Perinatal stress: Neurodevelopment: Early Life Adversity: Autism: Self-Injury: Neurohormones/NeuropeptidesA: Anxiety and Depression
Positions and Employment
1971-1974 Assistant Professor of Psychology, Ohio State University
1974-1978 Associate Professor of Psychology, Ohio State University
1978-1979 Professor of Psychology, Ohio State University
1979-2009 Director of Research, Program Psychologist, Fairview Developmental Center, Costa Mesa, CA
1979-2009 Professor-in-Residence, Psychobiology, University of California, Irvine (UCI)
1979-2009 Professor, Department of Psychiatry and Human Behavior, UCI
1984-2009 Vice-Chair, Department of Psychiatry and Human Behavior, UCI
2001-2007 Director, Applied Neurobehavioral Research Institute, State of California
2009-Present Professor Emeritus, Department of Psychiatry and Human Behavior, UCI
I am Professor Emeritus at the University of California, Irvine (UCI). I have been Professor of Psychiatry and Human behavior at UCI since 1979, and in parallel, was Chief of Research for the Developmental Research Institute, State of California (UCI affiliated) and Director of the Applied Neurodevelopmental Research Institute for the State of California. I have had extensive experience examining the influence of neuroactive factors on the brain and behavior. I was formally trained (with Lyle Miller, John Knott and Sanford Cohen) as a neuropsychologist with specialization in electrophysiology. However, in parallel, I had the remarkable “extra” opportunity as a graduate student to participate in studies that would change the field of endocrinology. The laboratories of my mentors, Abba Kastin and Andrew Schally (Nobel Laureate) were in an international race to discover hypothalamic releasing hormones (Schally succeeded hence the Nobel Prize in 1977) and to describe the extra-endocrine effects of many peptide hormones. The training I received and the opportunity to collaborate with this group extended to my time at Ohio State University and eventually at the University of California, Irvine. Our 2018 publication in the American Journal of Psychiatry describing the long term effects of prenatal exposure to placental hormones on brain structure in preadolescent children illustrates my long term commitment to the study of maternal/fetal signals.
I have maintained an extramural, peer-reviewed, funded research program for over thirty-two consecutive years and have published over 350 scientific papers. During the past thirty years, I have been Principal Investigator for a consecutive series of NIH-supported studies that examined the "programming" effects of maternal signals on the human fetus, birth outcomes, infant and child development including grants to conduct imaging studies of the brain in 6-9 year-old children with extensive prenatal histories. The findings from our developmental projects include over 1000 mother/fetal/infant/child dyads and over 100 published research papers and have contributed to the growing acceptance that prenatal exposure to maternal signals has consequences for neurological development and is a risk factor for poor postnatal maternal and infant developmental outcomes.
NEUROPEPTIDES AND BEHAVIOR: In the mid-1960's, I was introduced as a graduate student to polypeptide hormones ("neuropeptide" had not been coined) in the endocrinology laboratory of Abba Kastin and the biochemistry laboratory of the soon-to-be Nobel Laureate, Andrew Schally. The focus of the research was discovery of novel factors that controlled phenotypic expression. Melanocyte-Stimulating- Hormone (MSH) was known to influence pigmentation in amphibians, but new data published by the group at the University of Utrecht indicated that it may have effects in the mammalian brain. The evolutionary and teleological implications of what was conserved and why, became a life-long research theme. We followed our first published paper showing effects of MSH on appetitive learning in rodents with many others that included studies in amphibians, rodents (1) and ultimately in humans (2), including patients with impaired memory and attention. The results clearly supported the conclusion that the function of neuropeptides is conserved even if the expression is species specific. Moreover, we demonstrated not only that behavior is coded in peptides (as others also were reporting) but that the strength of the association was a function of their molecular weight (3). These scientific contributions encouraged the first Neuropeptide Conference convened in 1976 (hosted by Abba Kastin, Lyle Miller and me) and reported in a landmark volume published by Raven's Press. Subsequently, for 30 years (until 2010) I hosted the annual Winter Neuropeptide Conference that highlighted new research and resulted in four volumes of New York Academy of Sciences and several journal monographs and a recent invited retrospective report (4) describing the developmental consequences of fetal exposure to maternal/placental signals.
