whether vagal nerve stimulation could also improve social behaviors in autistic individuals raises the question of its potential measurable effects on blood levels of related hormones.
• Financial constraints severely limit research progress, with grant writing delaying important studies by years despite sound hypotheses and potential benefits.
• Autism research funding is highlighted as a priority area for both scientific advancement and the immediate benefit of affected individuals and families.

Vasopressin Pathways, Social Behavior, Autism (02:34:52)

• The study included a small cohort with 17 children receiving active vasopressin treatment and 13 receiving a placebo.
• After initial trials, participants in the placebo group were offered the active drug in an open-label extension to ensure all could benefit.
• The extension allowed for the collection of additional safety data and monitoring of the children's blood chemistry and cardiograms.
• There is a declining interest in studying oxytocin nasal spray as a treatment for autism due to lack of funding following a large failed trial, with some residual research possibly happening in Australia.
• Roche, a pharmaceutical company, conducted a trial with bapine, a V1a receptor antagonist which differs from the study's approach which promotes vasopressin to improve social behavior in autism.
• The presence of vasopressin in animal studies indicates it is pro-social in specific contexts, not necessarily aggressive as Roche's approach would suggest.
• Results from the ongoing larger trials are awaited to see if the positive findings from the pilot study regarding vasopressin treatment are replicated.

Vaccine Theory & Autism; Immunology (02:43:00)

• The hypothesis that vaccines could cause autism, with a focus on vaccine preservatives, was proposed by Andrew Wakefield.
• Wakefield's study was debunked, retracted, and he lost his medical license due to fraudulent data fabrication.
• Despite public concern and massive funds spent on subsequent studies, the prevailing evidence shows no correlation between vaccines and autism.
• Preservatives in vaccines might have been changed as a result of the investigation, although the precise motivations for Wakefield's actions are unclear.
• Scientists and medical doctors generally do not believe that vaccines cause autism, and typically vaccinate their own children.
• Discussion has emerged around the number of vaccinations children receive, differentiating between critical and non-critical vaccines.
• Historical fear has made many researchers hesitant to study immunology and autism, despite parents reporting immune dysregulation in their children.
• Dr. Karen Parker has not directly addressed the vaccine-autism issue, but focuses on identifying biological disruptions in autism, such as the role of vasopressin.
• Parker's work, involving vasopressin administration to children with low social functioning, suggests improvement in symptoms, moving toward understanding underlying mechanisms and novel treatments for autism.