In this insightful podcast, the wonderful Dr. Karen Parker, Ph.D., a professor of psychiatry and the director of the Social Neurosciences Research Program at Stanford University School of Medicine, joins Dr Andrew Huberman. Together, they delve into the captivating world of social connections and bonding, exploring the intricate biology behind these vital aspects of human life—from babies to adults. Dr. Parker sheds light on our current understanding of autism and autism spectrum disorders, unraveling the mysteries of what they entail. They take a closer look at the significant rise in autism cases in recent years and explore the reasons behind this surge. The conversation does not stop there; they also delve into both existing and emerging treatments for autism, providing valuable insights for anyone interested in child and human development. As they navigate this fascinating discussion, they touch upon the topic of Asperger's, now known as a part of the autism spectrum. This episode is a treasure trove for those curious about the formation of social bonds, communication, and the intricacies of autism and related conditions.
In recent years, there has been significant progress in the early detection of autism, allowing clinicians to reliably diagnose children as young as two to three years old, compared to the previous norm of 9 or 10 years of age. Increased awareness, aided by the availability of autism screeners for pediatricians, has contributed to this improvement. However, the prevalence of autism has risen, with current statistics indicating that 1 in 36 U.S. children have a diagnosis, compared to 1 in 44 just two years ago. Notably, autism exhibits a male bias, with studies suggesting that for every one girl diagnosed, three to four boys are impacted. It is crucial to acknowledge the clinical heterogeneity of autism, as each affected individual presents unique characteristics. The prevalence data are derived from monitoring sites established by the CDC across the U.S., where rates are periodically updated every few years [1].
Figure 1. Autism Screening and Diagnosis.
1. Maenner, M.J., et al., Frequency and pattern of documented diagnostic features and the age of autism identification. J Am Acad Child Adolesc Psychiatry, 2013. 52(4): p. 401-413.e8.
Typically, autism diagnosis precedes the implementation of various behavioral interventions. Studies, such as Baby Sibling studies, focus on infants at an increased risk of autism due to familial heritability. Some of these at-risk children are enrolled in behavioral studies as part of ongoing research. Notably, there is a correlation between parental professions, particularly in engineering, mathematics, or hard sciences, and an elevated likelihood of having children with autistic traits. Autistic traits, measured by instruments like the Social Responsiveness Scale and the Autism Quotient, are found to be more prevalent in individuals engaged in STEM fields, such as engineering, physics, and math, even if they do not have a formal autism diagnosis [2].
Figure 2. Dynamic and Systemic Perspective in Autism Spectrum Disorders [2].
2. Panisi, C. and M. Marini, Dynamic and Systemic Perspective in Autism Spectrum Disorders: A Change of Gaze in Research Opens to A New Landscape of Needs and Solutions. 2022. 12(2): p. 250.
Understanding autism as a spectrum involves considering various dimensions and not just a linear scale from severe to mild. The complexity arises from the diverse collection of traits exhibited by individuals, leading to the question of whether multiple spectrums intersect different dimensions. The heritability of autism, with 40 to 80% attributed to genetics, suggests a polygenic nature, with common genetic variants influencing the spectrum. The dosage of these variants may contribute to variations in functioning, ranging from higher to lower functioning individuals. Despite progress, the biological basis of autism remains incompletely understood, making diagnosis and treatment challenging. Recent studies have highlighted gene alterations related to synapses, emphasizing the neural network's role in autism. However, challenges in studying the disorder in individuals, especially children, hinder access to brain-related data, leading researchers to rely on animal models that often lack critical human-like features. Developing sophisticated and relevant models is crucial for advancing our understanding of autism and improving interventions [3].
Figure 3. Detection of autism spectrum disorder (ASD) in children and adults using machine learning [3].
3. Farooq, M.S., et al., Detection of autism spectrum disorder (ASD) in children and adults using machine learning. Scientific Reports, 2023. 13(1): p. 9605.