1. Sandman, C.A., Kastin, A.J., Schally, A.V., Kendall, J. & Miller, L.H. Neuroendocrine response to physical and psychological stress. Journal of Comparative and Psychological Psychology, 1973, 84, 386-390.
2. Sandman, C.A., George, J.M., *McCanne, T.R., Nolan, J.D., Kaswan, J. and Kastin, A.J. MSH/ACTH 4-10 influences behavioral and physiological measures of attention. Journal of Clinical Endocrinology and Metabolism, 1977, 44, 884-891
3. Sandman, C.A., *Beckwith, B.E. and Kastin, A.J. Are learning and attention related to the sequence of amino acids in ACTH/MSH peptides? Peptides, 1980, 1, 277-280.
4. Sandman, CA. Prenatal CRH: An integrating signal of fetal distress. Development and Psychopathology, 2018, 30, 941-952.)
PEPTIDE SEQUENCE AND POSSIBLE TREATMENTS: As the scientific community became aware that the structure of MSH was shared with the larger ACTH molecule and that both were embedded in a larger bioinactive prohormone (proopiomelanocortin, POMC), there was interest in the biological significance of their mutual structures. Moreover, it further was discovered that the structure of beta-endorphin, an endogenous opiate also was contained in POMC. These discoveries opened up new questions about the function and association among this family of behaviorally interesting molecules. I had unique access to novel sequences of the POMC molecule and the opportunity to examine and report the effects of short sequences on the brain and behavior. We reported that a seven amino chain shared by MSH and ACTH (4-10) was the behaviorally active segment (1). These findings encouraged Organon to develop analogs of this sequence and even shorter sequences (4-7) for trials to treat memory and attentional impairment. I was the first to treat neurodevelopmental disorders with these short sequences and had modest success in improving attention (2). But of greatest interest was our finding about the neurological consequences of centrally administered analogues of short chain segments of beta-endorphin. We reported in "Science" that administration of D-ala2-beta endorphin to rats resulted in a prolonged catatonic state and insensitivity to pain (3). In subsequent studies I (and others) discovered that treatment with opiate blockers resulted in hypersensitivity to external stimulation. I applied these findings to a group of patients who exhibited elevated pain threshold that resulted in life-threatening self-abusive behavior. The results of administration of opiate blockers were positive for subgroups of previously untreatable patients. Subsequently we found that the POMC fragments were uncoupled in these patients when they self-injure and that the degree of uncoupling predicted positive responses to the opiate blocker (4). The clinical significance of these findings has been debated but the research has been widely cited and there are cases of success that have been remarkable.
1. Sandman, C.A., George, J., Nolan, J.D., Van Riezen, H. & Kastin, A.J. Enhancement of attention in man with ACTH/MSH 4-10. Physiology and Behavior, 1975, 15, 427-431.
2. Sandman, C.A., George, J., Walker, B., Nolan, J.D. & Kastin, A.J. The neuropeptide MSH/ACTH 4-10 enhances attention in the mentally retarded. Pharmacology, Biochemistry and Behavior Monograph Supplement, l976, 5, pp. 23-28.
3. *Walker, J.M., Bernston, G.G., Sandman, C.A., Coy, D.H., Schally, A.V.,& Kastin, A.J. An analog of enkephalin (d-ala-2) having prolonged opiate-like effects in vivo. Science, 1977, 196, 85-87.
4. Sandman, C.A Touchette, P.E. *Marion, S.D & Chicz-DeMet, A. The role of proopiomelanocortin (POMC) in sequentially dependent self-injurious behavior. Developmental Psychobiology, 2008, 50, 680-689.
