- Email: [email protected]
16.3 Identifying Neurobiological Biomarkers of Eating Disorders: Novel Studies of Eating Disorders in Children and Adolescents
SYMPOSIA 16.0 — 16.3
SYMPOSIUM 16 THE WHAT, WHERE, AND WHEN OF CHILDHOOD PSYCHOPATHOLOGY: FIRST STEPS TOWARDS IDENTIFYING THE ETIOLOGICAL FACTORS THAT SHAPE BRAIN DEVELOPMENT Tonya Jo White, MD, PhD, Erasmus University Medical Center, [email protected]; Philip Shaw, MD, National Human Genome Research Institute, [email protected]; Essi Viding, PhD, University College London, e.viding@ucl. ac.uk Objectives: Emerging psychopathology involves a complex interplay between genetic and environmental factors that unfolds over time. Here we ask how specific factors alter or influence developmental trajectories and result in psychopathology. Thus, our goal is to consider “how” genetic and environmental factors impact brain development, “what” might act upon different brain regions, and “where” during key developmental periods (“when”). We consider both typical development and four psychiatric disorders, namely autism spectrum disorder, ADHD, anorexia nervosa, and bulimia nervosa. Methods: Neuroimaging studies have been performed involving four different cohorts. The Generation R Study is an epidemiologic study in which there are more than 5,000 scans over two waves of neuroimaging. In addition, more than 5,000 ultrasounds were collected at three different time points during prenatal life. Multiple environmental variables have been collected during pregnancy, including maternal folate levels, fatty acids, SSRI use, cigarette smoking, and cannabis use. Results: Even in a population-based sample group, specific environmental factors measured in pregnant mothers showed downstream effects in brain development in offspring. Factors that include maternal folate, hypothyroidism and hyperthyroidism, SSRI use, cannabis use, and cigarette smoking can have consequences on brain development extending into late childhood. Conclusions: Psychopathology involves an interplay between environmental and genetic factors. Because some modifiable environmental factors have been shown to be associated with altered brain development, this can serve as an important public health message related to optimizing the baby’s brain.
PSP, IMAGS, DEV http://dx.doi.org/10.1016/j.jaac.2017.07.668
16.1 PRENATAL AND EARLY POSTNATAL ENVIRONMENTAL FACTORS ASSOCIATED WITH OPTIMAL BRAIN DEVELOPMENT Tonya Jo White, MD, PhD, Erasmus University Medical Center, [email protected] Objectives: The prenatal and early postnatal period of life is a time of considerable brain development. During prenatal life, the brain emerges from a single cell to a brain that very much resembles an adult brain by the time of birth. Early postnatal development involves rapid myelination of neuronal fibers and synaptogenesis, arborization, and pruning. This time of extensive growth is also a critical period where environmental factors, such as nutritional factors (folate), thyroid, cannabis, and cigarette smoking, can influence optimal brain development. This presentation will focus on our work exploring how prenatal and early postnatal environmental factors can influence the developing brain. Methods: The study was embedded in the Generation R Study, a large population-based study of child development. Measurements included systematic ultrasound measurements during each of the three trimesters of fetal life, and MRI (structural and functional) screenings were conducted in 1,070 children (ages 6–9 years). Nutritional measurements included prenatal measurements of folate and postnatal measurements using the food frequency questionnaire. Results: We found decreased brain growth during prenatal life that was associated with mothers with low folate. Interestingly, these changes persisted into childhood, with decreased brain volume and aberrant connectivity found on MRI studies of the brain. A high-fat/high-sugar diet during infancy was associated with smaller hippocampal volumes in later childhood.
S326
www.jaacap.org
Conclusions: Nutritional factors, especially those at a time when the brain is undergoing rapid developmental changes, can shape optimal brain development.