Exploring the myriad factors influencing autism, various epidemiological studies have identified advanced parental age, prematurity, and maternal illness during pregnancy as potential risk factors. The discussion delves into the intriguing hypothesis regarding the correlation between early prenatal ultrasound exposure and migration errors during neuronal development, proposed by luminary researcher Pasko Rakic. However, despite such hypotheses, pinpointing a definitive environmental risk factor for autism proves challenging due to the complex interplay of genetic backgrounds in diverse populations. The conversation touches upon neurogenetic syndromes like Fragile X and Timothy syndrome, emphasizing the heterogeneity of autism and the need for genetically defined subgroups to conduct meaningful studies. The text also raises critical questions about the nature of autism, challenging the conventional understanding and prompting considerations about whether it represents a spectrum of disorders or conditions. The lack of a biologically defined basis for the behavioral diagnosis further complicates efforts to understand and classify autism, paralleling challenges faced in other medical fields before the advent of molecular tools. Ultimately, the text underscores the need for a more nuanced and biologically informed approach to unravel the complexities of autism [4].
Figure 4. Fragile X syndrome causes inheritance, symptoms, diagnosis & treatment [5].
4. Abrahams, B.S. and D.H. Geschwind, Connecting genes to brain in the autism spectrum disorders. Arch Neurol, 2010. 67(4): p. 395-9.
5. Fragile X syndrome. Available from: https://healthjade.net/fragile-x-syndrome/.
Oxytocin and vasopressin, ancient and evolutionarily conserved peptides, play crucial roles in social behavior across species, with variations in their physiological functions. Originally recognized for its peripheral effects, oxytocin is associated with uterine contractions and lactation, while vasopressin is involved in urinary regulation and blood pressure. Discovered for their peripheral roles, these hormones were later found to impact the brain, particularly in the context of social behaviors. Notably, the naming conventions and historical understanding of oxytocin and vasopressin were based on their peripheral actions, overlooking their intricate roles in neural processes. The discussion further explores the species-specific nature of oxytocin's impact on mother-infant bonding, highlighting the complexity of social interactions and the evolutionary context. Additionally, the text touches on the significance of social connectedness in human evolution and the potential role of oxytocin and vasopressin in disorders associated with social impairments, such as autism and substance abuse [6].
Figure 5. The role of oxytocin and vasopressin in emotional and social behaviors [7].
6. Rigney, N., et al., Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities. Endocrinology, 2022. 163(9).
7. Bachner-Melman, R. and R.P. Ebstein, Chapter 4 - The role of oxytocin and vasopressin in emotional and social behaviors, in Handbook of Clinical Neurology, E. Fliers, M. Korbonits, and J.A. Romijn, Editors. 2014, Elsevier. p. 53-68.
Research on oxytocin's role in humans has primarily focused on mothers and animal models, with limited investigation in primates. While its involvement in mother-infant bonding is extrapolated from various species, including sheep and rodents, its specific impact in humans remains complex. Oxytocin's receptors in the human brain are not yet fully understood, and studies often involve intranasal administration of oxytocin to explore its effects on social behaviors. Some research suggests that oxytocin can reduce the amygdala's response to fearful stimuli, indicating potential pro-social effects. Attempts to understand its impact on individuals with autism have involved single-dose studies in males, given intranasal oxytocin, with a focus on social tasks such as reading emotions from eyes or tracking eye gaze. While early results hinted at oxytocin's potential effectiveness in enhancing social motivation for some individuals with high-functioning autism, the complexity of autism and the diversity of social features within the spectrum necessitate further research to discern the specific subpopulations that may benefit from oxytocin therapy [8].
Figure 6. Oxytocin and Social Motivation [9].
8. Ito, E., R. Shima, and T. Yoshioka, A novel role of oxytocin: Oxytocin-induced well-being in humans. Biophys Physicobiol, 2019. 16: pp. 132-139.
