S OCIAL COGNITION IN PEOPLE WITH AUTISM : R OLE OF N EUROPEPTIDES - PDF document

S OCIAL COGNITION IN PEOPLE WITH AUTISM : R OLE OF N EUROPEPTIDES Karen J. Parker, PhD Department of Psychiatry and Behavioral Sciences March 4, 2016 Faculty Disclosure Statement  Nothing to disclose Talk Overview  What is autism?  Challenges for understanding and treating autism  Neuropeptide biomarker studies in patients with autism  Neuropeptide treatment trials in patients with autism  Monkey model: Naturally occurring social impairments

Autism Spectrum Disorder (ASD) Core social cognition impairments o Eye contact, joint attention o Recognize and respond to emotions in others o Understand others’ intentions o Reciprocal social interactions; peer relationships Three Cases: Same Disease Mechanisms? Same Therapeutics? IQ of 165 Math precocious, perfect pitch Socially interested – one friend but often bullied Comorbid anxiety and depression Impaired prosody Restricted interests (trains, dogs) Adherence to rigid routine Average IQ IDD Non ‐ verbal Socially avoidant No friends, impaired social interactions Severely impaired social function Delayed language acquisition Hand ‐ flapping, head ‐ banging Sensory abnormalities (noise) Repetitive speech Restricted interests (computers) Comorbid epilepsy and aggression ASD: Challenges and Barriers to Progress  Behavioral therapies: expensive and variably effective  Drug therapies: No effective therapeutic for social deficits o Existing drugs treat associated features (irritability); side effects  Basic biology of autism not well understood o Difficult to directly study disease biology o Human genetic studies will not experimentally unravel mechanisms o Few valid animal models  Why is biomarker identification important? Identify subtypes o Enable (potentially very) early detection o Provide a biological target for drug development o Provide a predictor of prognosis or treatment response o

Parker Lab Overview: Social Neurosciences Research Program Clinical research in children: Preclinical research in young monkeys: Biomarkers of social functioning Monkey model of social impairments Drug therapies to treat social deficits Understand basic biology, test therapeutics “Back Translation” “Forward Translation” http://med.stanford.edu/parkerlab.html Biomarker Discovery for Autism Neurobiological systems critical for adaptive social functioning are the most promising candidates: OXYTOCIN “Mother Love: What Turns it on?” ‐ Klopfer 1971 Oxytocin receptors are highly concentrated in brain areas involved in social behavior Montane Vole Prairie Vole Receptors Receptors in In the “Right” the “Wrong” Brain regions Brain regions Oxytocin → Oxytocin → Pair ‐ bond No Pair ‐ bond Insel and Shapiro 1992, PNAS

Oxytocin Administration Enhances Social Cognition in Humans Gazing at eyes Reading the Mind in the Eyes Sharing others’ emotional states Neg Pos Neutr Decreased amygdala response to fear ‐ inducing stimuli “Oxytocin ‐ Deficit” Hypothesis of Autism Prior Blood OXT Studies:  3 studies: OXT levels ASD < Controls  1 study: No difference  1 study: OXT levels ASD > Controls Various Limitations:  Small study cohorts  Normative data for control OXT levels  Non ‐ gold standard assay techniques  Non ‐ gold standard methods for ASD diagnosis  Did not examine OXT x social behavior  No sibling analyses to assess “broader autism phenotype” Genetic variability in OXTR gene: A risk factor for ASD? • Association studies: Several SNPs/haplotype blocks increase risk for ASD • Genome ‐ wide scans: 3p25 region may be associated with ASD • Candidate gene studies: Intronic OXTR SNPs (rs2254298 and rs53576) in neurotypical and various patient populations implicated in social functioning

Study Design and Participant Recruitment (with Drs. Hardan, Hallmayer, Phillips)  Children ages 3 to 12 years o N=79 with ASD o N=52 Unaffected sibs o N=62 neurotypical controls  IQ > 50; In good medical health  ASD: DSM ‐ IV ‐ TR; confirmed by ADOS and ADI ‐ R o  Non ‐ ASD: o No history of psychiatric problems  Blood collection ◦ OXT levels; OXTR gene variants  Social functioning o Vineland, NEPSY ‐ II, SRS Specific Aims  Aim 1: Test the prevalent but not well interrogated “OXT ‐ deficit” hypothesis of ASD ◦ Are blood OXT levels lower in children with ASD? Are sibling OXT levels intermediate? ◦ Affected by sex and/or OXTR SNPs?  Aim 2: Do blood OXT levels and OXTR SNPs: ◦ H1: Interact to produce ASD social phenotypes? ◦ H2: Exert Differential Social phenotypic effects in ASD? ◦ H3: Have similar social phenotypic effects independent of disease status? No Group Differences in Blood OXT Levels Parker et al 2014, PNAS