EPI, IMAGS, NEURODEV Supported by the Netherlands Organization for Health Research and Development Grant 91211021 http://dx.doi.org/10.1016/j.jaac.2017.07.669
16.2 MAPS OF THE DEVELOPING BRAIN AS GUIDES FOR FUTURE GENOMICS Philip Shaw, MD, National Institutes of Health, shaw@mail. nih.gov Objectives: The goal of this study is to identify common genetic variations associated with in vivo measures of the developing brain. Longitudinal data have proven to be valuable in mapping developmental processes, such as brain growth. Here, we consider how measures of a child’s developing brain can act as phenotypes for gene discovery and understanding. Methods: The study used longitudinal imaging and whole-genome single nucleotide polymorphism (SNP) data from two childhood cohorts, the LONG cohort [Bethesda; N ¼ 459, mean age 11.4 (SD 3.1) years and the Generation R population-based cohort (N ¼ 257, mean age 7.7 (0.9) years]. Neuroanatomic metrics were calculated as each child’s annual rate of change in the volume of the brain’s major structures (cerebral cortex, striatum, cerebellum, and white matter). A white matter microstructural metric (fractional anisotropy) was also defined from diffusion tensor imaging. Association analyses considered population stratification and relatedness (EMMAX and REAP software). A child’s cumulative genetic (polygenic) risk for ADHD was also calculated. Results: The maximum SNP associations were found for cerebral cortical growth (intergenic SNP near DLGAP1, P ¼ 6.1 x 108) and white matter growth (intergenic SNP near AKR1B10, P ¼ 2.6 x 108). Pathway analyses showed that genes implicated by nominally significant SNPs were enriched in axonal guidance signaling and the synthesis of proteoglycans, molecules that act as “signposts” for axonal pathfinding. Finally, we found that a child’s genetic risk for ADHD (polygenic risk) also had an impact on the growth rates of the cerebral cortex in one cohort [b ¼ 0.46 (0.19), t ¼ 2.6, P ¼ 0.01]. Analyses of the white matter microstructural data are ongoing. Conclusions: These initial studies demonstrate associations between growth and pathways of axonal development. These brain growth phenotypes may also be impacted by a child’s genetic risk for psychopathology.
ADOL, ADHD, GS Supported by NIH Intramural Research Programs http://dx.doi.org/10.1016/j.jaac.2017.07.670
16.3 IDENTIFYING NEUROBIOLOGICAL BIOMARKERS OF EATING DISORDERS: NOVEL STUDIES OF EATING DISORDERS IN CHILDREN AND ADOLESCENTS Nadia Micali, MD, MRCPsych, PhD, Icahn School of Medicine at Mount Sinai, [email protected] Objectives: Cross-sectional studies have identified neuropsychological markers associated with eating disorders (ED). Subjects at risk for ED or before onset have not been researched. By carrying out the first studies on children at risk for ED, we aimed to study neuropsychological markers of “at-risk” status across three sample groups: one population-based and two ongoing “high-risk” sample groups that aim to clarify brain and cognitive biomarkers of ED. Methods: Children at familial high risk for ED and control groups were assessed between ages 18 months and 11 years from the Avon Longitudinal Study of Parents and Children (N ¼ 7,000)—a large population-based study in the United Kingdom. Visuospatial functioning, attentional control, social communication, and facial emotion processing were assessed in children between ages 8 and 10 years. Children at high risk for ED (n ¼ 60) and control group subjects (n ¼ 30; recruited in pregnancy) have been followed up into childhood. We assessed development at age six days and one year. I will also
J OURNAL
OF THE
AMERICAN A CADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 56 NUMBER 10S OCTOBER 2017
SYMPOSIA 16.4 — 17.1
present preliminary findings on brain structure and white matter integrity in female children at high risk for ED (n ¼ 15) and control subjects (n ¼ 30) (ages 8–15 years) who underwent a brain MRI. Results: Children of mothers with anorexia nervosa and bulimia nervosa had better visuospatial abilities [B ¼ 1.34 (0.33–2.35)] and worse inhibitory control [OR ¼ 1.62 (1.21–2.17)], respectively, compared with control subjects. Early differences in motor [B ¼ 0.32 (18.4, 1.3)] and language [B ¼ 0.33 (13.6, 1.9)] development at age one year and autonomic dysfunction at six days postnatal were evident in children at risk for ED. Conclusions: Our findings extend current cross-sectional evidence of neurobiological abnormalities associated with ED, with novel findings on neuropsychological markers of ED, with implications for prevention and early intervention.
