Dr. Karen J. Parker is the inaugural Truong-Tan Broadcom Endowed Professor, Chair of the Major Laboratories Steering Committee, and Associate Chair for Research Strategy and Oversight, in the Department of Psychiatry and Behavioral Sciences at the Stanford University School of Medicine. She is also Professor, by courtesy, of Comparative Medicine at Stanford University.

Dr. Parker directs the Social Neurosciences Research Program, which seeks to advance understanding of the biological basis of social functioning across a range of species, and to translate these fundamental insights to drive diagnostic and treatment advances for patients with social impairment. Her core research interests include: oxytocin and vasopressin signaling pathways, development of valid animal models for streamlined translation and clinical impact, and biomarker discovery and therapeutic testing in children with autism spectrum disorder.

Dr. Parker’s research has been supported by the National Institutes of Health (NIH), Simons Foundation, and Department of Defense, published in leading scientific journals, and featured across diverse media outlets (e.g., NPR, CBS, New York Times, LA Times, Science, Scientific American). Dr. Parker received her undergraduate and graduate degrees from the University of Michigan. She completed postdoctoral training at Stanford University and joined the Stanford faculty thereafter. She is an Affiliate Scientist at the California National Primate Research Center, an elected fellow of the American College of Neuropsychopharmacology (ACNP), and a Kavli fellow of the U.S. National Academy of Sciences. She has attended key opinion leader meetings at the U.S. National Academies, NIH, and private foundations, and has held leadership positions on international research advisory committees (e.g., Society for Neuroscience; ACNP).

Academic Appointments

Administrative Appointments

  • Associate Chair, Research Strategy and Oversight, Stanford Department of Psychiatry (2019 - Present)
  • Chair, Major Laboratories Steering Committee, Stanford Department of Psychiatry (2019 - Present)
  • Vice Chair, Major Laboratories Steering Committee, Stanford Department of Psychiatry (2018 - 2019)
  • Affiliate Scientist, California National Primate Research Center (2012 - Present)

Honors & Awards

  • Fellow, American College of Neuropsychopharmacology
  • Chairman's Award for Advancing Science, Dept. of Psychiatry, Stanford University
  • George A. Miller Award, American Psychological Association
  • Kavli Fellow, U.S. National Academy of Sciences

Boards, Advisory Committees, Professional Organizations

  • Member of Executive Advisory Board, Wisconsin National Primate Research Center, University of Wisconsin, Madison (2023 - Present)
  • Member of Constitution and Rules Committee, American College of Neuropsychopharmacology (2021 - Present)
  • Faculty Advisor, BrainMind (2019 - Present)
  • Chair of Animal Research Committee, American College of Neuropsychopharmacology (2019 - 2020)
  • Member of Committee on Animals in Research, Society for Neuroscience (2018 - 2022)
  • Member of Animal Research Committee, American College of Neuropsychopharmacology (2017 - 2020)
  • Member of Women's Task Force, American College of Neuropsychopharmacology (2017 - 2020)
  • Editorial Board Member, Psychoneuroendocrinology (2013 - Present)
  • Member of BRLE Grant Review Panel, National Institutes of Health (2012 - 2018)

Professional Education

  • Postdoctoral, Stanford University, Psychiatry Neuroscience
  • Ph.D., University of Michigan, Biological Psychology
  • A.B., University of Michigan, Psychology

Current Research and Scholarly Interests

The principal goal of the Parker Lab Social Neurosciences Research Program at Stanford University is to better understand the biology of social functioning using an integrative, translational approach. Our behavioral research spans studies of individual differences in animal social development to studies of social cognition impairments in various clinical populations (e.g., in children with autism; in survivors of pediatric hypothalamic-pituitary tumors; in adults with depressive and anxiety disorders). Our biological studies employ epigenetic, gene expression, and neurotransmitter-based approaches to identify biomarkers of impaired social functioning, and we also conduct treatment trials to test the efficacy of novel pharmacotherapies to improve social abilities in animal models and in patients with social deficits. Our lab is particularly interested in testing whether “social” neuropeptide (e.g., oxytocin and arginine vasopressin) signaling pathways are implicated in human and non-human primate social behavior, and whether these neuropeptide pathways are robust biomarkers of, and treatment targets for, social impairments in clinical populations.

Clinical Trials

  • Intranasal Vasopressin Treatment in Children With Autism Recruiting

    The purpose of this clinical trial is to investigate the effectiveness of vasopressin nasal spray for treating symptoms associated with autism. Vasopressin is a hormone that is produced naturally within the body and has been implicated in regulating social behaviors. It has been proposed that administration of the hormone may also help improve social functioning in individuals with autism.

    View full details

  • Intranasal Oxytocin Treatment for Social Deficits in Children With Autism Not Recruiting

    Autism is a pervasive developmental disorder characterized by core deficits in social behavior and communication, and the presence of repetitive or stereotyped behaviors. It is one of three recognized disorders in the autism spectrum which affects an estimated 1 in 88 children in the United States. At present, pharmacotherapies target only associated features of autism, with no effective drug treatments for the social impairments. Several lines of evidence now suggest that the neuropeptide oxytocin (OT) may be an effective treatment for the core social deficits in autism. Here we will test the effects of twice daily intranasal OT (24 IU) over a 4-week period for enhancing social deficits in male and female children aged 6-12 years with autism. This research has high potential to lead to the development of more effective treatments and earlier interventions for children with autism.

    Stanford is currently not accepting patients for this trial. For more information, please contact Robin Libove, BS, (650) 736-1235.

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  • The Role of Vasopressin in the Social Deficits of Autism Not Recruiting

    Researchers at the Stanford University School of Medicine are seeking participants for a study examining the effectiveness of vasopressin, a neuropeptide, in treating children with autism spectrum disorder. Difficulty with social interactions is characteristic of people with autism, who often have problems interpreting facial expressions or maintaining eye contact while talking with someone. There are currently no effective medicines available to treat social problems in individuals with autism. Neuropeptides, such as vasopressin and oxytocin, are molecules used by neurons in the brain to communicate with one another. Vasopressin is closely related to oxytocin, which is currently being tested as a treatment for autism, and has been shown to enhance social functioning in animals. Animal studies have shown that when the proper functioning of vasopressin is experimentally altered, animals develop a variety of social deficits, including impaired memory for peers and a reduced interest in social interaction. Researchers found that when vasopressin was administered to mice with a genetically induced form of autism, their social functioning improved. Vasopressin is already approved by the Food and Drug Administration for use in humans, and has proved to be a successful treatment for some common pediatric conditions, including bedwetting. Similar to oxytocin, it also has been shown to improve social cognition and memory in people who do not have autism. The researchers will test the effects of vasopressin on social impairments in 50 boys and girls with autism, ages 6 to 12 years old. The study will last four weeks for each participant. Participants will receive either vasopressin or a placebo nasal spray. At the end of this phase of the study, those who received the placebo will have the option of participating in a four-week trial during which they will be given vasopressin. Stanford is the only site for the study. Participants do not need to live locally but will need to come to the Stanford University Department of Psychiatry and Behavioral Sciences for study visits.

    Stanford is currently not accepting patients for this trial. For more information, please contact Robin A Libove, BS, 650-736-1235.

    View full details


  • See Lab website for current projects:, Stanford University


    Stanford University; California National Primate Research Center; Caribbean Primate Research Center


2023-24 Courses

Stanford Advisees

All Publications

  • Tales from the life and lab of a female social neuroscientist COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY Parker, K. J. 2023; 16
  • Rhesus macaque social functioning is paternally, but not maternally, inherited by sons: potential implications for autism. Molecular autism Garner, J. P., Talbot, C. F., Del Rosso, L. A., McCowan, B., Kanthaswamy, S., Haig, D., Capitanio, J. P., Parker, K. J. 2023; 14 (1): 25


    BACKGROUND: Quantitative autistic traits are common, heritable, and continuously distributed across the general human population. Patterns of autistic traits within families suggest that more complex mechanisms than simple Mendelian inheritance-in particular, parent of origin effects-may be involved. The ideal strategy for ascertaining parent of origin effects is by half-sibling analysis, where half-siblings share one, but not both, parents and each individual belongs to a unique combination of paternal and maternal half-siblings. While this family structure is rare in humans, many of our primate relatives, including rhesus macaques, have promiscuous breeding systems that consistently produce paternal and maternal half-siblings for a given index animal. Rhesus macaques, like humans, also exhibit pronounced variation in social functioning.METHODS: Here we assessed differential paternal versus maternal inheritance of social functioning in male rhesus macaque offspring (N=407) using ethological observations and ratings on a reverse-translated quantitative autistic trait measurement scale. Restricted Maximum Likelihood mixed models with unbounded variance estimates were used to estimate the variance components needed to calculate the genetic contribution of parents as the proportion of phenotypic variance (sigma2P) between sons that could uniquely be attributed to their shared genetics (sigma2g), expressed as sigma2g/sigma2P (or the proportion of phenotypic variance attributable to genetic variance), as well as narrow sense heritability (h2).RESULTS: Genetic contributions and heritability estimates were strong and highly significant for sons who shared a father but weak and non-significant for sons who shared a mother. Importantly, these findings were detected using the same scores from the same sons in the same analysis, confirmed when paternal and maternal half-siblings were analyzed separately, and observed with two methodologically distinct behavioral measures. Finally, genetic contributions were similar for full-siblings versus half-siblings that shared only a father, further supporting a selective paternal inheritance effect.LIMITATIONS: These data are correlational by nature. A larger sample that includes female subjects, enables deeper pedigree assessments, and supports molecular genetic analyses is warranted.CONCLUSIONS: Rhesus macaque social functioning may be paternally, but not maternally, inherited by sons. With continued investigation, this approach may yield important insights into sex differences in autism's genetic liability.

    View details for DOI 10.1186/s13229-023-00556-3

    View details for PubMedID 37480043

  • ACOUSTICALLY-DRIVEN PHONEME REMOVAL THAT PRESERVES VOCAL AFFECT CUES. Proceedings of the ... IEEE International Conference on Acoustics, Speech, and Signal Processing. ICASSP (Conference) Noufi, C., Berger, J., Frank, M., Parker, K., Bowling, D. L. 2023; 2023


    In this paper, we propose a method for removing linguistic information from speech for the purpose of isolating paralinguistic indicators of affect. The immediate utility of this method lies in clinical tests of sensitivity to vocal affect that are not confounded by language, which is impaired in a variety of clinical populations. The method is based on simultaneous recordings of speech audio and electroglotto-graphic (EGG) signals. The speech audio signal is used to estimate the average vocal tract filter response and amplitude envelop. The EGG signal supplies a direct correlate of voice source activity that is mostly independent of phonetic articulation. These signals are used to create a third signal designed to capture as much paralinguistic information from the vocal production system as possible-maximizing the retention of bioacoustic cues to affect-while eliminating phonetic cues to verbal meaning. To evaluate the success of this method, we studied the perception of corresponding speech audio and transformed EGG signals in an affect rating experiment with online listeners. The results show a high degree of similarity in the perceived affect of matched signals, indicating that our method is effective.