FETAL PROGRAMMING: Most of the research described above was conducted in adult preparations and most of the effects were acute. In a series of studies in animal models, I have reported that in utero exposure of rats to POMC fragments permanently altered behavior and brain structure. Because these studies indicated that naturally occurring molecules had profound effects on the developing fetus, a series of studies during human pregnancy were initiated. During the past thirty-plus years and continuing, I have been Principal Investigator for a series of NIH-funded studies that examined the effects of prenatal signals and activation of the HPA/placental axis on birth outcomes, the human fetus and the developing child. The findings from my projects that include over 1000 women, contribute to the growing acceptance that fetal exposure to psychobiological signals of maternal stress is a risk factor for poor outcomes in offspring. Studies from my group were among the earliest to confirm that a hypothalamic releasing hormone (CRH) was released from the placenta in increasing concentrations as pregnancy advanced toward term and played a significant role in parturition and in child developmental outcomes (1). Among the most significant findings are our recent reports that human fetal exposure to maternal signals is associated with decreased cortical (2, 3) and subcortical volume and network efficiency (4) in children at 6-9 years of age. The conclusion of our studies is that the human fetus plays an active role in its own development as it prepares for life after birth (5). These studies are highly cited and make a major contribution to the Fetal Programming or Developmental Origins of Health and Disease (DOoHD) literature.
1. *Wadhwa, P.D., Garite, T.J., Porto, M., Chicz-DeMet, A., Dunkel-Schetter, C., & Sandman, C.A. Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth and fetal growth restriction: A prospective investigation. American Journal of Obstetrics and Gynecology, 2004, 191, 1063-1069.
2. Sandman, CA, *Buss, C, Head, K, & Davis, EP. Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biological Psychiatry, 2015, 77, 234-334 NIHMS613398.
3. *Buss, C., Davis, EP, Shahbaba, B, Pruessner, JC, Head, K, & Sandman, CA. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proceedings of the National Academy of Sciences, 2012, 109, E1312-1319.
4. * Kim, D-J, Davis, EP, Sandman, CA, Sporns, O., O'Donnell, BF, Buss, C., & Hetrick, WP. Longer gestation is associated with more efficient brain networks in preadolescent children. NeuroImage, 2014, 100, 619-627.
5. Sandman, CA, Davis, EP & Glynn, LM. Prescient human fetuses thrive. Psychological Science, 2012, 23, 93-100.
PROBING THE HUMAN FETUS AND SEX DIFFERENCES: One important issue for the DOoHD model is accounting for the contribution of variables intervening between an early life exposure and health outcome. My group has been interested in the earliest exposures--during fetal life-- and in the health outcomes that may be decades away. This latter issue is managed either by retrospective studies with their inherent flaws, or by selecting surrogate or prodromal measures of outcome in infants and children. But even if prodromal measures are selected that have predictive value (as we have), there still are the influences of postnatal exposures to consider. We have developed methods and analytic strategies to interrogate the human fetus. With both vibroacoustic and auditory stimulation we have assessed the ability of the fetus to exhibit startle responses, to habituate and dishabituate (1). With these tools we have been able to assess the association between fetal exposure to maternal signals of stress, including exposure to the HPA and placental axis and response to stimulation (2). We have found that elevated levels of placental CRH are associated with an immature fetal nervous system (3). Moreover, we have discovered sex differences in fetal responses that emerge as early as 25 weeks gestation and that brain networks in female fetuses are more sensitive to influences of circulating maternal cortisol (4). We recently have reviewed these and other sex differences in fetal programming in a paper rated as the most cited in this content area (5).
1. Sandman, C.A., *Wadhwa, P.D., *Hetrick, W.P., Porto, M., Peeke, & H.V.S. Human fetal heart rate dishabituation at 32 weeks gestation. Child Development, 1997, 68, 1031-1040.
2. Sandman, CA., *Wadhwa, P., Chicz-DeMet, A., Porto, M., & Garite, T. Maternal corticotropin-releasing hormone and habituation in the human fetus. Developmental Psychobiology, 1999, 34, 163-173.
3. *Class, Q.A., *Buss, C., Davis, E.P. Gierczak, M., Pattillo, C., Chicz-DeMet, A. & Sandman, C.A., Low levels of corticotrophin-releasing hormone during early pregnancy are associated with precocious maturation of the human fetus. Developmental Neuroscience, 2008, 30, 419-426.