IMAGS, EA, NEURODEV Supported by NIH http://dx.doi.org/10.1016/j.jaac.2017.07.671
16.4 TOWARDS THE IDENTIFICATION OF EARLY NEURAL SIGNATURES OF AUTISM USING NATURAL SLEEP FUNCTIONAL MAGNETIC RESONANCE IMAGING Adriana DiMartino, MD, New York University Child Study Center, [email protected] Objectives: Advances in early diagnosis of autism spectrum disorder (ASD) have brought both new opportunities and challenges. Although earlier interventions can be provided, the field still needs early prognostic markers. As illustrated by successes in other fields of medicine, achieving this goal is unlikely if investigations are solely restricted to behavioral domains without attention to the underlying physiology. With this background in mind, we have initiated examinations of natural sleep fMRI data of young children with ASD to capture early brain organization and its relationship with symptom domains known to be relevant for adult outcome. Methods: We examined task-free fMRI data obtained from 41 young children with confirmed ASD (age range 28–72 months; mean 52 14 months, 28 males) who completed a natural sleep scan. As a first step, we focused on functional striatal circuitry and the severity of restricted repetitive behaviors (RRB)—a key diagnostic feature that causes significant impairment and affects long-term outcome. Specifically, we examined the intrinsic functional connectivity (iFC) of the somatomotor (SM) functional division of the striatum as defined by prior data-driven approaches. In preparation for future prospective studies, we explored SM striatal iFC in relation to the interaction between age and RRB severity indexed by the Autism Diagnostic Observation Schedule— 2nd Edition (ADOS-2). Results: Clusters with a significant relationship between SM striatal iFC and the RRB by age interaction encompassed supplementary motor cortex, lateral aspects of primary motor cortex, and mid-insula. Conclusions: These cross-sectional results suggest that the development of striatal-cortical circuits may be mechanistically central to RRB changes and underscore the need of a longitudinal approach. This effort highlights the feasibility of sleep task-free fMRI to identify neuronal signatures of autism that can eventually serve as predictive markers of later outcome.
ASD, DEV, IMAGS http://dx.doi.org/10.1016/j.jaac.2017.07.672
SYMPOSIUM 17 DEVELOPMENTAL PERSPECTIVES ON AGGRESSION AND DISRUPTIVE BEHAVIORS AND IMPLICATIONS FOR TREATMENT Jeffrey Newcorn, MD, Icahn School of Medicine at Mount Sinai, [email protected]; Iliyan Ivanov, MD, Icahn School of Medicine at Mount Sinai, [email protected]
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 56 NUMBER 10S OCTOBER 2017
Objectives: Aggression is a behavioral trait that is present from early development and may follow various developmental trajectories. Aggressive behaviors are robustly present in youth diagnosed with disruptive behavior disorders (DBD), such as ADHD, ODD, and conduct disorder (CD); moreover, the link between childhood DBDs and later antisocial personality disorder (ASPD) has been well documented. However, the underlying neurobiological mechanisms that may either facilitate or offer protective effects on the transition from childhood DBD to ASPD are poorly understood. This symposium will discuss new findings from naturalistic and experimental studies that have examined the neurobiological substrates of aggressive behaviors and related diagnoses and consider implications for treatment of this population. Methods: Participants in these studies include both children and adolescents who have been followed longitudinally or have participated in various clinical or neuroimaging protocols. Participants in the neuroimaging studies had comprehensive assessments followed by pharmacological challenge or ongoing treatment; fMRI scans were performed using different reward processing and inhibitory control tasks. Results: Findings indicate that low serotonergic reactivity in children with ADHD may predict later ASPD, and a variety of neuroregulatory deficits are present in youth with aggression and DBDs. This includes both volumetric abnormalities and aberrant functional connectivity linking prefrontal cortex, limbic structures, and striatum. Stimulant and nonstimulant medications can potentially have a role in treating aggression and DBDs in youth with ADHD, and the best predictive model highlights the inter-relationships among ADHD symptoms, aggression, and mood dysregulation. Conclusions: This symposium will present the results of several studies indicating the neurobiological basis of aggression and disruptive behavior disorders in youth with ADHD. Etiological factors relevant to the developmental trajectories of aggression, relations to adult psychopathology, and possible treatments for aggression will be discussed.