    View details for DOI 10.1109/icassp49357.2023.10095942

    View details for PubMedID 37701064

    View details for PubMedCentralID PMC10495117

  • Rhesus monkey sociality is stable across time and linked to variation in the initiation but not receipt of prosocial behavior. American journal of primatology Talbot, C. F., Madrid, J. E., Del Rosso, L. A., Capitanio, J. P., Garner, J. P., Parker, K. J. 2022: e23442


    Rhesus monkeys and humans are highly social primates, yet both species exhibit pronounced variation in social functioning, spanning a spectrum of sociality. Naturally occurring low sociality in rhesus monkeys may be a promising construct by which to model social impairments relevant to human autism spectrum disorder (ASD), particularly if low sociality is found to be stable across time and associated with diminished social motivation. Thus, to better characterize variation in sociality and social communication profiles, we performed quantitative social behavior assessments on N=95 male rhesus macaques (Macaca mulatta) housed in large, outdoor groups. In Study 1, we determined the social classification of our subjects by rank-ordering their total frequency of nonsocial behavior. Monkeys with the greatest frequency of nonsocial behavior were classified as low-social (n=20) and monkeys with the lowest frequency of nonsocial behavior were classified as high-social (n=21). To assess group differences in social communication profiles, in Study 2, we quantified the rates of transient social communication signals, and whether these social signals were initiated by or directed towards the focal subject. Finally, in Study 3, we assessed the within-individual stability of sociality in a subset of monkeys (n=11 low-social, n=11 high-social) 2 years following our initial observations. Nonsocial behavior frequency significantly correlated across the two timepoints (Studies 1 and 3). Likewise, low-social versus high-social classification accurately predicted classification 2 years later. Low-social monkeys initiated less prosocial behavior than high-social monkeys, but groups did not differ in receipt of prosocial behavior, nor did they differ in threat behavior. These findings indicate that sociality is a stable, trait-like characteristic and that low sociality is linked to diminished initiation of prosocial behavior in rhesus macaques. This evidence also suggests that low sociality may be a useful construct for gaining mechanistic insight into the social motivational deficits often observed in people with ASD.

    View details for DOI 10.1002/ajp.23442

    View details for PubMedID 36268602

  • Reading the mind in the eyes in PTSD: Limited Moderation by the presence of a service dog. Journal of psychiatric research Woodward, S. H., Jamison, A. L., Khan, C., Gala, S., Bhowmick, C., Villasenor, D., Tamayo, G., Puckett, M., Parker, K. J. 2022; 155: 320-330


    Persons with posttraumatic stress disorder (PTSD) frequently experience relationship failures in family and occupational domains resulting in loss of social supports. Prior research has implicated impairments in social cognition. The Reading the Mind in the Eyes Test (RMET) measures a key component of social cognition, the ability to infer the internal states of other persons based on features of the eyes region of the face; however, studies administering this popular test to persons with PTSD have yielded mixed results. This study assessed RMET performance in 47 male U.S. military Veterans with chronic, severe PTSD. Employing a within-subjects design that avoided selection biases, it aimed specifically to determine whether components of RMET performance, including accuracy, response latency, and stimulus dwell time, were improved by the company of a service dog, an intervention that has improved social function in other populations. RMET accuracies and response latencies in this PTSD sample were in the normal range. The presence of a familiar service dog did not improve RMET accuracy, reduce response latencies, or increase dwell times. Dog presence increased the speed of visual scanning perhaps consistent with reduced social fear.

    View details for DOI 10.1016/j.jpsychires.2022.09.012

    View details for PubMedID 36174367

  • Linking oxytocin and arginine vasopressin signaling abnormalities to social behavior impairments in Prader-Willi syndrome. Neuroscience and biobehavioral reviews Oztan, O., Zyga, O., Stafford, D. E., Parker, K. J. 2022: 104870


    Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder. Global hypothalamic dysfunction is a core feature of PWS and has been implicated as a driver of many of PWS's phenotypic characteristics (e.g., hyperphagia-induced obesity, hypogonadism, short stature). Although the two neuropeptides (i.e., oxytocin [OXT] and arginine vasopressin [AVP]) most implicated in mammalian prosocial functioning are of hypothalamic origin, and social functioning is markedly impaired in PWS, there has been little consideration of how dysregulation of these neuropeptide signaling pathways may contribute to PWS's social behavior impairments. The present article addresses this gap in knowledge by providing a comprehensive review of the preclinical and clinical PWS literature-spanning endogenous neuropeptide measurement to exogenous neuropeptide administration studies-to better understand the roles of OXT and AVP signaling in this population. The preponderance of evidence indicates that OXT and AVP signaling are indeed dysregulated in PWS, and that these neuropeptide pathways may provide promising targets for therapeutic intervention in a patient population that currently lacks a pharmacological strategy for its debilitating social behavior symptoms.

    View details for DOI 10.1016/j.neubiorev.2022.104870

    View details for PubMedID 36113782

  • Advances in human oxytocin measurement: challenges and proposed solutions. Molecular psychiatry Tabak, B. A., Leng, G., Szeto, A., Parker, K. J., Verbalis, J. G., Ziegler, T. E., Lee, M. R., Neumann, I. D., Mendez, A. J. 2022


    Oxytocin, a neuropeptide known for its role in reproduction and socioemotional processes, may hold promise as a therapeutic agent in treating social impairments in patient populations. However, research has yet to uncover precisely how to manipulate this system for clinical benefit. Moreover, inconsistent use of standardized and validated oxytocin measurement methodologies-including the design and study of hormone secretion and biochemical assays-present unresolved challenges. Human studies measuring peripheral (i.e., in plasma, saliva, or urine) or central (i.e., in cerebrospinal fluid) oxytocin concentrations have involved very diverse methods, including the use of different assay techniques, further compounding this problem. In the present review, we describe the scientific value in measuring human endogenous oxytocin concentrations, common issues in biochemical analysis and study design that researchers face when doing so, and our recommendations for improving studies using valid and reliable methodologies.

    View details for DOI 10.1038/s41380-022-01719-z

    View details for PubMedID 35999276

  • Socio-behavioral dysfunction in disorders of hypothalamic-pituitary involvement: The potential role of disease-induced oxytocin and vasopressin signaling deficits. Neuroscience and biobehavioral reviews Clarke, L., Zyga, O., Pineo-Cavanaugh, P. L., Jeng, M., Fischbein, N. J., Partap, S., Katznelson, L., Parker, K. J. 2022: 104770


    Disorders involving hypothalamic and pituitary (HPIT) structures-including craniopharyngioma, Langerhans cell histiocytosis, and intracranial germ cell tumors-can disrupt brain and endocrine function. An area of emerging clinical concern in patients with these disorders is the co-occurring socio-behavioral dysfunction that persists after standard hormone replacement therapy. Although the two neuropeptides most implicated in mammalian social functioning (oxytocin and arginine vasopressin) are of hypothalamic origin, little is known about how disease-induced damage to HPIT structures may disrupt neuropeptide signaling and, in turn, impact patients' socio-behavioral functioning. Here we provide a clinical primer on disorders of HPIT involvement and a review of neuropeptide signaling and socio-behavioral functioning in relevant animal models and patient populations. This collective evidence suggests that neuropeptide signaling disruptions contribute to socio-behavioral deficits experienced by patients with disorders of HPIT involvement. A better understanding of the biological underpinnings of patients' socio-behavioral symptoms is now needed to enable the development of the first targeted pharmacological strategies by which to manage patients' socio-behavioral dysfunction.

    View details for DOI 10.1016/j.neubiorev.2022.104770

    View details for PubMedID 35803395

  • Leveraging a translational research approach to drive diagnostic and treatment advances for autism. Molecular psychiatry Parker, K. J. 2022


    Autism spectrum disorder (ASD) is a prevalent and poorly understood neurodevelopmental disorder. There are currently no laboratory-based diagnostic tests to detect ASD, nor are there any disease-modifying medications that effectively treat ASD's core behavioral symptoms. Scientific progress has been impeded, in part, by overreliance on model organisms that fundamentally lack the sophisticated social and cognitive abilities essential for modeling ASD. We therefore saw significant value in studying naturally low-social rhesus monkeys to model human social impairment, taking advantage of a large outdoor-housed colony for behavioral screening and biomarker identification. Careful development and validation of our animal model, combined with a strong commitment to evaluating the translational utility of our preclinical findings directly in patients with ASD, yielded a robust neurochemical marker (cerebrospinal fluid vasopressin concentration) of trans-primate social impairment and a first-in-class medication (intranasal vasopressin) shown in a small phase 2a pilot trial to improve social abilities in children with ASD. This translational research approach stands to advance our understanding of ASD in a manner not readily achievable with existing animal models, and can be adapted to investigate a variety of other human brain disorders which currently lack valid preclinical options, thereby streamlining translation and amplifying clinical impact more broadly.

    View details for DOI 10.1038/s41380-022-01532-8

    View details for PubMedID 35365807

  • Oxytocin and the social facilitation of placebo effects. Molecular psychiatry Itskovich, E., Bowling, D. L., Garner, J. P., Parker, K. J. 2022


    Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this "improvement" reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, therebyproviding a biological basis for assessing this fundamental non-specific element of medical care.

    View details for DOI 10.1038/s41380-022-01515-9

    View details for PubMedID 35338314

  • Characterizing Emotion Recognition and Theory of Mind Performance Profiles in Unaffected Siblings of Autistic Children FRONTIERS IN PSYCHOLOGY Uljarevic, M., Bott, N. T., Libove, R. A., Phillips, J. M., Parker, K. J., Hardan, A. Y. 2022; 12: 736324


    Emotion recognition skills and the ability to understand the mental states of others are crucial for normal social functioning. Conversely, delays and impairments in these processes can have a profound impact on capability to engage in, maintain, and effectively regulate social interactions. Therefore, this study aimed to compare the performance of 42 autistic children (Mage = 8.25 years, SD = 2.22), 45 unaffected siblings (Mage = 8.65 years, SD = 2.40), and 41 typically developing (TD) controls (Mage = 8.56 years, SD = 2.35) on the Affect Recognition (AR) and Theory of Mind (TOM) subtests of the Developmental Neuropsychological Assessment Battery. There were no significant differences between siblings and TD controls. Autistic children showed significantly poorer performance on AR when compared to TD controls and on TOM when compared to both TD controls and unaffected siblings. An additional comparison of ASD, unaffected sibling and TD control subsamples, matched on full-scale IQ, revealed no group differences for either AR or TOM. AR and TOM processes have received less research attention in siblings of autistic children and remain less well characterized. Therefore, despite limitations, findings reported here contribute to our growing understanding of AR and TOM abilities in siblings of autistic children and highlight important future research directions.

    View details for DOI 10.3389/fpsyg.2021.736324

    View details for Web of Science ID 000766850000001

    View details for PubMedID 35283803

    View details for PubMedCentralID PMC8907847

  • Autism-associated biomarkers: test-retest reliability and relationship to quantitative social trait variation in rhesus monkeys. Molecular autism Oztan, O., Talbot, C. F., Argilli, E., Maness, A. C., Simmons, S. M., Mohsin, N., Del Rosso, L. A., Garner, J. P., Sherr, E. H., Capitanio, J. P., Parker, K. J. 2021; 12 (1): 50


    BACKGROUND: Rhesus monkeys (Macaca mulatta) exhibit pronounced individual differences in social traits as measured by the macaque Social Responsiveness Scale-Revised. The macaque Social Responsiveness Scale was previously adapted from the Social Responsiveness Scale, an instrument designed to assess social and autistic trait variation in humans. To better understand potential biological underpinnings of this behavioral variation, we evaluated the trait-like consistency of several biological measures previously implicated in autism (e.g., arginine vasopressin, oxytocin, and their receptors, as well as ERK1/2, PTEN, and AKT(1-3) from the RAS-MAPK and PI3K-AKT pathways). We also tested which biological measures predicted macaque Social Responsiveness Scale-Revised scores.METHODS: Cerebrospinal fluid and blood samples were collected from N=76 male monkeys, which, as a sample, showed a continuous distribution on the macaque Social Responsiveness Scale-Revised. In a subset of these subjects (n=43), samples were collected thrice over a 10-month period. The following statistical tests were used: "Case 2A" intra-class correlation coefficients of consistency, principal component analysis, and general linear modeling.RESULTS: All biological measures (except AKT) showed significant test-retest reliability within individuals across time points. We next performed principal component analysis on data from monkeys with complete biological measurement sets at the first time point (n=57), to explore potential correlations between the reliable biological measures and their relationship to macaque Social Responsiveness Scale-Revised score; a three-component solution was found. Follow-up analyses revealed that cerebrospinal fluid arginine vasopressin concentration, but no other biological measure, robustly predicted individual differences in macaque Social Responsiveness Scale-Revised scores, such that monkeys with the lowest cerebrospinal fluid arginine vasopressin concentration exhibited the greatest social impairment. Finally, we confirmed that this result held in the larger study sample (in which cerebrospinal fluid arginine vasopressin values were available from n=75 of the subjects).CONCLUSIONS: These findings indicate that cerebrospinal fluid arginine vasopressin concentration is a stable trait-like measure and that it is linked to quantitative social trait variation in male rhesus monkeys.