9. Gordon, I., et al., Oxytocin and social motivation. Developmental Cognitive Neuroscience, 2011. 1(4): p. 471-493.
Research on oxytocin's potential as a treatment for autism has involved measuring oxytocin levels in both blood and spinal fluid, with the question of whether blood levels accurately reflect brain activity remaining contentious. Studies in mouse models of neurogenetic syndromes associated with social impairment, such as Fragile X and Prader-Willi syndrome, have indicated that oxytocin deficiency correlates with genetic modifications. A clinical trial at Stanford explored oxytocin intervention in children with autism, revealing that those with lower baseline blood oxytocin levels exhibited more significant benefits from the treatment. However, a subsequent multi-site phase three trial failed to demonstrate overall effectiveness, raising questions about the complexity of oxytocin's impact and the challenges of maintaining rigorous protocols across multiple sites. Despite the controversy and negative outcomes in some studies, the possibility of a subset of individuals with lower oxytocin levels benefiting from oxytocin replacement therapy remains an open question that requires further investigation and funding [10].
10. Yamasue, H. and G. Domes, Oxytocin and Autism Spectrum Disorders. Curr Top Behav Neurosci, 2018. 35: p. 449-465.
The discussion delves into the challenges of identifying and diagnosing autism, highlighting the heterogeneous nature of the condition and the difficulty in targeting specific neurochemical deficiencies in affected individuals. The potential benefits of drugs, such as oxytocin, in rewiring the brain for autistic children are explored. Still, the complexity of autism and the lack of standardized screening contribute to uncertainties in treatment outcomes. The conversation emphasizes the need for early intervention, with considerations for age-related neuroplasticity. Barriers to widespread behavioral testing for autism are discussed, citing scalability issues, resource disparities, and the challenges faced by clinicians in diagnosing the condition. The conversation concludes with a call for more accessible and rapid diagnostic tools, possibly involving biomarker panels, to expedite early interventions and address the delayed diagnosis often experienced by children in disadvantaged communities [11].
Figure 7. Computed tomography in autism spectrum disorders [12].
11. Desarkar, P., et al., Assessing and Stabilizing Aberrant Neuroplasticity in Autism Spectrum Disorder: The Potential Role of Transcranial Magnetic Stimulation. Front Psychiatry, 2015. 6: p. 124.
12. Keeratitanont, K., et al., Brain laterality evaluated by F-18 fluorodeoxyglucose positron emission computed tomography in autism spectrum disorders. 2022. 15.
The conversation explores the role of oxytocin and vasopressin in the brain, emphasizing the complexity of their distribution and effects. The focus shifts to vasopressin, particularly in the context of its significance in male social behavior. The speaker shares insights from studies involving Prairie voles and the impact of vasopressin on inducing pair bonding and paternal care. The discussion extends to the contrasting behavior of Montane voles, highlighting the evolutionary and social dynamics between monogamous and non-monogamous species. The speaker recounts personal experiences studying meadow voles, discovering unexpected monogamous behaviors in winter conditions. Notably, the speaker describes a vivid experiment where vasopressin administration in winter males triggers nurturing behaviors towards offspring, offering intriguing insights into the hormone's influence. The narrative underscores the speaker's enduring fascination with vasopressin, anticipating a return to further exploration of its intricate role in neurobiology [13].
Figure 8. Oxytocin and vasopressin (OT-AVP) pathways are associated with social interaction [14].
13. Rigney, N., G.J. de Vries, and A. Petrulis, Modulation of social behavior by distinct vasopressin sources. 2023. 14.
14. Hashem, S., et al., Genetics of structural and functional brain changes in autism spectrum disorder. Translational Psychiatry, 2020. 10.