4. *Kim, D-J, Davis, EP, Sandman, CA , Sporns, O., O'Donnell, BF, Buss, C, & Hetrick, WP.
Prenatal maternal cortisol has sex-specific associations with child brain network properties. Cerebral Cortex, 2016, 27, 5230-5241. doi:10.1093/cercor/bh w303.
5. Sandman, CA, Glynn, LM, & Davis EP. Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. Journal of Psychosomatic Research, 2013, 75, 327-335
UNIQUE SAMPLE OF SUBJECTS: As described above, with NIH support and my long-time colleagues, we developed a sample of over 1200 mother/fetal/infant prospectively studied dyads. The children range in age from 1-18 years and over 85 papers have been published from these participants (1). We have shared data with other colleagues who offer unique skills or questions (2-4). Among the most recent is collaboration with Indiana University using our DTI data and their connectome project (5). From this collaboration we reported that brain networks in 6-10-year-old children were associated with gestational age at birth. The global network efficiency and connectivity of rich club regions were significantly decreased in children born early indicating immaturity of structural connections among the core regions. As mentioned above, we also have reported sex differences in rich club networks and global and local efficiency. These highly cited findings support the conclusion that there are long-lasting and very significant costs to early delivery even within the normal range.
1. Sandman, CA & Davis, EP. Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Reviews of Endocrinology & Metabolism, 2012, 7, 445-459.
2. *Hilmert, CJ, *Dominquez, TP, Dunkel-Schetter, C, Srivivas, SK, Glynn, LM, Hobel, CJ., & Sandman, CA. Lifetime racism and blood pressure changes during pregnancy: Implications for fetal growth. Health Psychology, 2013, 33, 43-51
3. *Synder, HR, Hankin, BL, Sandman, CA, Head, K, & Davis EP. Distinct patterns of reduced prefrontal and limbic grey matter volume in childhood general and internalizing psychopathology. Clinical Psychological Science, 2017, 5, 1001-1013.
4. Goldberg, WA, *Lucas-Thompson, RG, Germo, GR, *Keller, MA, Davis, EP & Sandman, CA. Eye of the beholder? maternal mental health and the quality of infant sleep. Social Science and Medicine, 2013, 79, 101-108.
5. *Kim, D-J, Davis, EP, Sandman, CA, Sporns, O., O'Donnell, BF, *Buss, C. &, Hetrick, WP. Longer gestation is associated with more efficient brain networks in preadolescent children. NeuroImage, 2014, 100, 619-627.
My research program has been featured in the popular media including Science, Fortune, Newsweek, Time, Prevention, Psychology Today, Parenting, Good Housekeeping, many newspaper articles, as well as on educational television (PBS--the Mind and California Stories). Several studies have been abstracted in popular specialty professional journals. Based on my research, I have been an expert witness in criminal and civil court (including the Federal level).
Our 2012 study "Prescient human fetuses thrive" was considered one of the ten most counter-intuitive studies in the history of psychology.
Our 2013 study, "Is there a viability-vulnerability tradeoff? Sex differences in fetal programming" was rated as one of the 8% studies in all of science that was verified.