    View details for DOI 10.1186/s13229-021-00442-w

    View details for PubMedID 34238350

  • Assessment of medical morbidities in a rhesus monkey model of naturally occurring low sociality. Autism research : official journal of the International Society for Autism Research Myers, A. K., Talbot, C. F., Del Rosso, L. A., Maness, A. C., Simmons, S. M., Garner, J. P., Capitanio, J. P., Parker, K. J. 2021


    People with autism spectrum disorder (ASD) exhibit a variety of medical morbidities at significantly higher rates than the general population. Using an established monkey model of naturally occurring low sociality, we investigated whether low-social monkeys show an increased burden of medical morbidities compared to their high-social counterparts. We systematically reviewed the medical records of N = 152 (n = 73 low-social; n = 79 high-social) rhesus macaques (Macaca mulatta) to assess the number of traumatic injury, gastrointestinal, and inflammatory events, as well as the presence of rare medical conditions. Subjects' nonsocial scores, determined by the frequency they were observed in a nonsocial state (i.e., alone), and macaque Social Responsiveness Scale-Revised (mSRS-R) scores were also used to test whether individual differences in social functioning were related to medical morbidity burden. Medical morbidity type significantly differed by group, such that low-social monkeys incurred higher rates of traumatic injury compared to high-social monkeys. Nonsocial scores and mSRS-R scores also significantly and positively predicted traumatic injury rates, indicating that monkeys with the greatest social impairment were most impacted on this health measure. These findings from low-social monkeys are consistent with well-documented evidence that people with ASD incur a greater number of traumatic injuries and receive more peer bullying than their neurotypical peers, and add to growing evidence for the face validity of this primate model. LAY SUMMARY: People with autism exhibit multiple medical problems at higher rates than the general population. We conducted a comprehensive medical record review of monkeys that naturally exhibit differences in sociality and found that low-social monkeys are more susceptible to traumatic injuries than high-social monkeys. These results are consistent with reports that people with autism also incur greater traumatic injury and peer bullying and add to growing evidence for the validity of this monkey model.

    View details for DOI 10.1002/aur.2512

    View details for PubMedID 33847078

  • The factor structure of the macaque social responsiveness scale-revised predicts social behavior and personality dimensions. American journal of primatology Talbot, C. F., Maness, A. C., Capitanio, J. P., Parker, K. J. 2021: e23234


    Most primate species are highly social. Yet, within species, pronounced individual differences in social functioning are evident. In humans, the Social Responsiveness Scale (SRS) measures variation in social functioning. The SRS provides a quantitative measure of social functioning in natural social settings and can be used as a screening tool for autistic traits. The SRS was previously adapted for use in chimpanzees and recently refined for rhesus macaques, resulting in the macaque Social Responsiveness Scale-Revised (mSRS-R). Here, we performed an exploratory factor analysis on the mSRS-R in a large sample of male rhesus macaques (N=233). We investigated the relationships of the resulting mSRS-R factors to quantitative social behavior (alone, proximity, contact, groom, and play) and to previously-established personality dimensions (Sociability, Confidence, Irritability, and Equability). Factor analysis yielded three mSRS-R factors: Poor Social Motivation, Poor Social Attractiveness, and Inappropriate Behavior. mSRS-R factors mapped closely to social behavior and personality dimensions in rhesus macaques, providing support for this instrument's convergent and discriminant validity. Animals with higher Poor Social Motivation were more likely to be observed alone and less likely to be observed in contact and grooming with conspecifics. Animals with higher Poor Social Attractiveness were less likely to be observed playing but more likely to be observed grooming with conspecifics. Inappropriate Behavior did not predict any behavioral measure. Finally, animals with higher Poor Social Motivation and higher Poor Social Attractiveness had less sociable personalities, whereas animals with more Inappropriate Behavior were more confident and more irritable. These findings suggest that the mSRS-R is a promising, psychometrically robust tool that can be deployed to better understand the psychological factors contributing to individual differences in macaque social functioning and, with relevant species-specific modification, the SRS may hold promise for investigating variation in social functioning across diverse primate taxa.

    View details for DOI 10.1002/ajp.23234

    View details for PubMedID 33529400

  • Long-term effects of intermittent early life stress on primate prefrontal-subcortical functional connectivity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Yuan, R., Nechvatal, J. M., Buckmaster, C. L., Ayash, S., Parker, K. J., Schatzberg, A. F., Lyons, D. M., Menon, V. 2021


    Correlational studies of humans suggest that exposure to early life stress has long-term effects on neural circuits involved in vulnerability and resilience to mental health disorders. Stress-related mental health disorders are more prevalent in women than in men. Here, female squirrel monkeys are randomized to intermittently stressful (IS) social separations or a non-separated (NS) control condition conducted from 17 to 27 weeks of age. Nine years later in mid-life adulthood, resting-state functional magnetic resonance imaging was employed to parcellate prefrontal cortex (PFC). Resulting subdivisions were then used to characterize functional connectivity within PFC, and between PFC subdivisions and subcortical regions that are known to be altered by stress. Extensive hyper-connectivity of medial and orbitofrontal PFC with amygdala, hippocampus, and striatum was observed in IS compared to NS monkeys. Functional hyper-connectivity in IS monkeys was associated with previously reported indications of diminished anxiety-like behavior induced by prepubertal stress. Hyper-connectivity of PFC with amygdala and with hippocampus was also associated with increased ventral striatal dopamine D2 and/or D3 receptor (DRD2/3) availability assessed with positron emission tomography (PET) of [11C]raclopride binding in adulthood. Ventral striatal DRD2/3 availability has been linked to cognitive control, which plays a key role in stress coping as an aspect of emotion regulation. These findings provide causal support for enduring neurobiological effects of early life stress and suggest novel targets for new treatments of stress-related mental health disorders.

    View details for DOI 10.1038/s41386-021-00956-0

    View details for PubMedID 33495547

  • Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism. Autism research : official journal of the International Society for Autism Research Itskovich, E., Zyga, O., Libove, R. A., Phillips, J. M., Garner, J. P., Parker, K. J. 2020


    Impairment in social interaction is a core feature of autism spectrum disorder (ASD), but the factors which contribute to this social skill deficiency are poorly understood. Previous research has shown that cognitive ability can impact social skill development in ASD. Yet, children with ASD whose cognitive abilities are in the normal range nevertheless demonstrate deficits in social skill. More recently, the social motivation theory of ASD has emerged as a framework by which to understand how failure to seek social experiences may lead to social skill deficits. This study was designed to better understand the relationships between cognitive ability, social motivation, and social skill in a well-characterized cohort of children with ASD (n = 79), their unaffected siblings (n = 50), and unrelated neurotypical controls (n = 60). The following instruments were used: The Stanford-Binet intelligence quotient (IQ), the Social Responsiveness Scale's Social Motivation Subscale, and the Vineland Adaptive Behavior Scales' Socialization Standard Score. We found that lower cognitive ability contributed to diminished social skill, but did so universally in all children. In contrast, social motivation strongly predicted social skill only in children with ASD, such that those with the lowest social motivation exhibited the greatest social skill impairment. Notably, this relationship was observed across a large range of intellectual ability but was most pronounced in those with IQs ≥ 80. These findings establish a unique link between social motivation and social skill in ASD and support the hypothesis that low social motivation may impair social skill acquisition in this disorder, particularly in children without intellectual disability. LAY SUMMARY: The relationships between cognitive ability, social motivation, and social skill are poorly understood. Here we report that cognitive ability predicts social skill in all children, whereas social motivation predicts social skill only in children with autism. These results establish a unique link between social motivation and social skill in autism, and suggest that low social motivation may impair social skill acquisition in this disorder, particularly in those without intellectual disability.

    View details for DOI 10.1002/aur.2409

    View details for PubMedID 33280272

  • Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism AUTISM RESEARCH Itskovich, E., Zyga, O., Libove, R. A., Phillips, J. M., Garner, J. P., Parker, K. J. 2020

    View details for DOI 10.1002/aur.2409

    View details for Web of Science ID 000578768000001

  • A psychometrically robust screening tool to rapidly identify socially impaired monkeys in the general population. Autism research : official journal of the International Society for Autism Research Talbot, C. F., Garner, J. P., Maness, A. C., McCowan, B., Capitanio, J. P., Parker, K. J. 2020


    Naturally, low-social rhesus macaques exhibit social impairments with direct relevance to autism spectrum disorder (ASD). To more efficiently identify low-social individuals in a large colony, we exploited, refined, and psychometrically assessed the macaque Social Responsiveness Scale (mSRS), an instrument previously derived from the human ASD screening tool. We performed quantitative social behavior assessments and mSRS ratings on a total of N = 349 rhesus macaques (Macaca mulatta) housed in large, outdoor corrals. In one cohort (N = 116), we conducted inter-rater and test-retest reliabilities, and in a second cohort (N = 233), we evaluated the convergent construct and predictive validity of the mSRS-Revised (mSRS-R). Only 17 of the original 36 items demonstrated inter-rater and test-retest reliability, resulting in the 17-item mSRS-R. The mSRS-R showed strong validity: mSRS-R scores robustly predicted monkeys' social behavior frequencies in home corrals. Monkeys that scored 1.5 standard deviations from the mean on nonsocial behavior likewise exhibited significantly more autistic-like traits, and mSRS-R scores predicted individuals' social classification (low-social vs. high-social) with 96% accuracy (likelihood ratio chi-square = 25.07; P<0.0001). These findings indicate that the mSRS-R is a reliable, valid, and sensitive measure of social functioning, and like the human SRS, can be used as a high-throughput screening tool to identify socially impaired individuals in the general population. LAY SUMMARY: Variation in autistic traits can be measured in humans using the Social Responsiveness Scale (SRS). Here, we revised this scale for rhesus macaques (i.e., the mSRS-R), and showed that macaques exhibit individual differences in mSRS-R scores, and at the behavioral extremes, low-social vs. high-social monkeys exhibit more autistic-like traits. These results suggest that the mSRS-R can be used as a screening tool to rapidly and accurately identify low-social monkeys in the general population.

    View details for DOI 10.1002/aur.2335

    View details for PubMedID 32677285

  • Variation, plasticity, and alternative mating tactics: Revisiting what we know about the socially monogamous prairie vole ADVANCES IN THE STUDY OF BEHAVIOR, VOL 52 Madrid, J. E., Parker, K. J., Ophir, A. G., Naguib, M., Barrett, L., Healy, S. D., Podos, J., Simmons, L. W., Zuk, M. 2020; 52: 203–42
  • Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder. Proceedings of the National Academy of Sciences of the United States of America Oztan, O. n., Garner, J. P., Constantino, J. N., Parker, K. J. 2020


    Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the "social" neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at -70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

    View details for DOI 10.1073/pnas.1919050117

    View details for PubMedID 32341146

  • Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research Mariscal, M. G., Oztan, O., Rose, S. M., Libove, R. A., Jackson, L. P., Sumiyoshi, R. D., Trujillo, T. H., Carson, D. S., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2019


    Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.