The narrative follows the speaker's trajectory into autism research, spurred by a convergence of factors including the underfunding of autism research, grassroots efforts by dedicated parents, and philanthropic initiatives led by Jim Simons. Encouraged by the lack of knowledge about the biological basis of autism, the speaker, already engaged in stress vulnerability and resilience research, explores the potential role of neuropeptides, particularly oxytocin, in understanding social interaction impairments associated with autism. The journey into autism research culminates in a significant blood oxytocin study involving 200 children, funded by the Simons Foundation. Contrary to the prevailing oxytocin deficit hypothesis, the study reveals that blood oxytocin levels are not a distinct marker of autism. This realization prompts the speaker to consider the nuanced role of blood oxytocin levels. It leads to the design of a clinical trial, aiming to identify subgroups within the autism spectrum that may benefit from targeted treatment based on their blood oxytocin levels [15].
Figure 9. Autism, oxytocin, and interoception [15].
15. Quattrocki, E. and K. Friston, Autism, oxytocin and interoception. Neuroscience & Biobehavioral Reviews, 2014. 47: p. 410-430.
The speaker discusses the development of a primate model for autism, driven by the limitations observed in mouse models and the need for a more clinically relevant approach. Inspired by the continuous distribution of autistic traits in the general human population and the notion of genetic liability, the speaker focuses on Old World monkeys, particularly rhesus macaques, as close relatives to humans used in biomedical research. Collaborating with the California National Primate Research Center, the team refines a social responsiveness scale for monkeys, enabling the identification of individuals exhibiting social impairments. These monkeys, observed in non-invasive settings, display features reminiscent of autistic-like traits, prompting the development of specific tests to assess core aspects of autism in the model. The thorough validation of this behavioral phenotype contributes to a more nuanced and clinically relevant approach to modeling autism in primates, opening avenues for further exploration and understanding of the condition [16].
Figure 10. Non-human Primate Models to Investigate Mechanisms of Infection-Associated Fetal and Pediatric [16].
16. Li, M., et al., Non-human Primate Models to Investigate Mechanisms of Infection-Associated Fetal and Pediatric Injury, Teratogenesis and Stillbirth. 2021. 12.
The discussion emphasizes the limitations of relying solely on rodent models for medication testing, citing examples such as the drug thalidomide, initially deemed safe based on mouse testing but causing severe limb abnormalities in humans. Another instance involves the synthetic heroin MPTP, which induced rapid parkinsonism in humans but not in mice. The speakers stressed the importance of considering the relevance of the model species to the studied condition and the potential negative consequences of overlooking the differences between rodents and primates. The conversation acknowledges the ethical considerations of animal experimentation while highlighting the critical need for justified scientific practices to ensure the safety and efficacy of medications, particularly those targeting complex cognitive functions such as social cognition. Additionally, the mention of emerging technologies like stem cell and organoid research suggests promising alternatives for disease studies without solely relying on animal models [17].
17. Atkins, J.T., et al., Pre-clinical animal models are poor predictors of human toxicities in phase 1 oncology clinical trials. British Journal of Cancer, 2020. 123(10): p. 1496-1501.
The researchers explored biomarker discovery in monkeys exhibiting varying degrees of social affiliative, aiming to differentiate low-social from high-social individuals. Utilizing blood and cerebral spinal fluid (CSF) measurements for neurotransmitter systems implicated in social behavior, they employed a statistical algorithm to classify monkeys based on their social competence with 93% accuracy. Notably, CSF vasopressin levels emerged as a key driver in this classification, demonstrating consistency within individuals across time. Replicating their findings in another monkey cohort, the researchers established vasopressin as a potential biomarker for social functioning. Further analysis revealed a close association between CSF vasopressin levels and grooming behavior, a critical social bonding activity in many monkey species. The study's success in identifying a potential biomarker offers insights into understanding social impairments and holds implications for future research, potentially extending to human studies [18].