AGG, NEUROA, NECHEM http://dx.doi.org/10.1016/j.jaac.2017.07.674
17.1 SEROTONERGIC FUNCTION AND EARLY ADULTHOOD OUTCOMES IN CHILDREN WITH DISRUPTIVE BEHAVIOR DISORDERS Iliyan Ivanov, MD, Icahn School of Medicine at Mount Sinai, [email protected] Objectives: Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include ADHD and, more notably, comorbid ADHD and conduct disorder (CD). As independent studies have provided evidence for the purported role of abnormal serotonergic functions in aggressive youth and adults, little evidence exists on the role of serotonin on the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relationship between serotonergic functions in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood will predict the development of adult ASPD. Methods: We studied 40 adults (males ¼ 37, females ¼ 3; ages 23–26 years; mean age 24.57 years, SD 14.47) divided into two groups: participants with (n ¼ 21) and without ASPD (n ¼ 19). We used logistic regression to assess whether serotonergic measures in childhood (ages 7–11 years) assessed via prolactin and cortisol response to a fenfluramine challenge predicted the development of ASPD in early adulthood. Results: Logistic regression models showed that prolactin response in childhood was not a significant predictor of adult ASPD but was linked to strong sex effect (i.e., significantly elevated prolactin response in females). In contrast, low cortisol response (an indirect measure of central serotonin) significantly predicted adult ASPD (P ¼ 0.043) above and beyond CD, which was another independent predictor of ASPD. Conclusions: This report provides new evidence of the link between low serotonergic functions in childhood and adult psychopathology, particularly the development of ASPD. More specifically, this link seems to be prominent in boys diagnosed with ADHD who may also have comorbid CD. Clinical relevance is related to the development of new methods of assessment of
www.jaacap.org
S327
SYMPOSIUM 16 THE WHAT, WHERE, AND WHEN OF CHILDHOOD PSYCHOPATHOLOGY: FIRST STEPS TOWARDS IDENTIFYING THE ETIOLOGICAL FACTORS THAT SHAPE BRAIN DEVELOPMENT Tonya Jo White, MD, PhD, Erasmus University Medical Center, [email protected]; Philip Shaw, MD, National Human Genome Research Institute, [email protected]; Essi Viding, PhD, University College London, e.viding@ucl. ac.uk Objectives: Emerging psychopathology involves a complex interplay between genetic and environmental factors that unfolds over time. Here we ask how specific factors alter or influence developmental trajectories and result in psychopathology. Thus, our goal is to consider “how” genetic and environmental factors impact brain development, “what” might act upon different brain regions, and “where” during key developmental periods (“when”). We consider both typical development and four psychiatric disorders, namely autism spectrum disorder, ADHD, anorexia nervosa, and bulimia nervosa. Methods: Neuroimaging studies have been performed involving four different cohorts. The Generation R Study is an epidemiologic study in which there are more than 5,000 scans over two waves of neuroimaging. In addition, more than 5,000 ultrasounds were collected at three different time points during prenatal life. Multiple environmental variables have been collected during pregnancy, including maternal folate levels, fatty acids, SSRI use, cigarette smoking, and cannabis use. Results: Even in a population-based sample group, specific environmental factors measured in pregnant mothers showed downstream effects in brain development in offspring. Factors that include maternal folate, hypothyroidism and hyperthyroidism, SSRI use, cannabis use, and cigarette smoking can have consequences on brain development extending into late childhood. Conclusions: Psychopathology involves an interplay between environmental and genetic factors. Because some modifiable environmental factors have been shown to be associated with altered brain development, this can serve as an important public health message related to optimizing the baby’s brain.