    View details for DOI 10.1002/aur.2135

    View details for PubMedID 31132232

  • A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)
  • Nonlinear relationship between early life stress exposure and subsequent resilience in monkeys. Scientific reports Parker, K. J., Buckmaster, C. L., Hyde, S. A., Schatzberg, A. F., Lyons, D. M. 2019; 9 (1): 16232


    Retrospective correlational studies of humans suggest that moderate but not minimal or substantial early life stress exposure promotes the development of stress inoculation-induced resilience. Here we test for a nonlinear relationship between early life stress and resilience by comparing varying "doses" of early life stress. Juvenile squirrel monkeys underwent one of five treatment conditions between 17-27 weeks of age: Stress inoculation (SI) with continuous access to mother (SI + Mom; one stress element), SI without continuous access to mother (SI; two stress elements), SI without continuous access to mother and with alprazolam injection pretreatments (SI + Alz; three stress elements), SI without continuous access to mother and with vehicle injection pretreatments (SI + Veh; three stress elements), or standard housing (No SI; zero stress elements). Alprazolam was used to test whether anxiolytic medication diminished SI effects. Subjects exposed to one or two early life stressors subsequently responded with fewer indications of anxiety (e.g., decreased maternal clinging, increased object exploration, smaller cortisol increases) compared to No SI subjects. Subjects exposed to three early life stressors did not differ on most measures from one another or from No SI subjects. These findings provide empirical support for a nonlinear J-shaped relationship between early life stress exposure and subsequent resilience.

    View details for DOI 10.1038/s41598-019-52810-5

    View details for PubMedID 31700103

  • Cerebrospinal fluid vasopressin and symptom severity in children with autism. Annals of neurology Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., Parker, K. J. 2018


    Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30152888

  • Adaptive developmental plasticity in rhesus macaques: the serotonin transporter gene interacts with maternal care to affect juvenile social behaviour. Proceedings. Biological sciences Madrid, J. E., Mandalaywala, T. M., Coyne, S. P., Ahloy-Dallaire, J., Garner, J. P., Barr, C. S., Maestripieri, D., Parker, K. J. 2018; 285 (1881)


    Research has increasingly highlighted the role that developmental plasticity-the ability of a particular genotype to produce variable phenotypes in response to different early environments-plays as an adaptive mechanism. One of the most widely studied genetic contributors to developmental plasticity in humans and rhesus macaques is a serotonin transporter gene-linked polymorphic region (5-HTTLPR), which determines transcriptional efficiency of the serotonin transporter gene in vitro and modifies the availability of synaptic serotonin in these species. A majority of studies to date have shown that carriers of a loss-of-function variant of the 5-HTTLPR, the short (s) allele, develop a stress-reactive phenotype in response to adverse early environments compared with long (l) allele homozygotes, leading to the prevalent conceptualization of the s-allele as a vulnerability allele. However, this framework fails to address the independent evolution of these loss-of-function mutations in both humans and macaques as well as the high population prevalence of s-alleles in both species. Here we show in free-ranging rhesus macaques that s-allele carriers benefit more from supportive early social environments than l-allele homozygotes, such that s-allele carriers which receive higher levels of maternal protection during infancy demonstrate greater social competence later in life. These findings provide, to our knowledge, the first empirical support for the assertion that the s-allele grants high undirected biological sensitivity to context in primates and suggest a mechanism through which the 5-HTTLPR s-allele is maintained in primate populations.

    View details for PubMedID 29925616

  • Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Garner, J. P., Oztan, O., Tarara, E. R., Li, J., Sclafani, V., Del Rosso, L. A., Chun, K., Berquist, S. W., Chez, M. G., Partap, S., Hardan, A. Y., Sherr, E. H., Capitanio, J. P. 2018; 10 (439)


    Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.

    View details for PubMedID 29720452

  • Plasma anandamide concentrations are lower in children with autism spectrum disorder MOLECULAR AUTISM Karhson, D. S., Krasinska, K. M., Dallaire, J., Libove, R. A., Phillips, J. M., Chien, A. S., Garner, J. P., Hardan, A. Y., Parker, K. J. 2018; 9: 18


    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112).Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034).These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

    View details for PubMedID 29564080

  • Vigilance for threat accounts for inter-individual variation in physiological responses to adversity in rhesus macaques: A cognition × environment approach. Developmental psychobiology Mandalaywala, T. M., Petrullo, L. A., Parker, K. J., Maestripieri, D., Higham, J. P. 2017; 59 (8): 1031-1038


    Early life adversity (ELA) can lead to poor health later in life. However, there is significant variation in outcomes, with some individuals displaying resilience even in the face of adversity. Using longitudinal data collected from free-ranging rhesus macaques between birth and 3 years, we examined whether individual variation in vigilance for threat, an early emerging attentional bias, can account for variation in long-term outcomes between individuals reared in similar environments. We found that ELA and vigilance during infancy interact to predict physiological dysregulation in Sympathetic Nervous System (SNS) and Hypothalamic-Pituitary-Adrenal (HPA) stress responses during juvenility. During high stress periods, High ELA juveniles with high vigilance exhibit less asymmetry than High ELA juveniles with low vigilance. This suggests that although increased vigilance is viewed as a negative consequence of ELA, it might also be a mechanism by which vulnerable individuals proactively buffer themselves from negative outcomes in unstable or threatening environments.

    View details for DOI 10.1002/dev.21572

    View details for PubMedID 29071705

    View details for PubMedCentralID PMC5690846

  • Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life. Scientific reports Madrid, J. E., Oztan, O., Sclafani, V., Del Rosso, L. A., Calonder, L. A., Chun, K., Capitanio, J. P., Garner, J. P., Parker, K. J. 2017; 7 (1): 12935


    The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits.

    View details for DOI 10.1038/s41598-017-13109-5

    View details for PubMedID 29021623

    View details for PubMedCentralID PMC5636831

  • Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124


    Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

    View details for DOI 10.1073/pnas.1705521114

    View details for PubMedID 28696286

    View details for PubMedCentralID PMC5544319

  • Biomarker discovery for disease status and symptom severity in children with autism. Psychoneuroendocrinology Oztan, O. n., Jackson, L. P., Libove, R. A., Sumiyoshi, R. D., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2017; 89: 39–45


    Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

    View details for PubMedID 29309996

  • Vigilance for threat accounts for inter-individual variation in physiological responses to adversity in rhesus macaques: A cognition × environment approach. Developmental Psychobiology Mandalaywala, T. M., Petrullo, L. A., Parker, K. J., Maestripieri, D., Higham, J. P. 2017: 1031–38


    Early life adversity (ELA) can lead to poor health later in life. However, there is significant variation in outcomes, with some individuals displaying resilience even in the face of adversity. Using longitudinal data collected from free-ranging rhesus macaques between birth and 3 years, we examined whether individual variation in vigilance for threat, an early emerging attentional bias, can account for variation in long-term outcomes between individuals reared in similar environments. We found that ELA and vigilance during infancy interact to predict physiological dysregulation in Sympathetic Nervous System (SNS) and Hypothalamic-Pituitary-Adrenal (HPA) stress responses during juvenility. During high stress periods, High ELA juveniles with high vigilance exhibit less asymmetry than High ELA juveniles with low vigilance. This suggests that although increased vigilance is viewed as a negative consequence of ELA, it might also be a mechanism by which vulnerable individuals proactively buffer themselves from negative outcomes in unstable or threatening environments.

    View details for DOI 10.1002/dev.21572

    View details for PubMedCentralID PMC5690846

  • Effects of early life adversity on cortisol/salivary alpha-amylase symmetry in free-ranging juvenile rhesus macaques HORMONES AND BEHAVIOR Petrullo, L. A., Mandalaywala, T. M., Parker, K. J., Maestripieri, D., Higham, J. P. 2016; 86: 78-84


    Early life adversity (ELA) affects physiological and behavioral development. One key component is the relationship between the developing Hypothalamic-Pituitary-Adrenal (HPA) axis and the Sympathetic Nervous System (SNS). Recent studies suggest a relationship between early life adversity and asymmetry in cortisol (a measure of HPA activation) and salivary alpha-amylase (sAA: a correlate of SNS activation) responses to stress among human children, but to our knowledge there have been no comparable studies in nonhumans. Here, we investigate the responses of these two analytes in "low stress" and "high stress" situations in free-ranging juvenile rhesus macaques (Macaca mulatta) on Cayo Santiago, Puerto Rico. Behavioral data on maternal maltreatment were collected during the first 3months of life to determine individual rates of ELA, and saliva samples were collected from subjects noninvasively during juvenility. Irrespective of ELA, salivary alpha-amylase levels were lower in low stress situations and higher in high stress situations. For cortisol however, high ELA subjects exhibited higher low stress concentrations and blunted acute responses during high stress situations compared to moderate and low ELA subjects. Cortisol and sAA values were positively correlated among low ELA subjects, suggesting symmetry, but were uncorrelated or negatively correlated among moderate and high ELA subjects, suggesting asymmetry in these individuals. These findings indicate dysregulation of the stress response among juveniles maltreated during infancy: specifically, attenuated cortisol reactivity coupled with typical sAA reactivity characterize the stress response profiles of juveniles exposed to higher rates of ELA during the first 3months of life.

    View details for DOI 10.1016/j.yhbeh.2016.05.004

    View details for Web of Science ID 000388056600010

    View details for PubMedID 27170429

  • Early Predictors of Impaired Social Functioning in Male Rhesus Macaques (Macaca mulatta). PloS one Sclafani, V., Del Rosso, L. A., Seil, S. K., Calonder, L. A., Madrid, J. E., Bone, K. J., Sherr, E. H., Garner, J. P., Capitanio, J. P., Parker, K. J. 2016; 11 (10)


    Autism spectrum disorder (ASD) is characterized by social cognition impairments but its basic disease mechanisms remain poorly understood. Progress has been impeded by the absence of animal models that manifest behavioral phenotypes relevant to ASD. Rhesus monkeys are an ideal model organism to address this barrier to progress. Like humans, rhesus monkeys are highly social, possess complex social cognition abilities, and exhibit pronounced individual differences in social functioning. Moreover, we have previously shown that Low-Social (LS) vs. High-Social (HS) adult male monkeys exhibit lower social motivation and poorer social skills. It is not known, however, when these social deficits first emerge. The goals of this study were to test whether juvenile LS and HS monkeys differed as infants in their ability to process social information, and whether infant social abilities predicted later social classification (i.e., LS vs. HS), in order to facilitate earlier identification of monkeys at risk for poor social outcomes. Social classification was determined for N = 25 LS and N = 25 HS male monkeys that were 1-4 years of age. As part of a colony-wide assessment, these monkeys had previously undergone, as infants, tests of face recognition memory and the ability to respond appropriately to conspecific social signals. Monkeys later identified as LS vs. HS showed impairments in recognizing familiar vs. novel faces and in the species-typical adaptive ability to gaze avert to scenes of conspecific aggression. Additionally, multivariate logistic regression using infant social ability measures perfectly predicted later social classification of all N = 50 monkeys. These findings suggest that an early capacity to process important social information may account for differences in rhesus monkeys' motivation and competence to establish and maintain social relationships later in life. Further development of this model will facilitate identification of novel biological targets for intervention to improve social outcomes in at-risk young monkeys.

