- Email: [email protected]
23.2 TOWARDS PRECISION MEDICINE FOR AUTISM SPECTRUM DISORDERS
SYMPOSIA 23.2 – 24.0
23.2 TOWARDS PRECISION MEDICINE FOR AUTISM SPECTRUM DISORDERS Kevin Pelphrey, PhD, Physiology and Pharmacology, George Washington University and Children’s National Medical Center, 2132 Windward Shore Drive, Washington, DC 23451 Objectives: I will describe neuroimaging research to chart the development of brain mechanisms for social cognition in typically developing infants, children, and adolescents. I will talk about the ways in which we have used our findings to predict the response of young children with ASD to specific behavioral and pharmacological treatment protocols. Methods: My studies used functional neuroimaging techniques, including fMRI and functional near infrared spectroscopy, in well characterized sample groups of young children with and without ASD. Results: Neuroimaging-based stratification biomarkers accurately predict responses to an evidence-based behavioral treatment—pivotal response treatment—in young children with ASD. Neuropredictors included the following: 1) pretreatment levels of evoked brain activity in neuroanatomical circuits supporting social perception and social reward/motivation; 2) multivariate patterns of pretreatment brain responses in the orbitofrontal cortex—a key component of the neural system supporting social motivation; and 3) pretreatment functional connectivity between the orbital frontal cortex and brain regions implicated in social perception—the posterior superior temporal sulcus and fusiform gyrus. It is noteworthy that these neuropredictors outperformed all available pretreatment demographic and behavioral measures of social functioning, language level, and cognitive abilities. Conclusions: These findings mark the very first evidence of prediction/ stratification biomarkers in young children with ASD. Moreover, the results offer a promising opportunity for the use of pretreatments or concurrent treatments to improve the functioning of the neuropredictive markers identified here, thereby increasing the effectiveness of treatments for core social deficits in children with ASD.
ASD IMAGS TREAT Supported by NIMH Grant R01MH100028 http://dx.doi.org/10.1016/j.jaac.2016.07.251
23.3 PRENATAL EPIGENETIC EFFECTS ON BRAIN DEVELOPMENT AND BEHAVIOR: TRANSLATIONAL APPROACHES Frances A. Champagne, PhD, Department of Psychology, Columbia University, 1190 Amsterdam Avenue, 406 Schermerhorn Hall, New York, NY 10027 Objectives: The prenatal period is a time of rapid neurodevelopmental change and thus represents a sensitive period for developmental disruption after exposure to stress and toxins, with implications for physical and psychiatric health outcomes. We have been exploring the epigenetic impact of prenatal exposures (particularly endocrine disruption and maternal stress) in animal models and humans to build a translational framework. Methods: In the first series of studies, we exposed pregnant mice to the endocrine disruptor bisphenol A (BPA) and examined behavior, brain gene expression, and epigenetic outcomes in adult offspring. We then conducted epigenetic analyses on cord blood samples from a human cohort in which there was prenatal assessment of BPA. In a second series of studies, we assessed prenatal psychosocial stress in mothers during fetal neurodevelopment and conducted epigenetic analyses of human placentas. We then examined gene expression outcomes in rodent placentas after chronic variable stress during pregnancy. Results: We discovered the following: 1) in mice, prenatal BPA has sexspecific effects, leading to increased epigenetic silencing of the brain-derived neurotrophic factor gene (Bdnf), decreased hippocampal expression of Bdnf, and impaired memory in male offspring; 2) elevated gestational BPA exposure is associated with epigenetic silencing of Bdnf in human cord blood samples (in males only); 3) maternal stress during pregnancy is associated with increased epigenetic silencing of 11b-hydroxysteroid dehydrogenase 2 (Hsd-11b2) in human placentas, and this epigenetic effect mediates the effect
S294
www.jaacap.org
of stress on impaired neurodevelopment; and 4) in prenatally stressed rodents, placental expression of Hsd-11b2 is decreased. Conclusions: Evidence from both laboratory animal models and human studies suggest the epigenetic impact of prenatal adversity. The integration of these across-species approaches strengthens the causal inferences that can be made when predicting the impact of experience on long-term neurobiological and behavioral outcomes.