PSP, IMAGS, DEV http://dx.doi.org/10.1016/j.jaac.2017.07.668
16.1 PRENATAL AND EARLY POSTNATAL ENVIRONMENTAL FACTORS ASSOCIATED WITH OPTIMAL BRAIN DEVELOPMENT Tonya Jo White, MD, PhD, Erasmus University Medical Center, [email protected] Objectives: The prenatal and early postnatal period of life is a time of considerable brain development. During prenatal life, the brain emerges from a single cell to a brain that very much resembles an adult brain by the time of birth. Early postnatal development involves rapid myelination of neuronal fibers and synaptogenesis, arborization, and pruning. This time of extensive growth is also a critical period where environmental factors, such as nutritional factors (folate), thyroid, cannabis, and cigarette smoking, can influence optimal brain development. This presentation will focus on our work exploring how prenatal and early postnatal environmental factors can influence the developing brain. Methods: The study was embedded in the Generation R Study, a large population-based study of child development. Measurements included systematic ultrasound measurements during each of the three trimesters of fetal life, and MRI (structural and functional) screenings were conducted in 1,070 children (ages 6–9 years). Nutritional measurements included prenatal measurements of folate and postnatal measurements using the food frequency questionnaire. Results: We found decreased brain growth during prenatal life that was associated with mothers with low folate. Interestingly, these changes persisted into childhood, with decreased brain volume and aberrant connectivity found on MRI studies of the brain. A high-fat/high-sugar diet during infancy was associated with smaller hippocampal volumes in later childhood.
S326
www.jaacap.org
Conclusions: Nutritional factors, especially those at a time when the brain is undergoing rapid developmental changes, can shape optimal brain development.
EPI, IMAGS, NEURODEV Supported by the Netherlands Organization for Health Research and Development Grant 91211021 http://dx.doi.org/10.1016/j.jaac.2017.07.669
16.2 MAPS OF THE DEVELOPING BRAIN AS GUIDES FOR FUTURE GENOMICS Philip Shaw, MD, National Institutes of Health, shaw@mail. nih.gov Objectives: The goal of this study is to identify common genetic variations associated with in vivo measures of the developing brain. Longitudinal data have proven to be valuable in mapping developmental processes, such as brain growth. Here, we consider how measures of a child’s developing brain can act as phenotypes for gene discovery and understanding. Methods: The study used longitudinal imaging and whole-genome single nucleotide polymorphism (SNP) data from two childhood cohorts, the LONG cohort [Bethesda; N ¼ 459, mean age 11.4 (SD 3.1) years and the Generation R population-based cohort (N ¼ 257, mean age 7.7 (0.9) years]. Neuroanatomic metrics were calculated as each child’s annual rate of change in the volume of the brain’s major structures (cerebral cortex, striatum, cerebellum, and white matter). A white matter microstructural metric (fractional anisotropy) was also defined from diffusion tensor imaging. Association analyses considered population stratification and relatedness (EMMAX and REAP software). A child’s cumulative genetic (polygenic) risk for ADHD was also calculated. Results: The maximum SNP associations were found for cerebral cortical growth (intergenic SNP near DLGAP1, P ¼ 6.1 x 108) and white matter growth (intergenic SNP near AKR1B10, P ¼ 2.6 x 108). Pathway analyses showed that genes implicated by nominally significant SNPs were enriched in axonal guidance signaling and the synthesis of proteoglycans, molecules that act as “signposts” for axonal pathfinding. Finally, we found that a child’s genetic risk for ADHD (polygenic risk) also had an impact on the growth rates of the cerebral cortex in one cohort [b ¼ 0.46 (0.19), t ¼ 2.6, P ¼ 0.01]. Analyses of the white matter microstructural data are ongoing. Conclusions: These initial studies demonstrate associations between growth and pathways of axonal development. These brain growth phenotypes may also be impacted by a child’s genetic risk for psychopathology.