Partial list of Honors
NIMH Predoctoral Fellowship
Stallone Foundation Award for studies in Autism
MacArthur Foundation Network; Invited member
IBM/Psychological Corporation THINKable award
Nightingale Research Foundation Cambridge Faculty (Great Britain) award
Decennial Award, Winter Neuropeptide Conference
International Consensus Panel on Psychoactive Drugs; Chair, section on Opiate Blockers
National Institutes of Mental Health, Chair, conference on dual diagnosis
Fellow, International Society of Psychophysiology
Fellow, International Neuropeptide Society
Study Sections and site visitor for NIA, NIMH, NIDA and NICHD: Chair, BBBP6 Study Section, National Institutes of Health
National Institute of Child Health and Development; Leader, Workshop on Fetal
American Association of Mental Retardation Distinguished Scientific Discovery
Award for studies of biological basis of mental retardation
I am a third generation Californian. I graduated from Santa Cruz High School with athletic awards in three sports and no academic accomplishments. I attended Cabrillo Community College and received my AA degree and athletic awards in two sports. I matriculated to Fresno State with the intention of majoring in Physical Education but shifted my focus to history and psychology. I received my Bachelor's Degree with about 50 more units than I needed and then a Master's degree with Distinction. I had many clinical experiences under the supervision of Professor Frank Powell that influenced my life. During this time, encounters with Cesar Chavez on his pilgrimage from Delano to Sacramento, and exposure to media accounts of social injustice in the Deep South ignited an outrage that required action. I applied and was accepted to graduate programs in the south to satisfy my desires to obtain a PhD in psychology and to participate in civil rights activities where it counted. In graduate school at LSU, I had extraordinary mentors who, and opportunities that, have had a lasting influence on my life. In addition, I received an education in the power of non-violence to effect change. I was recruited to Ohio State and the University of Michigan during my fourth year in graduate school and ultimately accepted a tenure track position with the Buckeyes. I was promoted to Full Professor after my sixth year and then left Ohio State after my eighth year to accept positions at UC Irvine and jointly with the State of California, in 1979. Leaving Ohio State was, and still is, the most difficult decision of my life. I am married to Jennifer Barron, PhD. We share four girls between 36-57 years of age and we have four grand-kids.
Sandman, CA. Prenatal CRH: An integrating signal of fetal distress. Development and Psychopathology, 2018, 30, 941-952.
Sandman, CA, Curran, MM, Davis, EP, Glynn, LM, Head, K & Baram, TZ. Cortical thinning and neuropsychiatric outcomes in children exposed to prenatal adversity: A role for placental CRH? American Journal of Psychiatry, 2018, 175, 471-479: doi: 10.1176/appi.ajp.2017.16121433.
Davis, EP, Hankin, BL, Glynn, LM, Head, K., Kim, DJ & Sandman, CA. Prenatal maternal stress, child cortical thickness and adolescent depressive symptoms. Child Development, 2020, doi: 10.1111/cdev.13252. [Epub ahead of print] PMID: 31073997
Kim DJ, Davis EP, Sandman CA, Glynn L, Sporns O, O'Donnell BF, Hetrick WP. Childhood poverty and the organization of structural brain connectome. Neuroimage,. 2019, Jan 1;184:409-416. doi: 10.1016/j.neuroimage.2018.09.041. Epub 2018 Sep 17. PMID: 30237035
Davis, EP, Stout, SA, Molet, J, Vegetabile, B, Glynn, LM, Sandman, CA, Kein, K, Stern, J, & Baram, TZ. Early life exposure to unpredictable maternal sensory signals influences cognitive development: a cross-species approach. Proceedings of the National Academy of Sciences, 2017,114, 10390-10395. doi: 10.1073/pnas.1703444114. Epub 2017 Sep 11
RECENT FROM OVER 320 PUBLICATIONS
Buss, C., Davis, EP, Shahbaba, B, Pruessner, JC, Head, K, & Sandman, CA. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proceedings of the National Academy of Sciences, 2012, 109, E1312-1319.
Baram, TZ, Davis, EP, Obenaus, A, Sandman, CA, Small, S, Solodkin, A & Stern, H. Fragmentation and unpredictability of early-life xperience in mental disorders. American Journal of Psychiatry, 2012, 169, 907-915. PMID 22885631.
Sandman, CA & Davis, EP. Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Review of endocrinology & Metabolism, 2012, 7, 445-459.
Sandman, CA, Glynn, LM, & Davis EP. Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. Journal of Psychosomatic Research, 2013, 75, 327-335.
Davis, EP., Sandman, CA., Buss, C., Wing, DA., & Head, K. Fetal glucocorticoid exposure is associated with preadolescent brain development. Biological Psychiatry, 2013, 74, 647-655.
Glynn LM & Sandman CA. Evaluation of the association between placental corticotrophin-releasing hormone and postpartum depressive symptoms. Psychosomatic Medicine, 2014, 76(5):355-362.