    View details for DOI 10.1371/journal.pone.0165401

    View details for PubMedID 27788195

    View details for PubMedCentralID PMC5082922

  • Endocannabinoid signaling in social functioning: an RDoC perspective. Translational Psychiatry Karhson, D. S., Hardan, A. Y., Parker, K. J. 2016

    View details for DOI 10.1038/tp.2016.169

  • Cup tool use by squirrel monkeys AMERICAN JOURNAL OF PRIMATOLOGY Buckmaster, C. L., Hyde, S. A., Parker, K. J., Lyons, D. M. 2015; 77 (12): 1323-1332


    Captive-born male and female squirrel monkeys spontaneously 'invented' a cup tool use technique to Contain (i.e., hold and control) food they reduced into fragments for consumption and to Contain water collected from a valve to drink. Food cup use was observed more frequently than water cup use. Observations indicate that 68% (n = 39/57) of monkeys in this population used a cup (a plastic slip cap) to Contain food, and a subset of these monkeys, 10% (n = 4/39), also used a cup to Contain water. Cup use was optional and did not replace, but supplemented, the hand/arm-to-mouth eating and direct valve drinking exhibited by all members of the population. Strategies monkeys used to bring food and cups together for food processing activity at preferred upper-level perching areas, in the arboreal-like environment in which they lived, provides evidence that monkeys may plan food processing activity with the cups. Specifically, prior to cup use monkeys obtained a cup first before food, or obtained food and a cup from the floor simultaneously, before transporting both items to upper-level perching areas. After food processing activity with cups monkeys rarely dropped the cups and more often placed the cups onto perching. Monkeys subsequently returned to use cups that they previously placed on perching after food processing activity. The latter behavior is consistent with the possibility that monkeys may keep cups at preferred perching sites for future food processing activity and merits experimental investigation. Reports of spontaneous tool use by squirrel monkeys are rare and this is the first report of population-level tool use. These findings offer insights into the cognitive abilities of squirrel monkeys and provide a new context for behavior studies with this genus and for comparative studies with other primates. Am. J. Primatol. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajp.22486

    View details for Web of Science ID 000363892500008

    View details for PubMedID 26436899

  • Dopamine D4 receptor genotype variation in free-ranging rhesus macaques and its association with juvenile behavior. Behavioural brain research Coyne, S. P., Lindell, S. G., Clemente, J., Barr, C. S., Parker, K. J., Maestripieri, D. 2015; 292: 50-55


    A polymorphism in the dopamine receptor D4 (DRD4) gene has been associated with significant variation in behavioral impulsivity, novelty-seeking, and risk-taking in humans and other animals. Rhesus macaques are an excellent animal model for research on the genetic basis of behavior using the candidate gene approach. Little is known, however, about allelic variation in DRD4 in large free-ranging populations of rhesus macaques and how this allelic variation relates to emotion regulation and behavior. In this study, we genotyped for the DRD4 polymorphism 178 individuals of different age and sex categories in the free-ranging rhesus macaque population on the island of Cayo Santiago, PR. Moreover, we examined the possible association between DRD4 allelic variation and three measures of juvenile behavior (time spent in proximity to the mother, avoidance of other individuals, and behavioral restlessness). Five different DRD4 alleles (5R, 5.5R, 6R, 6.5R, and 7R) were identified in the subject population. The most common allele was the 5R allele (78.5%), followed by the 7R allele (16.1%). Juveniles carrying the long form of the DRD4 allele (7R) spent less time in proximity to their mothers, avoided other individuals more often, and scored higher on behavioral restlessness than juveniles carrying the shorter alleles. Behavioral restlessness was also influenced by maternal DRD4 genotype. These results highlight both similarities and differences in the relative occurrence of DRD4 alleles and their association with behavior in this rhesus macaque population, other nonhuman primate species or populations, and humans.

    View details for DOI 10.1016/j.bbr.2015.06.014

    View details for PubMedID 26073765

  • Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children MOLECULAR PSYCHIATRY Carson, D. S., Berquist, S. W., Trujillo, T. H., Garner, J. P., Hannah, S. L., Hyde, S. A., Sumiyoshi, R. D., Jackson, L. P., MOSS, J. K., Strehlow, M. C., Cheshier, S. H., Partap, S., Hardan, A. Y., Parker, K. J. 2015; 20 (9): 1085-1090


    The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.

    View details for DOI 10.1038/mp.2014.132

    View details for Web of Science ID 000360175500009

  • Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)


    Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

    View details for DOI 10.1371/journal.pone.0132224

    View details for Web of Science ID 000358597100030

    View details for PubMedCentralID PMC4511760

  • Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates PEPTIDES Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16


    Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

    View details for DOI 10.1016/j.peptides.2014.08.003

    View details for Web of Science ID 000344232700003

  • Physiological and behavioural responses to weaning conflict in free-ranging primate infants. Animal behaviour Mandalaywala, T. M., Higham, J. P., Heistermann, M., Parker, K. J., Maestripieri, D. 2014; 97: 241-247


    Weaning, characterized by maternal reduction of resources, is both psychologically and energetically stressful to mammalian offspring. Despite the importance of physiology in this process, previous studies have reported only indirect measures of weaning stress from infants, because of the difficulties of collecting physiological measures from free-ranging mammalian infants. Here we present some of the first data on the relationship between weaning and energetic and psychological stress in infant mammals. We collected data on 47 free-ranging rhesus macaque infants on Cayo Santiago, Puerto Rico, showing that faecal glucocorticoid metabolite (fGCM) concentrations were directly related to the frequency of maternal rejection, with fGCM concentrations increasing as rates of rejection increased. Infants with higher fGCM concentrations also engaged in higher rates of mother following, and mother following was associated with increased time on the nipple, suggesting that infants that experienced greater weaning-related stress increased their efforts to maintain proximity and contact with their mothers. Infants experiencing more frequent rejection uttered more distress vocalizations when being rejected; however, there was no relationship between rates of distress vocalizations and fGCM concentrations, suggesting a disassociation between behavioural and physiological stress responses to weaning. Elevated glucocorticoid concentrations during weaning may function to mobilize energy reserves and prepare the infant for continued maternal rejection and shortage of energetic resources.

    View details for DOI 10.1016/j.anbehav.2014.09.016

    View details for PubMedID 25431499

    View details for PubMedCentralID PMC4242433

  • Early Experience Affects the Strength of Vigilance for Threat in Rhesus Monkey Infants PSYCHOLOGICAL SCIENCE Mandalaywala, T. M., Parker, K. J., Maestripieri, D. 2014; 25 (10): 1893-1902
  • Early experience affects the strength of vigilance for threat in rhesus monkey infants. Psychological science Mandalaywala, T. M., Parker, K. J., Maestripieri, D. 2014; 25 (10): 1893-902


    Both human and nonhuman primates exhibit a cognitive bias to social threat, but little is known about how this bias develops. We investigated the development of threat bias in free-ranging infant rhesus macaques (Macaca mulatta) at 3 months (n = 45) and 9 months (n = 46) of age. Three-month-olds did not display bias, but 9-month-olds exhibited increased maintenance of attention to threatening social stimuli. To examine whether the social environment affected this increased vigilance for threat, we collected behavioral data on maternal rank and protectiveness across the first 12 weeks of life for infants tested at 9 months. Among 9-month-olds, those of high-ranking and more protective mothers displayed greater vigilance for threat than those of lower-ranking and less protective mothers. These results demonstrate that infant social cognition is shaped by mothers both directly (via protectiveness) and indirectly (through social rank).

    View details for DOI 10.1177/0956797614544175

    View details for PubMedID 25125426

    View details for PubMedCentralID PMC4192014

  • Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C., Phillips, J. M., Hallmayer, J. F., Hardan, A. Y. 2014; 111 (33): 12258-12263


    The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

    View details for DOI 10.1073/pnas.1402236111

    View details for Web of Science ID 000340438800080

    View details for PubMedID 25092315

  • Emotion dysregulation and the core features of autism spectrum disorder. Journal of autism and developmental disorders Samson, A. C., Phillips, J. M., Parker, K. J., Shah, S., Gross, J. J., Hardan, A. Y. 2014; 44 (7): 1766-1772


    The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child Behavior Checklist. Compared to typically developing controls, children and adolescents with ASD showed more emotion dysregulation and had significantly greater symptom severity on all scales. Within ASD participants, emotion dysregulation was related to all core features of the disorder, but the strongest association was with repetitive behaviors. These findings may facilitate the development of more effective therapeutic strategies targeting emotion dysregulation in order to optimize long-term outcomes for individuals with ASD.

    View details for DOI 10.1007/s10803-013-2022-5

    View details for PubMedID 24362795

  • Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol. Journal of psychiatric research Yuen, K. W., Garner, J. P., Carson, D. S., Keller, J., Lembke, A., Hyde, S. A., Kenna, H. A., Tennakoon, L., Schatzberg, A. F., Parker, K. J. 2014; 51: 30-36


    The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes.

    View details for DOI 10.1016/j.jpsychires.2013.12.012

    View details for PubMedID 24405552

  • The three-hit concept of vulnerability and resilience: Toward understanding adaptation to early-life adversity outcome PSYCHONEUROENDOCRINOLOGY Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., De Kloet, E. R. 2013; 38 (9): 1858-1873


    Stressful experiences during early-life can modulate the genetic programming of specific brain circuits underlying emotional and cognitive aspects of behavioral adaptation to stressful experiences later in life. Although this programming effect exerted by experience-related factors is an important determinant of mental health, its outcome depends on cognitive inputs and hence the valence an individual assigns to a given environmental context. From this perspective we will highlight, with studies in rodents, non-human primates and humans, the three-hit concept of vulnerability and resilience to stress-related mental disorders, which is based on gene-environment interactions during critical phases of perinatal and juvenile brain development. The three-hit (i.e., hit-1: genetic predisposition, hit-2: early-life environment, and hit-3: later-life environment) concept accommodates the cumulative stress hypothesis stating that in a given context vulnerability is enhanced when failure to cope with adversity accumulates. Alternatively, the concept also points to the individual's predictive adaptive capacity, which underlies the stress inoculation and match/mismatch hypotheses. The latter hypotheses propose that the experience of relatively mild early-life adversity prepares for the future and promotes resilience to similar challenges in later-life; when a mismatch occurs between early and later-life experience, coping is compromised and vulnerability is enhanced. The three-hit concept is fundamental for understanding how individuals can either be prepared for coping with life to come and remain resilient or are unable to do so and succumb to a stress-related mental disorder, under seemingly identical circumstances.

    View details for DOI 10.1016/j.psyneuen.2013.06.008

    View details for Web of Science ID 000325188300045

    View details for PubMedID 23838101

    View details for PubMedCentralID PMC3773020

  • Neonatal CSF oxytocin levels are associated with parent report of infant soothability and sociability. Psychoneuroendocrinology Clark, C. L., St John, N., Pasca, A. M., Hyde, S. A., Hornbeak, K., Abramova, M., Feldman, H., Parker, K. J., Penn, A. A. 2013; 38 (7): 1208-1212


    Oxytocin (OT) has been linked to social behavior in rodents, non-human primates, and adult humans, but almost nothing is known about brain OT activity in human newborns or its impact on social development. To better understand the role of OT biology in human social functioning, a multi-disciplinary, longitudinal study was conducted. Cerebral spinal fluid (CSF) OT levels from 18 human neonates were evaluated and examined in relationship to social-seeking behavior at term, at 3 months, and at 6 months of age. Higher neonatal CSF OT levels were consistently associated with solicitation of parental soothing and interest in social engagement with others. This is the first study to link CSF OT levels to normative human social functioning. Research is now required to test whether early OT levels serve as a biomarker for subsequent social abnormalities.