Blood OXT levels: Predict social functioning in all children Children with autism who have lower oxytocin levels are at increased risk for social deficits Parker et al 2014, PNAS OXTR genetic variants: Predict social functioning in all children Parker et al 2014, PNAS Children with autism who have certain OXTR variants are at increased risk for social deficits OXTR Numbers: Diminished in Autism and Related to Social Impairments 160 Vineland Daily Living Skills Domain 180 Social Responsiveness Scale 160 140 140 120 120 100 80 100 60 80 40 60 20 40 ASD 20 HC 0 0 -5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.5 -5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.5 OXTR Gene expression (-  CT) OXTR Gene expression (-  CT) Autism Screening Tool (reverse scored) Parker lab, unpublished data

OXT Biomarker Studies: Summary and Thoughts for Informed Treatment Trials  Blood OXT levels and OXTR genotypes contribute to the severity of social deficits in children with autism  Diminished OXTR gene expression is related to ASD and variation in social functioning  Who is most likely to benefit from OXT treatment? Six Published OXT Treatment Trials Stanford Intranasal Oxytocin Treatment Trial Our study: Boys and girls ages 6 ‐ 12 N=47 signed consents N=30 completed Aim 1: Does oxytocin treatment enhance social functioning in children with autism?

Stanford Intranasal Oxytocin Treatment Trial Change in Social Responsiveness Scale Total Score 40 30 = OXT Responder = OXT Non-Responder 20 10 0 -10 -20 -30 -40 Aim 2: Do pre ‐ treatment measurements (e.g., type/severity of social impairments; blood ‐ based biomarkers) predict treatment efficacy? Arginine Vasopressin (AVP; aka ADH): An unexplored ASD biomarker and therapeutic Animal research:  AVP vs. OXT selectively enhances social functioning in male rodents  Selective AVPR V 1a antagonists impair social functioning even in the presence of normal OXT signaling in mice, rats, and voles  AVPRv1a in primate extended neural amygdala – not oxytocin! Human neurotypical research:  Enhances memory for happy and angry social information  Enhances identification of social words  Enhances cooperative behavior Human clinical research:  Enhances speech/word formation (post ‐ stroke aphasia)  Improves short/long ‐ term memory (central diabetes insipidus) Blood vasopressin levels positively predict theory of mind scores in children with autism 22 Theory of Mind Score 20 18 16 Non-ASD Children ASD Children 14 0.4 0.6 0.8 1.0 2.0 Plasma AVP Concentration (pg/ml) Carson et al 2015, PLOS ONE

First Intranasal Vasopressin Treatment Trial Our study: Boys and girls ages 6 ‐ 12 years N=50 signed consents N=20 completed Aim 1: Does vasopressin treatment enhance social functioning in children with autism? Aim 2: Do blood ‐ based biomarkers predict treatment efficacy? ASD: Challenges and Barriers to Progress  Need better animal models o Mouse models (deletion of 16p11.2; duplication of 15q11 ‐ 13) do not show social deficits o Complex social cognition most relevant to ASD simply not present in mice o Gene expression and brain anatomy differ significantly in rodents vs. humans and monkeys Human Genetics Evidence Points to Benefits for Studying “Naturally Occurring” Social Deficits Genetics of Autism, 2016 Constantino & Todd Genetic Burden is largely polygenic; Can engineer a Fragile ‐ X but not a polygenic monkey Arch Gen Psychiatry . 2003;60(5):524 ‐ 530

Naturally Occurring Social Impairments in a Rhesus Macaque Population Monkey social behavior: • Like humans, stable individual differences in social behavior • At the extremes: low social vs. high social male monkeys • Initiate and receive fewer affiliative interactions • Solicit grooming less • Spend less time grooming and playing with conspecifics • Display more inappropriate social behaviors • Diminished social interest and less social competence • Where and how to rapidly identify extreme monkeys? Where to Develop the Model? The California National Primate Research Center Resource: • 5,000+ rhesus monkeys • Large cohort = greater number of monkeys at the extremes • Housed in outdoor ½ acre corrals • Mixed M/F groups of 90 ‐ 175 animals • All ages; study across lifespan • Bred to preserve genetic heterogeneity • How to rapidly and accurately identify the extremes? BBA as a High ‐ Throughput Screening Tool? Predicting the Social Extremes BBA Data Known Low Social Monkeys Known High Social Monkeys