Sandman, CA, Head, K., Muftuler, LT., Su, L., Buss, C., & Davis, EP. Shape of the basal ganglia in preadolescent children is associated with cognitive performance. NeuroImage, 2014, 99, 93-102.
Kim, D-J, Davis, EP, Sandman, CA, Sporns, O., O'Donnell, BF, Buss, C., & Hetrick, WP. Longer gestation is associated with more efficient brain networks in preadolescent children. NeuroImage, 2014, 100, 619-627.
Sandman CA, Glynn LM, & Davis EP. Neurobehavioral consequences of fetal exposure to gestational stress. In: Kisilevsky BS, Reissland N, Eds. Fetal Development: Research on Brain and Behavior, Environmental Influences and Emerging Technologies. 2016, pp 229-265. Springer, New York, NY: ISBN: 978-3-319-22023-9
Sandman, CA, Class, QA, Glynn, LM & Davis, EP. Neurobehavioral disorders and Developmental Origins of Health and Disease. In CS Rosenfeld (Ed) The Epigenome and Developmental Origins of Health and Disease. Academic Press/Elsevier, Waltham, MA, 2015. pp 235-266 ISBN: 978-0-12-801383-0 doi:10.1016/B978-0-12-801383-0.12001-8
Sandman, CA. Mysteries of the human fetus revealed. Child Development, 2015, SEP 80(3), 124-137.
Sandman, CA. Prenatal Development. In (Miller, H, Ed) The SAGE Encyclopedia of Theory in Psychology. in press.
Sandman, CA. Fetal exposure to placental corticotropic-releasing hormone (pCRH) programs developmental trajectories. Peptides, 2015, 72, 145-153
Sandman, CA, Buss, C, Head, K, & Davis, EP. Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biological Psychiatry, 2015, 77, 234-334 NIHMS613398.
Kim, D-J, Davis, EP, Sandman, CA , Sporns, O., O'Donnell, BF, Buss, C, & Hetrick, WP. Children's intellectual ability is associated with structural network integrity. NeuroImage, 2016, 124, 550-556.
Fox, M., Sandman, CA, Davis, EP. &Glynn, LM. Intra-individual consistency in endocrine profiles across successive pregnancies. Journal of Clinical Endocrinology and Metabolism, in press doi: 10.1210/jc.2015-2620
319. Howland, MA, Sandman, CA, Glynn, LM, Crippen, C & Davis, EP. Fetal exposure to placental corticotropin-releasing hormone is associated with child self-reported Internalizing Symptoms. Psychoneuroendocrinology, 2016, 67, 10-17.
Schoemaker, D., Buss, C, Head, K, Sandman, CA, Davis, EP, Chakravarty, MM, Gauthier, S, Pruessner, JC. Hippocampus and amygdala volumes from magnetic resonance images in children: Assessing accuracy of FreeSurfer and FSL against manual segmentation. NeuroImage, 2016, 129, 1-14
R01/HD65823 Davis (PI) 2010-2015 NIH/NICHD; Role: Co-Investigator Vulnerability to Prenatal Glucocorticoids Programs Infant Development Primary aim is to determine the influence of administration of betamethasone in women at risk for preterm delivery on placental CRH, gestational age at birth and infant outcomes.
NIMH Role: Project 2 Principal Investigator
Influence of Fragmented early life exposures on emotional and cognitive vulnerabilities
Primary aim of this Conte Center is to examine the influence of fetal exposure to inconsistent or fragmented maternal signals on emotional and cognitive development in animal and human models.
R01/HD051852 Sandman (PI) 07/06-06/12
NIH/NICHD; Role: PI
Fetal Programming of Early Development
Primary aim of this study is to examine the developmental outcomes of children who were exposed to prenatal biological and psychosocial stress. Emotional regulation, cognition, anatomy of brain structures, and HPA axis regulation are measured in children who have an extensive history of prenatal stress exposure.
Expert Witness in Federal, State and Municipal Courts