    View details for DOI 10.1016/j.psyneuen.2012.10.017

    View details for PubMedID 23507187

  • Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Tirouvanziam, R., Obukhanych, T. V., Laval, J., Aronov, P. A., Libove, R., Banerjee, A. G., Parker, K. J., O'Hara, R., Herzenberg, L. A., Herzenberg, L. A., Hardan, A. Y. 2012; 42 (5): 827-836


    The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

    View details for DOI 10.1007/s10803-011-1314-x

    View details for Web of Science ID 000302771500017

    View details for PubMedID 21713591

  • Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome PSYCHONEUROENDOCRINOLOGY Hall, S. S., Lightbody, A. A., McCarthy, B. E., Parker, K. J., Reiss, A. L. 2012; 37 (4): 509-518


    Fragile X syndrome (FXS) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms. Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations. We investigated whether oxytocin (OT), a hormone with prosocial and anxiolytic effects, could alleviate symptoms of social anxiety in this population. A randomized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo, 24 IU OT and 48 IU OT. Measures of eye gaze frequency, heart rate, respiratory sinus arrhythmia (RSA), heart rate variability (HRV) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration. Ten low-functioning males with FXS (aged 13-28 years) traveled to Stanford for the initial visit: 8 completed the study. Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose. There was no effect of OT on heart rate, RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others. These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS. Further double-blind placebo-controlled studies of OT, conducted in combination with behavioral treatment programs, may be warranted.

    View details for DOI 10.1016/j.psyneuen.2011.07.020

    View details for Web of Science ID 000302044800007

    View details for PubMedID 21862226

    View details for PubMedCentralID PMC3353652

  • Psychological Stress in Childhood and Susceptibility to the Chronic Diseases of Aging: Moving Toward a Model of Behavioral and Biological Mechanisms PSYCHOLOGICAL BULLETIN Miller, G. E., Chen, E., Parker, K. J. 2011; 137 (6): 959-997


    Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.

    View details for DOI 10.1037/a0024768

    View details for Web of Science ID 000296471000004

    View details for PubMedID 21787044

  • A novel form of oxytocin in New World monkeys BIOLOGY LETTERS Lee, A. G., Cool, D. R., Grunwald, W. C., Neal, D. E., Buckmaster, C. L., Cheng, M. Y., Hyde, S. A., Lyons, D. M., Parker, K. J. 2011; 7 (4): 584-587


    Oxytocin is widely believed to be present and structurally identical in all placental mammals. Here, we report that multiple species of New World monkeys possess a novel form of oxytocin, [P8] oxytocin. This mutation arises from a substitution of a leucine to a proline in amino acid position 8. Further analysis of this mutation in Saimiri sciureus (squirrel monkey) indicates that [P8] oxytocin is transcribed and translated properly. This mutation is specific to oxytocin, as the peptide sequence for arginine vasopressin, a structurally related nonapeptide, is unaltered. These findings dispel the notion that all placental mammals possess a 'universal' oxytocin sequence, and highlight the need for research on the functional significance of this novel nonapeptide in New World monkeys.

    View details for DOI 10.1098/rsbl.2011.0107

    View details for PubMedID 21411453

  • Identifying key features of early stressful experiences that produce stress vulnerability and resilience in primates NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Parker, K. J., Maestripieri, D. 2011; 35 (7): 1466-1483


    This article examines the complex role of early stressful experiences in producing both vulnerability and resilience to later stress-related psychopathology in a variety of primate models of human development. Two types of models are reviewed: Parental Separation Models (e.g., isolate-rearing, peer-rearing, parental separations, and stress inoculation) and Maternal Behavior Models (e.g., foraging demands, variation in maternal style, and maternal abuse). Based on empirical evidence, it is argued that early life stress exposure does not increase adult vulnerability to stress-related psychopathology as a linear function, as is generally believed, but instead reflects a quadratic function. Features of early stress exposure including the type, duration, frequency, ecological validity, sensory modality, and developmental timing, within and between species, are identified to better understand how early stressful experiences alter neurobiological systems to produce such diverse developmental outcomes. This article concludes by identifying gaps in our current knowledge, providing directions for future research, and discussing the translational implications of these primate models for human development and psychopathology.

    View details for DOI 10.1016/j.neubiorev.2010.09.003

    View details for Web of Science ID 000292428200003

    View details for PubMedID 20851145

    View details for PubMedCentralID PMC3023826

  • Somatic and neuroendocrine responses to standard and biologically salient acoustic startle stimuli in monkeys PSYCHONEUROENDOCRINOLOGY Parker, K. J., Hyde, S. A., Buckmaster, C. L., Tanaka, S. M., Brewster, K. K., Schatzberg, A. F., Lyons, D. M., Woodward, S. H. 2011; 36 (4): 547-556


    The startle response, a simple defensive response to a sudden stimulus signaling proximal threat, has been well studied in rodents and humans, but has been rarely examined in monkeys. The first goal of the present studies was to develop a minimally immobilizing startle measurement paradigm and validate its usefulness by testing two core features of the startle response (habituation and graded responsivity) in squirrel monkey subjects. Two different types of startle stimuli were used: standard broad-band noise bursts, and species-specific alarm vocalizations ("yaps") which are elicited in response to threat in both wild and captive animals. The second goal of the present studies was to test whether yaps produce enhanced startle responsivity due to their increased biological salience compared to simple, non-biologically relevant noise bursts. The third goal of the present studies was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis response to startle stimuli, as little is known about the stress-activating role of startle stimuli in any species. These experiments determined that the whole-body startle response in relatively unrestrained squirrel monkeys habituates across repeated stimulus presentations and is proportional to stimulus intensity. In addition, differential habituation was observed across biologically salient vs. standard acoustic startle stimuli. Responses to "yaps" were larger initially but attenuated more rapidly over trials. Responses to "yaps" were also larger in the early subepochs of the response window but then achieved a lower level than responses to noise bursts in the later subepochs. Finally, adrenocorticotropic hormone and cortisol concentrations were significantly elevated above baseline after startle stimuli presentation, though monkeys did not exhibit differential HPA axis responses to the two types of startle stimuli. The development of monkey startle methodology may further enhance the utility of this paradigm in translational studies of human stress-related psychiatric disorders.

    View details for DOI 10.1016/j.psyneuen.2010.08.009

    View details for Web of Science ID 000288922300013

    View details for PubMedID 20869176

    View details for PubMedCentralID PMC3020232

  • Mu-opioid Receptor (OPRM1) Variation, Oxytocin Levels and Maternal Attachment in Free-Ranging Rhesus Macaques Macaca mulatta BEHAVIORAL NEUROSCIENCE Higham, J. P., Barr, C. S., Hoffman, C. L., Mandalaywala, T. M., Parker, K. J., Maestripieri, D. 2011; 125 (2): 131-136


    Understanding the genetic and neuroendocrine basis of the mother-infant bond is critical to understanding mammalian affiliation and attachment. Functionally similar nonsynonymous mu-opioid receptor (OPRM1) SNPs have arisen and been maintained in humans (A118G) and rhesus macaques Macaca mulatta (C77G). In rhesus macaques, variation in OPRM1 predicts individual differences in infant affiliation for mothers. Specifically, infants carrying the G allele show increased distress on separation from their mothers, and spend more time with them upon reunion, than individuals homozygous for the C allele. In humans, individuals possessing the G allele report higher perceptions of emotional pain on receiving rejection by social partners. We studied maternal behavior over the course of a year among free-ranging female rhesus macaques on Cayo Santiago, Puerto Rico. We then trapped females and collected blood samples from which we assessed OPRM1 genotype; we also collected cerebrospinal fluid samples from which we measured oxytocin (OT) levels. We show that females possessing the G allele restrain their infants more (i.e., prevent infants from separating from them by pulling them back) than females homozygous for the C allele. Females possessing the G allele also show higher OT levels when lactating, and lower OT levels when neither lactating nor pregnant, than females homozygous for the C allele. This is the first study to demonstrate an association between OPRM1 genotype and maternal attachment for infants, and is one of the first studies of any free-ranging primate population to link functional genetic variation to behavior via potentially related neuroendocrine mechanisms.

    View details for DOI 10.1037/a0022695

    View details for Web of Science ID 000289182000001

    View details for PubMedID 21463018

  • Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls PSYCHONEUROENDOCRINOLOGY Thompson, R. J., Parker, K. J., Hallmayer, J. F., Waugh, C. E., Gotlib, I. H. 2011; 36 (1): 144-147


    The nonapeptide oxytocin and its receptor have been implicated in the regulation of mammalian social behavior and stress physiology. Evidence is accumulating that the quality of the parental environment is associated with oxytocin biology in children. The present study was designed to examine the interaction of the single nucleotide polymorphism (SNP) rs2254298 within the oxytocin receptor (OXTR) gene and quality of parental environment in predicting children's psychosocial functioning. More specifically, in a sample of 92 Caucasian adolescent girls (9-14 years old), we examined whether adverse parental environment, operationalized as mothers' history of recurrent major depressive disorder, interacts with the rs2254298 SNP on the OXTR gene to predict daughters' symptoms of depression and anxiety. Caucasian girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety. These findings highlight the potential importance of this OXTR gene polymorphism in the etiology of depression and anxiety disorders.

    View details for DOI 10.1016/j.psyneuen.2010.07.003

    View details for Web of Science ID 000286299100016

    View details for PubMedID 20708845

    View details for PubMedCentralID PMC2997902

  • Animal Models of Early Life Stress: Implications for Understanding Resilience DEVELOPMENTAL PSYCHOBIOLOGY Lyons, D. M., Parker, K. J., Schatzberg, A. F. 2010; 52 (7): 616-624


    In the mid-1950s, Levine and his colleagues reported that brief intermittent exposure to early life stress diminished indications of subsequent emotionality in rats. Here we review ongoing studies of a similar process in squirrel monkeys. Results from these animal models suggest that brief intermittent exposure to stress promotes the development of arousal regulation and resilience. Implications for programs designed to enhance resilience in human development are discussed.

    View details for DOI 10.1002/dev.20500

    View details for Web of Science ID 000283570400002

    View details for PubMedID 20957724

  • Preliminary evidence that plasma oxytocin levels are elevated in major depression PSYCHIATRY RESEARCH Parker, K. J., Kenna, H. A., Zeitzer, J. M., Keller, J., Blasey, C. M., Amico, J. A., Schatzberg, A. F. 2010; 178 (2): 359-362


    It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

    View details for DOI 10.1016/j.psychres.2009.09.017

    View details for Web of Science ID 000279988900025

    View details for PubMedID 20494448

    View details for PubMedCentralID PMC2902664

  • Effects of Age on Cerebrospinal Fluid Oxytocin Levels in Free-Ranging Adult Female and Infant Rhesus Macaques BEHAVIORAL NEUROSCIENCE Parker, K. J., Hoffman, C. L., Hyde, S. A., Cummings, C. S., Maestripieri, D. 2010; 124 (3): 428-433


    There is growing interest in examining oxytocin and social functioning in human and non-human primates. Studies of human oxytocin biology are typically restricted to peripheral assessments because opportunities to collect cerebrospinal fluid (CSF) are rare. Several studies have examined CSF oxytocin levels in captive adult primates, but none to our knowledge have been conducted under free-ranging conditions and inclusive of infants. The main goal of this study was to establish feasibility of quantifying CSF oxytocin levels in free-ranging adult female and infant rhesus monkeys living on Cayo Santiago, PR. CSF oxytocin levels were examined in relation to individuals' demographic and reproductive characteristics as well as plasma cortisol levels. CSF oxytocin concentrations ranged from 36.02 to 134.41 pg/ml in adult females (ages 7-26 years; N = 31) and 35.94 to 77.3 pg/ml in infants (ages 38-134 days; N = 17). CSF oxytocin levels were positively correlated with adult female age and negatively correlated with infant age. The former correlation was driven by reproductive status. CSF oxytocin levels were unrelated to dominance rank or plasma cortisol levels. In contrast to a previous study of plasma oxytocin concentrations in this population, CSF oxytocin levels did not differ significantly between lactating and non-lactating females. These findings: 1) provide feasibility data for examining CSF oxytocin levels in free-ranging non-human primates and 2) indicate that CSF oxytocin levels may be a biomarker of age-related central nervous system changes across lifespan development. Research is now required to examine CSF oxytocin levels in the context of social functioning in free-ranging rhesus monkeys.