ANI DEV NEURODEV Suported by NIMH Grant 1R01MH092580-01A1 and the National Institute Environmental Health Sciences 2P01ES009600-11 http://dx.doi.org/10.1016/j.jaac.2016.07.252
23.4 BEHAVIORAL, BIOLOGICAL, AND EPIGENETIC CONSEQUENCES OF DIFFERENT EARLY SOCIAL EXPERIENCES: POSSIBLE MECHANISMS FOR CROSS-GENERATIONAL TRANSMISSION Stephen J. Suomi, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD Objectives: Extensive research over the past several decades has documented the behavioral, biological, and, more recently, the epigenetic consequences of adverse early social environments, including experimentallyinduced maternal deprivation and naturally occurring incidents of maternal neglect and abuse. Ongoing research is now investigating the consequences of differences in social status on development. Methods: Rhesus monkeys in nature live in large, distinctive groups organized around several female-headed families that span multiple generations. In each group there are multiple social dominance hierarchies both between and within families, as well as a separate hierarchy for males that have immigrated into the group. Social status has been assessed using Elo-rating that tracks rank changes over time by constantly updating values based on wins and losses in consecutive pair-wise exchanges. Results: Regarding between-family hierarchies, there are major differences in both social opportunities on a daily basis and long-term physical and psychological health outcomes between members of high vs. low-ranking families. It appears that relative social dominance status is generally transmitted from mothers to their female offspring, i.e., high-ranking mothers typically rear daughters who themselves are high-ranking, at least initially, and low-ranking mothers usually have daughters who turn out to be lowranking themselves. Very recent data suggest that such cross-generational transmission of relative dominance status may be in part epigenetically mediated through the placenta. Conclusions: Differences in long-term social status beginning early in life can have profound behavioral, biological, and epigenetic consequences throughout development and beyond for rhesus monkeys, and at least some of these consequences can be transferred to the next generation.
ANI DEV STRESS http://dx.doi.org/10.1016/j.jaac.2016.07.782
SYMPOSIUM 24 NEW INVESTIGATIONS ON THE RELATIONSHIP BETWEEN WORKING MEMORY AND ATTENTION-DEFICIT/HYPERACTIVITY DISORDER Thomas J. Spencer, MD, Psychiatry, Massachusetts General Hospital, 55 Fruit Street, YAW6900, Boston, MA 02114-2621; Jeffrey H. Newcorn, MD Objectives: The objective of this symposium is to address the relationship between working memory (WM) and ADHD. Methods: We examined referred youth ADHD WM deficits for functional, social, and academic outcomes. In our resting-state fMRI study, we enrolled adults with childhood-onset ADHD with and without WM deficits.
J OURNAL
OF THE
AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 55 NUMBER 10S OCTOBER 2016
23.2 TOWARDS PRECISION MEDICINE FOR AUTISM SPECTRUM DISORDERS Kevin Pelphrey, PhD, Physiology and Pharmacology, George Washington University and Children’s National Medical Center, 2132 Windward Shore Drive, Washington, DC 23451 Objectives: I will describe neuroimaging research to chart the development of brain mechanisms for social cognition in typically developing infants, children, and adolescents. I will talk about the ways in which we have used our findings to predict the response of young children with ASD to specific behavioral and pharmacological treatment protocols. Methods: My studies used functional neuroimaging techniques, including fMRI and functional near infrared spectroscopy, in well characterized sample groups of young children with and without ASD. Results: Neuroimaging-based stratification biomarkers accurately predict responses to an evidence-based behavioral treatment—pivotal response treatment—in young children with ASD. Neuropredictors included the following: 1) pretreatment levels of evoked brain activity in neuroanatomical circuits supporting social perception and social reward/motivation; 2) multivariate patterns of pretreatment brain responses in the orbitofrontal cortex—a key component of the neural system supporting social motivation; and 3) pretreatment functional connectivity between the orbital frontal cortex and brain regions implicated in social perception—the posterior superior temporal sulcus and fusiform gyrus. It is noteworthy that these neuropredictors outperformed all available pretreatment demographic and behavioral measures of social functioning, language level, and cognitive abilities. Conclusions: These findings mark the very first evidence of prediction/ stratification biomarkers in young children with ASD. Moreover, the results offer a promising opportunity for the use of pretreatments or concurrent treatments to improve the functioning of the neuropredictive markers identified here, thereby increasing the effectiveness of treatments for core social deficits in children with ASD.