Figure 11. Respiratory Effects of the Antidiuretic Hormone [19]
18. Carson, D.S., et al., Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism. PLoS One, 2015. 10(7): p. e0132224.
19. Proczka, M., et al., Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone. 2021. 12.
In pursuit of understanding autism's biological basis, the researcher explored the potential of CSF biomarkers, particularly vasopressin, in monkeys exhibiting social affiliative behaviors. The successful monkey study prompted the extension of this investigation to human subjects. Facing challenges in obtaining CSF from children for research purposes, the researcher creatively collaborated with clinicians, obtaining remnant samples from lumbar punctures conducted for clinical reasons. A comparison of CSF vasopressin levels in children with and without autism revealed a remarkable ability to classify individuals, suggesting vasopressin as a potential biomarker for autism. A subsequent replication with a well-characterized cohort supported the finding, indicating lower CSF vasopressin levels in individuals with autism regardless of biological sex. Collaborations with researchers possessing unique sample resources enabled the exploration of neonatal and infant CSF samples, aiming to uncover potential biomarkers before the onset of behavioral symptoms. These efforts contribute to a deeper understanding of autism's biological underpinnings, offering valuable insights for future research and potential clinical applications [20].
Figure 12. Vasopressin a Possible Treatment Option for Autism Spectrum Disorder [20].
20. László, K., et al., Vasopressin as Possible Treatment Option in Autism Spectrum Disorder. 2023. 11(10): p. 2603.
The researcher delves into the implications of low vasopressin levels in individuals with autism, exploring the potential link between vasopressin and social cognition deficits. While considering cerebrospinal fluid (CSF) as a reservoir for brain-related chemicals, the study, involving both monkey and human subjects, focuses on understanding vasopressin's role in autism. The researcher hypothesizes a deficiency in vasopressin production and discusses forthcoming experiments, including postmortem brain tissue analysis, to examine vasopressin production, gene expression, and cell count. The potential therapeutic implications arise, suggesting a subset of children with autism might benefit from vasopressin replacement. Additionally, the discussion extends to physiological features associated with vasopressin, such as excessive thirst and urination, raising the possibility of overlooked connections between autism and these features. The researcher acknowledges the need for further studies and emphasizes the importance of interdisciplinary collaboration to uncover comprehensive insights into autism's underlying mechanisms [21].
Figure 13. Neuromodulation via the Cerebrospinal Fluid [22].
21. Faraci, F.M., W.G. Mayhan, and D.D. Heistad, Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V1)-receptors. 1990. 258(1): p. R94-R98.
22. Bjorefeldt, A., et al., Neuromodulation via the Cerebrospinal Fluid: Insights from Recent in Vitro Studies. 2018. 12.
The researcher discusses the cautious approach to addressing inquiries about vasopressin availability, emphasizing the need for controlled clinical trials due to potentially severe adverse effects on blood pressure and vasodilation. Collaborating with a child psychiatrist, the researcher conducted a groundbreaking vasopressin treatment trial in children with autism, utilizing the Social Responsiveness Scale (SRS) as a primary outcome measure. The trial, employing a randomized, placebo-controlled design, revealed significant improvements in social abilities among children treated with vasopressin compared to the placebo group. The study explored parent reports, clinician evaluations, and laboratory-based tests, demonstrating convergent validity. The researcher acknowledges budget constraints limiting additional measures, and the immediate versus long-term effects remain unknown. Despite inquiries about personal experimentation, the researcher hasn't tested vasopressin personally, citing the responsible and compassionate approach adopted by clinicians in understanding the drugs they administer. The conversation touches on the potential for neuroplasticity and the need for further investigations, highlighting the promising outcomes and potential therapeutic impact of vasopressin in addressing social deficits in autism [23].
23. Parker, K.J., et al., A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Sci Transl Med, 2019. 11(491).
The researcher acknowledges that not all children in the vasopressin treatment trial showed a positive response, emphasizing the ongoing efforts to replicate the study in a larger sample for more conclusive results. The pilot trial lacked stratification of participants, prompting concerns about whether the initial success was due to chance or if vasopressin has broader applications within the autistic population. The researcher highlights anecdotal reports, such as a parent's observation of their child engaging in unprecedented social interactions while on vasopressin. The nasal spray delivery method, though non-specific, allows vasopressin access to the brain, raising questions about its impact on specific circuits, social motivation, or sensory processing. The discussion underscores the complexity of social cognition and the need for advanced imaging studies to identify brain regions affected by vasopressin, potentially paving the way for more targeted interventions. The urgency of finding solutions for parents and the ethical responsibility to explore impactful medications, even without a fully understood mechanism of action, underscores the importance of advancing scientifically sound research in the field of autism treatment [24].