    View details for DOI 10.1037/a0019576

    View details for Web of Science ID 000278466000015

    View details for PubMedID 20528088



    Severe early life stress (ELS) is associated with negative outcomes. It is not clear, however, what impact moderate ELS has. A growing stress inoculation literature suggests that moderate (vs. low or high) ELS is associated with diminished behavioral and physiological anxiety responses. At the same time, studies of trait anxiety suggest that moderate (vs. low) ELS is associated with greater self-reported anxiety. This study tested the hypothesis that stress inoculation effects are evident for implicit (nonconscious) but not explicit (conscious) aspects of anxiety.Ninety-seven healthy women were assessed for ELS and explicit anxiety using questionnaires and assessed for implicit anxiety using a version of the Implicit Association Test.Results indicated a quadratic relation between ELS and implicit anxiety, such that moderate ELS was associated with lower implicit anxiety levels than low or high ELS. By contrast, the relation between ELS and explicit anxiety was linear.These findings support the stress inoculation hypothesis and suggest that stress inoculation applies for implicit but not explicit aspects of anxiety.

    View details for DOI 10.1002/da.20592

    View details for Web of Science ID 000269685500008

    View details for PubMedID 19569055

    View details for PubMedCentralID PMC3364103

  • Prefrontal Plasticity and Stress Inoculation-Induced Resilience DEVELOPMENTAL NEUROSCIENCE Katz, M., Liu, C., Schaer, M., Parker, K. J., Ottet, M., Epps, A., Buckmaster, C. L., Bammer, R., Moseley, M. E., Schatzberg, A. F., Eliez, S., Lyons, D. M. 2009; 31 (4): 293-299


    Coping with mild early life stress tends to make subsequent coping efforts more effective and therefore more likely to be used as a means of arousal regulation and resilience. Here we show that this developmental learning-like process of stress inoculation increases ventromedial prefrontal cortical volumes in peripubertal monkeys. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that the process of coping with early life stress increases prefrontal myelination and expands a region of cortex that broadly controls arousal regulation and resilience.

    View details for DOI 10.1159/000216540

    View details for PubMedID 19546566

  • Developmental cascades linking stress inoculation, arousal regulation, and resilience FRONTIERS IN BEHAVIORAL NEUROSCIENCE Lyons, D. M., Parker, K. J., Katz, M., Schatzberg, A. F. 2009; 3


    Stressful experiences that are challenging but not overwhelming appear to promote the development of arousal regulation and resilience. Variously described in studies of humans as inoculating, steeling, or toughening, the notion that coping with early life stress enhances arousal regulation and resilience is further supported by longitudinal studies of squirrel monkey development. Exposure to early life stress inoculation diminishes subsequent indications of anxiety, increases exploration of novel situations, and decreases stress-levels of cortisol compared to age-matched monkeys raised in undisturbed social groups. Stress inoculation also enhances prefrontal-dependent cognitive control of behavior and increases ventromedial prefrontal cortical volumes. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that early life stress inoculation triggers developmental cascades across multiple domains of adaptive functioning. Prefrontal myelination and cortical expansion induced by the process of coping with stress support broad and enduring trait-like transformations in cognitive, motivational, and emotional aspects of behavior. Implications for programs designed to promote resilience in humans are discussed.

    View details for DOI 10.3389/neuro.08.032.2009

    View details for Web of Science ID 000208031500032

    View details for PubMedID 19826626

    View details for PubMedCentralID PMC2759374

  • Preliminary evidence that hippocampal volumes in monkeys predict stress levels of adrenocorticotropic hormone BIOLOGICAL PSYCHIATRY Lyons, D. M., Parker, K. J., Zeitzer, J. M., Buckmaster, C. L., Schatzberg, A. F. 2007; 62 (10): 1171-1174


    Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH).Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations.Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010).These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.

    View details for DOI 10.1016/i.biopsych.2007.03.012

    View details for Web of Science ID 000250905800015

    View details for PubMedID 17573043

    View details for PubMedCentralID PMC2129091

  • Early life stress and novelty seeking behavior in adolescent monkeys PSYCHONEUROENDOCRINOLOGY Parker, K. J., Rainwater, K. L., Buckmaster, C. L., Schatzberg, A. F., Lindley, S. E., Lyons, D. M. 2007; 32 (7): 785-792


    Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.

    View details for DOI 10.1016/j.psyneuen.2007.05.008

    View details for Web of Science ID 000249510200003

    View details for PubMedID 17604913

    View details for PubMedCentralID PMC2716798

  • Social stress-related behavior affects hippocampal cell proliferation in mice PHYSIOLOGY & BEHAVIOR Mitra, R., Sundlass, K., Parker, K. J., Schatzberg, A. F., Lyons, D. M. 2006; 89 (2): 123-127


    Although social stress inhibits neurogenesis in the adult hippocampus, the extent to which individual differences in stress-related behavior affect hippocampal cell proliferation is not well understood. Based on results from resident-intruder stress tests administered to adult male mice, here we report that individual differences in hippocampal cell proliferation are related to the frequency of defensive behavior, and not the amount of aggression received or the frequency of fleeing. In contrast, access to voluntary wheel-running exercise did not affect hippocampal cell proliferation in either stressed or non-stressed mice. Social stress-induced inhibition of cell proliferation was restricted to the hippocampus, as neither stress nor access to wheel-running exercise altered cell proliferation in the amygdala. These findings indicate that individual differences in stress-related behavior influence cell proliferation in the mouse hippocampus, and may have important implications for understanding structural and functional hippocampal impairments in human psychiatric patients.

    View details for DOI 10.1016/j.physbeh.2006.05.047

    View details for Web of Science ID 000240414300001

    View details for PubMedID 16837015

  • Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primates PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Buckmaster, C. L., Sundlass, K., Schatzberg, A. F., Lyons, D. M. 2006; 103 (8): 3000-3005


    The stress inoculation hypothesis presupposes that brief intermittent stress exposure early in life induces the development of subsequent stress resistance in human and nonhuman primates. Rodent studies, however, suggest a role for maternal care rather than stress exposure per se (i.e., the maternal mediation hypothesis). To investigate these two hypotheses, we examined maternal care and the development of stress resistance after exposure to brief intermittent infant stress (IS), mother-infant stress (MIS), or no stress (NS) protocols administered to 30 monkeys between postnatal weeks 17 and 27. Unlike rodents, the IS condition did not permanently increase primate maternal care, nor did measures of total maternal care predict subsequent offspring hypothalamic-pituitary-adrenal-axis responsivity. Although MIS infants received less maternal care than IS and NS infants, both IS and MIS monkeys developed subsequent stress resistance. These findings indicate that rearing differences in the development of stress resistance are more closely related to differences in prior stress exposure than to differences in maternal care. A second experiment confirmed this conclusion in a different cohort of 25 monkeys exposed as infants to high foraging-demand (HFD) or low foraging-demand (LFD) conditions. HFD infants exhibited intermittent elevations in cortisol levels and received less maternal care than LFD infants. In keeping with a key prediction of the stress inoculation hypothesis, HFD males responded to stress in adulthood with diminished hypothalamic-pituitary-adrenal-axis activation compared with LFD males. Results from both experiments demonstrate that stress inoculation, rather than high levels of maternal care, promotes the development of primate stress resistance.

    View details for DOI 10.1073/pnas.0506571103

    View details for Web of Science ID 000235554900093

    View details for PubMedID 16473950

    View details for PubMedCentralID PMC1413772

  • Intranasal oxytocin administration attenuates the ACTH stress response in monkeys PSYCHONEUROENDOCRINOLOGY Parker, K. J., Buckmaster, C. L., Schatzberg, A. F., Lyons, D. M. 2005; 30 (9): 924-929


    Social relationships protect against the development of stress-related psychiatric disorders, yet little is known about the neurobiology that regulates this phenomenon. Recent evidence suggests that oxytocin (OT), a neuropeptide involved in social bond formation, may play a role. This experiment investigated the effects of chronic intranasal OT administration on acute stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation in adult female squirrel monkeys. Subjects were randomized to one of two experimental conditions. Monkeys were intranasally administered either 50 microg oxytocin (N = 6 monkeys) or 0 microg oxytocin (N = 6 monkeys)/300 microl saline once a day for eight consecutive days. Immediately after drug administration on the eighth day, all monkeys were exposed to acute social isolation. Blood samples for determinations of adrenocorticotropic hormone (ACTH) and cortisol concentrations were collected after 30 and 90 min of stress exposure. Consistent with an anti-stress effect, OT-treated monkeys exhibited lower ACTH concentrations compared to saline-treated monkeys after 90 min of social isolation (F(1,7) = 6.891; P = 0.034). No drug-related differences in cortisol levels were observed, indicating that OT does not directly attenuate the adrenal stress response. Intranasal peptide administration has been shown to penetrate the central nervous system, and research must determine whether intranasally delivered OT exerts its effect(s) at a pituitary and/or brain level. This primate model offers critical opportunities to improve our understanding of the anti-stress effects of OT and may lead to novel pharmacological treatments for stress-related psychiatric disorders.

    View details for DOI 10.1016/j.psyneuen.2005.04.002

    View details for Web of Science ID 000231003800012

    View details for PubMedID 15946803

  • Mild early life stress enhances prefrontal-dependent response inhibition in monkeys BIOLOGICAL PSYCHIATRY Parker, K. J., Buckmaster, C. L., Justus, K. R., Schatzberg, A. F., Lyons, D. M. 2005; 57 (8): 848-855


    Severely stressful early experiences have been implicated in the pathophysiology of psychiatric disorders. In contrast, exposure to mild early life stress (i.e., stress inoculation) strengthens emotional and neuroendocrine resistance to subsequent stressors. Herein we extend this research to examine the effects of mild early life stress on cognition.Squirrel monkeys were randomized to a mild intermittent stress (IS; n = 11) or nonstress (NS; n = 9) condition from 17 to 27 weeks postpartum. At 1.5 years of age, monkeys were assessed for response inhibition on a test previously shown to reflect prefrontal-dependent cognitive function.IS monkeys demonstrated fewer response inhibition errors compared with NS monkeys. There were no rearing-related differences in aspects of performance that did not require inhibitory control. Compared with NS monkeys, IS monkeys had lower basal plasma pituitary-adrenal stress hormone levels. No rearing-related differences on neuroendocrine measures obtained 15 minutes after testing were found.Results from this experiment provide the first evidence that exposure to mildly stressful early experiences improves prefrontal-dependent response inhibition in primates. Combined with our previous data, findings from this animal model suggest that exposure to mild early life stress may enhance the development of brain systems that regulate emotional, neuroendocrine, and cognitive control.