ASD IMAGS TREAT Supported by NIMH Grant R01MH100028 http://dx.doi.org/10.1016/j.jaac.2016.07.251
23.3 PRENATAL EPIGENETIC EFFECTS ON BRAIN DEVELOPMENT AND BEHAVIOR: TRANSLATIONAL APPROACHES Frances A. Champagne, PhD, Department of Psychology, Columbia University, 1190 Amsterdam Avenue, 406 Schermerhorn Hall, New York, NY 10027 Objectives: The prenatal period is a time of rapid neurodevelopmental change and thus represents a sensitive period for developmental disruption after exposure to stress and toxins, with implications for physical and psychiatric health outcomes. We have been exploring the epigenetic impact of prenatal exposures (particularly endocrine disruption and maternal stress) in animal models and humans to build a translational framework. Methods: In the first series of studies, we exposed pregnant mice to the endocrine disruptor bisphenol A (BPA) and examined behavior, brain gene expression, and epigenetic outcomes in adult offspring. We then conducted epigenetic analyses on cord blood samples from a human cohort in which there was prenatal assessment of BPA. In a second series of studies, we assessed prenatal psychosocial stress in mothers during fetal neurodevelopment and conducted epigenetic analyses of human placentas. We then examined gene expression outcomes in rodent placentas after chronic variable stress during pregnancy. Results: We discovered the following: 1) in mice, prenatal BPA has sexspecific effects, leading to increased epigenetic silencing of the brain-derived neurotrophic factor gene (Bdnf), decreased hippocampal expression of Bdnf, and impaired memory in male offspring; 2) elevated gestational BPA exposure is associated with epigenetic silencing of Bdnf in human cord blood samples (in males only); 3) maternal stress during pregnancy is associated with increased epigenetic silencing of 11b-hydroxysteroid dehydrogenase 2 (Hsd-11b2) in human placentas, and this epigenetic effect mediates the effect
S294
www.jaacap.org
of stress on impaired neurodevelopment; and 4) in prenatally stressed rodents, placental expression of Hsd-11b2 is decreased. Conclusions: Evidence from both laboratory animal models and human studies suggest the epigenetic impact of prenatal adversity. The integration of these across-species approaches strengthens the causal inferences that can be made when predicting the impact of experience on long-term neurobiological and behavioral outcomes.
ANI DEV NEURODEV Suported by NIMH Grant 1R01MH092580-01A1 and the National Institute Environmental Health Sciences 2P01ES009600-11 http://dx.doi.org/10.1016/j.jaac.2016.07.252
23.4 BEHAVIORAL, BIOLOGICAL, AND EPIGENETIC CONSEQUENCES OF DIFFERENT EARLY SOCIAL EXPERIENCES: POSSIBLE MECHANISMS FOR CROSS-GENERATIONAL TRANSMISSION Stephen J. Suomi, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD Objectives: Extensive research over the past several decades has documented the behavioral, biological, and, more recently, the epigenetic consequences of adverse early social environments, including experimentallyinduced maternal deprivation and naturally occurring incidents of maternal neglect and abuse. Ongoing research is now investigating the consequences of differences in social status on development. Methods: Rhesus monkeys in nature live in large, distinctive groups organized around several female-headed families that span multiple generations. In each group there are multiple social dominance hierarchies both between and within families, as well as a separate hierarchy for males that have immigrated into the group. Social status has been assessed using Elo-rating that tracks rank changes over time by constantly updating values based on wins and losses in consecutive pair-wise exchanges. Results: Regarding between-family hierarchies, there are major differences in both social opportunities on a daily basis and long-term physical and psychological health outcomes between members of high vs. low-ranking families. It appears that relative social dominance status is generally transmitted from mothers to their female offspring, i.e., high-ranking mothers typically rear daughters who themselves are high-ranking, at least initially, and low-ranking mothers usually have daughters who turn out to be lowranking themselves. Very recent data suggest that such cross-generational transmission of relative dominance status may be in part epigenetically mediated through the placenta. Conclusions: Differences in long-term social status beginning early in life can have profound behavioral, biological, and epigenetic consequences throughout development and beyond for rhesus monkeys, and at least some of these consequences can be transferred to the next generation.
ANI DEV STRESS http://dx.doi.org/10.1016/j.jaac.2016.07.782
SYMPOSIUM 24 NEW INVESTIGATIONS ON THE RELATIONSHIP BETWEEN WORKING MEMORY AND ATTENTION-DEFICIT/HYPERACTIVITY DISORDER Thomas J. Spencer, MD, Psychiatry, Massachusetts General Hospital, 55 Fruit Street, YAW6900, Boston, MA 02114-2621; Jeffrey H. Newcorn, MD Objectives: The objective of this symposium is to address the relationship between working memory (WM) and ADHD. Methods: We examined referred youth ADHD WM deficits for functional, social, and academic outcomes. In our resting-state fMRI study, we enrolled adults with childhood-onset ADHD with and without WM deficits.
J OURNAL
OF THE
AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 55 NUMBER 10S OCTOBER 2016