Figure 14. The Biology of Vasopressin [25].
24. Mitra, A.K., Oxytocin, and vasopressin: the social networking buttons of the body. AIMS Molecular Science, 2021. 8(1): p. 32-50.
25. Sparapani, S., et al., The Biology of Vasopressin. 2021. 9(1): p. 89.
The researcher highlights a compelling mouse study that investigates the relationship between gut microbiota, oxytocin, vasopressin, and social behavior. In genetically modified mice with social impairments and low blood oxytocin levels, administering a probiotic normalized social functioning, increased oxytocin and vasopressin levels in the hypothalamus, and upregulated gene expression. The study suggests that the gut microbiome's influence on the vagus nerve, which has a direct projection to the hypothalamus, plays a crucial role in regulating social behavior. Severing the vagus nerve diminished the rescue effect on oxytocin levels and social behavior, indicating the importance of the vagal pathway in this response. The researcher finds this connection intriguing and contemplates the potential implications for understanding the microbiome's impact on social behavior in autism. Additionally, the researcher mentions the relevance of fecal transplants and expresses interest in exploring vagal nerve stimulation as a means to alter social behavior in individuals with autism, emphasizing the need for further investigation into these mechanisms [26].
Figure 15. How the gut microbiota regulates blood pressure [26].
26. Marques, F.Z., C.R. Mackay, and D.M. Kaye, Beyond gut feelings: how the gut microbiota regulates blood pressure. Nature Reviews Cardiology, 2018. 15(1): p. 20-32.
The researcher discusses a contrasting pharmaceutical trial that used a vasopressin v1a receptor antagonist (bapin) in treating autism, unlike the vasopressin agonist used in his or her study. The pharmaceutical trial, conducted by Roche, employed an approach that seemed counterintuitive, blocking vasopressin pathways instead of augmenting them. The trial's primary outcome measure, the social responsiveness scale, yielded negative results, leading to a futility analysis and trial termination. The researcher expresses skepticism about the choice of an antagonist and highlights the lack of a clear mechanism for their approach. In contrast, the researcher emphasizes the pro-social evidence from their work using vasopressin agonists, especially given positive findings in both animal models and an initial pilot trial in children with autism. The ongoing larger trial aims to further validate their initial pilot findings and potentially provide more insights into the efficacy of vasopressin administration for improving social behavior in individuals with autism [27].
Figure 16. The Roles of Oxytocin and CD38 in Social or Parental Behavior [27].
27. Lopatina, O., et al., The Roles of Oxytocin and CD38 in Social or Parental Behaviors. 2013. 6.
The conversation delves into the historical context of vaccine-related fears in the wake of Andrew Wakefield's fraudulent study linking vaccines to autism. The researcher clarifies that the study was debunked, and Wakefield lost his medical license due to data fabrication. The subsequent investigations, despite debunking the link, led to changes in vaccine preservatives for public reassurance. The researcher emphasizes the consensus within the scientific and medical community, indicating no correlation between vaccines and autism. However, the discussion shifts to concerns about the increasing number of vaccinations over the years, with some questioning which vaccines are critical. The researcher notes that due to the controversy, some researchers avoided studying immunology and autism. Recently, there is a growing acknowledgment of immune system dysregulation in some individuals with autism, prompting further investigation. The researcher highlights the importance of evidence-based discussions, the need to listen to parent stakeholders, and the challenges scientists face in choosing research topics amid fears and cancel culture [28].
28. Gerber, J.S. and P.A. Offit, Vaccines and autism: a tale of shifting hypotheses. Clin Infect Dis, 2009. 48(4): p. 456-61.