    View details for Web of Science ID 000228280700004

    View details for PubMedID 15820705

  • Prospective investigation of stress inoculation in young monkeys ARCHIVES OF GENERAL PSYCHIATRY Parker, K. J., Buckmaster, C. L., Schatzberg, A. F., Lyons, D. M. 2004; 61 (9): 933-941


    Retrospective studies in humans have identified characteristics that promote stress resistance, including childhood exposure to moderately stressful events (ie, stress inoculation).Because of limited opportunities for prospective studies in children, we tested whether exposure to moderate stress early in life produces later stress resistance in a primate model.Twenty squirrel monkeys were randomized to intermittent stress inoculation (IS; n = 11) or a nonstress control condition (NS; n = 9) from postnatal weeks 17 to 27. At postnatal week 35, each mother-offspring dyad underwent testing in a moderately stressful novel environment for inferential measures of offspring anxiety (ie, maternal clinging, mother-offspring interactions, object exploration, and food consumption) and stress hormone concentrations (corticotropin [ACTH] and cortisol). At postnatal week 50, after acclimation to an initially stressful wire-mesh box attached to the home cage, independent young monkeys underwent testing for inferential measures of anxiety (ie, voluntary exploration and play) in the box.In the novel environment test, IS compared with NS offspring demonstrated diminished anxiety as measured by decreased maternal clinging (P =.02), enhanced exploratory behavior (P =.005), and increased food consumption (P =.02). Mothers of IS offspring accommodated offspring-initiated exploration (P =.009) and served as a secure base more often compared with NS mothers (P =.047). Compared with NS offspring, IS offspring had lower basal plasma ACTH (P =.001) and cortisol (P =.001) concentrations and lower corticotropin (P =.04) and cortisol (P =.03) concentrations after stress. In the subsequent home-cage wire-box test, IS offspring demonstrated enhanced exploratory (P<.001) and play (P =.008) behaviors compared with NS offspring.These results provide the first prospective evidence that moderately stressful early experiences strengthen socioemotional and neuroendocrine resistance to subsequent stressors. This preclinical model offers essential opportunities to improve our understanding and enhance prevention of human stress-related psychiatric disorders by elucidating the etiology and neurobiology of stress resistance.

    View details for Web of Science ID 000223726200009

    View details for PubMedID 15351772

  • Female meadow voles (Microtus pennsylvanicus) demonstrate same-sex partner preferences JOURNAL OF COMPARATIVE PSYCHOLOGY Parker, K. J., Lee, T. M. 2003; 117 (3): 283-289


    Female meadow voles (Microtus pennsylvanicus) are territorial during warm months but demonstrate social tolerance under low temperatures. In spring, females nest together and some pairs participate in communal nursing and rearing of young. Because communal nursing involves significant cooperation, selective pair-bonds may develop between 2 nestmates. Using a choice apparatus, the authors determined that (a) captive females demonstrated partner preferences for a nestmate; (b) partner preferences were enduring and persisted after dyadic separation; and (c) following the loss of a nestmate, females did not develop preferences for a new nestmate, even after extended cohabitation. Data support the hypothesis that captive meadow voles develop selective and enduring same-sex social bonds that may, under free-living conditions, facilitate communal nesting and cooperative rearing of young.

    View details for DOI 10.1037/0735-7036.117.3.283

    View details for Web of Science ID 000185458600006

    View details for PubMedID 14498804

  • Circadian and homeostatic regulation of hypocretin in a primate model: Implications for the consolidation of wakefulness JOURNAL OF NEUROSCIENCE Zeitzer, J. M., Buckmaster, C. L., Parker, K. J., Hauck, C. M., Lyons, D. M., Mignot, E. 2003; 23 (8): 3555-3560


    In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.

    View details for Web of Science ID 000182475200052

    View details for PubMedID 12716965

  • Euroendocrine aspects of hyperportisolism in major depression HORMONES AND BEHAVIOR Parker, K. J., Schatzberg, A. F., Lyons, D. M. 2003; 43 (1): 60-66


    A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

    View details for DOI 10.1016/S0018-506X(02)00016-8

    View details for Web of Science ID 000182658400009

    View details for PubMedID 12614635

  • Interaction of photoperiod and testes development is associated with paternal care in Microtus pennsylvanicus (meadow voles) PHYSIOLOGY & BEHAVIOR Parker, K. J., Lee, T. M. 2002; 75 (1-2): 91-95


    During the summer breeding season, free-living meadow voles do not engage in paternal care. However, in fall when female territoriality declines, social nesting and breeding activity may overlap and adult males nest with females and young. In the laboratory, meadow voles housed under short day (SD) lengths exhibit more and better quality paternal care than those housed under long day (LD) lengths. This observation is commensurate with the hypothesis that SD paternal care may increase fitness by decreasing pup mortality during colder months. However, SD males also demonstrate variability in paternal care. We hypothesize that this variability may be due to male fertility status; SD infertile males, incapable of siring offspring, should be less likely to care for pups than fertile males, for whom paternal care may confer fitness benefits. The goal of this experiment was to determine whether paternal behavior differed between fertile LD males, fertile SD males (i.e. males that were gonadally photoperiod-unresponsive to SD lengths), and infertile SD males (i.e. males that were gonadally photoperiod-responsive to SD lengths), as indexed by paired testes weights and behavioral evaluation. Fertile SD males exhibited proportionally more paternal behavior than infertile SD males or fertile LD males, which did not differ from each other. Fertile SD males also exhibited paternal behavior faster, spent more time in contact with pups, and engaged in longer and more frequent bouts of pup-directed grooming and huddling than either infertile SD males or fertile LD males. Collectively, these data suggest that photoperiod and fertility status may interact to exert both inhibitory and permissive control over the expression of paternal behavior in adult meadow voles.

    View details for Web of Science ID 000175195300012

    View details for PubMedID 11890957

  • Social and environmental factors influence the suppression of pup-directed aggression and development of paternal behavior in captive meadow voles (Microtus pennsylvanicus) JOURNAL OF COMPARATIVE PSYCHOLOGY Parker, K. J., Lee, T. M. 2001; 115 (4): 331-336


    During summer, female meadow voles (Microtus pennsylvanicus) maintain territories and males do not engage in paternal care. As day length shortens, territories dissolve and males nest with females and young. Because paternal behavior has never been studied in free-living meadow voles during colder months or in the laboratory under short photoperiods, the authors examined whether males housed in short day (SD) lengths exhibited more frequent or better quality paternal behavior than males housed in long day (LD) lengths. Sexually and parentally inexperienced (naive) SD males exhibited proportionally more and qualitatively better paternal care than naive LD males. SD males were more responsive than LD males to classic social cues associated with prepartum aggression inhibition and paternal onset. SD sires also displayed qualitatively better paternal behavior than LD sires. These data suggest that meadow vole paternal state is regulated by specific social and environmental cues that may contain reliable information about ecological conditions that favor paternal care.

    View details for DOI 10.1037//0735-7036.115.4.331

    View details for Web of Science ID 000173402200001

    View details for PubMedID 11824895

  • Day length and sociosexual cohabitation alter central oxytocin receptor binding in female meadow voles (Microtus pennsylvanicus) BEHAVIORAL NEUROSCIENCE Parker, K. J., Phillips, K. M., Kinney, L. F., Lee, T. M. 2001; 115 (6): 1349-1356


    In voles (Microtus), central oxytocin (OT) receptor patterns are associated with interspecific social organization. Social, monogamous voles have more OT receptors in the extended amygdala than asocial, nonmonogamous voles. Nonmonogamous meadow voles (Microtus pennsylvanicus), which exhibit seasonal changes in social organization (long day [LD] females are territorial, short day [SD] females live socially), provide a model for examining whether OT receptor patterns are associated with seasonal changes in intraspecific social behaviors. The authors examined whether sexually inexperienced (naive) SD females had more OT receptor binding than naive LD females. Naive SD females had greater OT receptor binding in the lateral septum (LS), lateral amygdala (LatAmyg), and central amygdala (CenAmyg) than less social, naive LD females. Because both SD and LD females acquire partner preferences, the authors assessed whether OT receptor binding was associated with partner preference onset. For LD females, partner preference onset corresponded with greater OT receptor binding in the anterior olfactory nucleus, LS, and bed nucleus of the stria terminalis, compared with naive LD females. In contrast, naive SD females and those exhibiting partner preferences did not differ. However, SD females that failed to acquire partner preferences showed less OT binding in the LatAmyg and CenAmyg. This study is the first to show that central OT receptor patterns are associated with seasonal changes in intraspecific social organization and partner preference onset in a nonmonogamous rodent.

    View details for Web of Science ID 000172687600018

    View details for PubMedID 11770065

  • Paternal behavior is associated with central neurohormone receptor binding patterns in meadow voles (Microtus pennsylvanicus) BEHAVIORAL NEUROSCIENCE Parker, K. J., Kinney, L. F., Phillips, K. M., Lee, T. M. 2001; 115 (6): 1341-1348


    Paternal and nonpaternal voles (microtus) have different arginine-vasopressin (AVP) and oxytocin (OT) receptor patterns in the extended amygdala, a neural pathway associated with parental behavior. Using receptor autoradiography, the authors examined whether AVP and OT receptor patterns were associated with facultative paternal behavior in either sexually and parentally inexperienced or experienced meadow voles (Microtus pennsylvanicus). Experienced, in contrast to inexperienced, males had less AVP binding in the lateral septum (LS), more AVP binding in the anterior olfactory nucleus (AON), and more OT binding in the AON, bed nucleus of the stria terminalis, LS, and lateral amygdala. Thus, specific AVP receptor patterns, which co-occur with paternal care in consistently paternal voles, also may be associated with paternal care (when present) in typically nonpaternal species. This study also demonstrated a possible relationship between OT receptor patterns and paternal state in male mammals.

    View details for Web of Science ID 000172687600017

    View details for PubMedID 11770064

  • Central vasopressin administration regulates the onset of facultative paternal behavior in Microtus pennsylvanicus (Meadow voles) HORMONES AND BEHAVIOR Parker, K. J., Lee, T. M. 2001; 39 (4): 285-294


    Pharmacological experiments have implicated a role for central arginine vasopressin (AVP) in regulating paternal behavior in monogamous prairie voles. Although nonmonogamous meadow voles exhibit appreciable paternal care when housed under winter, short day lengths (SD), no research has examined whether the same neurobiological systems are involved in regulating paternal behavior in a nonmonogamous species when it behaves paternally. The goal of these experiments was to determine whether central administration of AVP, but not cerebrospinal fluid (CSF), affected the suppression of pup-directed aggression and/or the onset of paternal behavior in meadow voles. Data from experiment 1 implicated a role for AVP in facilitating changes in male behavior: central administration of 1 ng of AVP (but not 3 ng or CSF) inhibited pup-directed aggression in previously pup-aggressive males, and 3 ng of AVP (but not 1 ng or CSF) induced paternal behavior in previously nonpaternal males. In contrast, AVP (1 and 3 ng) did not enhance paternal behavior in already paternal males. Experiment 2 tested the specificity of AVP. Previous research indicated that 24 h of unmated cohabitation with a female reliably induced paternal behavior in SD males. Hence, experiment 2 examined whether administration of a V(1a) AVP antagonist (AVPA), but not CSF, prior to 24 h of unmated cohabitation would block the onset of paternal behavior. Males that received CSF displayed paternal behavior faster and engaged in more investigatory and paternal behaviors than males that received AVPA. Thus, pharmacological experiments support the hypothesis that AVP likely regulates paternal behavior in both facultatively and consistently paternal vole species.

    View details for DOI 10.1006/hbeh.2001.1655

    View details for Web of Science ID 000169257100005

    View details for PubMedID 11374914

  • Development of selective partner preferences in captive male and female Microtus pennsylvanicus (meadow voles) Animal Behaviour Parker KJ, Phillips KM, Lee TM 2001; 61 (6): 1217-1226