ADOL, ADHD, GS Supported by NIH Intramural Research Programs http://dx.doi.org/10.1016/j.jaac.2017.07.670
16.3 IDENTIFYING NEUROBIOLOGICAL BIOMARKERS OF EATING DISORDERS: NOVEL STUDIES OF EATING DISORDERS IN CHILDREN AND ADOLESCENTS Nadia Micali, MD, MRCPsych, PhD, Icahn School of Medicine at Mount Sinai, [email protected] Objectives: Cross-sectional studies have identified neuropsychological markers associated with eating disorders (ED). Subjects at risk for ED or before onset have not been researched. By carrying out the first studies on children at risk for ED, we aimed to study neuropsychological markers of “at-risk” status across three sample groups: one population-based and two ongoing “high-risk” sample groups that aim to clarify brain and cognitive biomarkers of ED. Methods: Children at familial high risk for ED and control groups were assessed between ages 18 months and 11 years from the Avon Longitudinal Study of Parents and Children (N ¼ 7,000)—a large population-based study in the United Kingdom. Visuospatial functioning, attentional control, social communication, and facial emotion processing were assessed in children between ages 8 and 10 years. Children at high risk for ED (n ¼ 60) and control group subjects (n ¼ 30; recruited in pregnancy) have been followed up into childhood. We assessed development at age six days and one year. I will also
J OURNAL
OF THE
AMERICAN A CADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 56 NUMBER 10S OCTOBER 2017
SYMPOSIA 16.4 — 17.1
present preliminary findings on brain structure and white matter integrity in female children at high risk for ED (n ¼ 15) and control subjects (n ¼ 30) (ages 8–15 years) who underwent a brain MRI. Results: Children of mothers with anorexia nervosa and bulimia nervosa had better visuospatial abilities [B ¼ 1.34 (0.33–2.35)] and worse inhibitory control [OR ¼ 1.62 (1.21–2.17)], respectively, compared with control subjects. Early differences in motor [B ¼ 0.32 (18.4, 1.3)] and language [B ¼ 0.33 (13.6, 1.9)] development at age one year and autonomic dysfunction at six days postnatal were evident in children at risk for ED. Conclusions: Our findings extend current cross-sectional evidence of neurobiological abnormalities associated with ED, with novel findings on neuropsychological markers of ED, with implications for prevention and early intervention.
IMAGS, EA, NEURODEV Supported by NIH http://dx.doi.org/10.1016/j.jaac.2017.07.671
16.4 TOWARDS THE IDENTIFICATION OF EARLY NEURAL SIGNATURES OF AUTISM USING NATURAL SLEEP FUNCTIONAL MAGNETIC RESONANCE IMAGING Adriana DiMartino, MD, New York University Child Study Center, [email protected] Objectives: Advances in early diagnosis of autism spectrum disorder (ASD) have brought both new opportunities and challenges. Although earlier interventions can be provided, the field still needs early prognostic markers. As illustrated by successes in other fields of medicine, achieving this goal is unlikely if investigations are solely restricted to behavioral domains without attention to the underlying physiology. With this background in mind, we have initiated examinations of natural sleep fMRI data of young children with ASD to capture early brain organization and its relationship with symptom domains known to be relevant for adult outcome. Methods: We examined task-free fMRI data obtained from 41 young children with confirmed ASD (age range 28–72 months; mean 52 14 months, 28 males) who completed a natural sleep scan. As a first step, we focused on functional striatal circuitry and the severity of restricted repetitive behaviors (RRB)—a key diagnostic feature that causes significant impairment and affects long-term outcome. Specifically, we examined the intrinsic functional connectivity (iFC) of the somatomotor (SM) functional division of the striatum as defined by prior data-driven approaches. In preparation for future prospective studies, we explored SM striatal iFC in relation to the interaction between age and RRB severity indexed by the Autism Diagnostic Observation Schedule— 2nd Edition (ADOS-2). Results: Clusters with a significant relationship between SM striatal iFC and the RRB by age interaction encompassed supplementary motor cortex, lateral aspects of primary motor cortex, and mid-insula. Conclusions: These cross-sectional results suggest that the development of striatal-cortical circuits may be mechanistically central to RRB changes and underscore the need of a longitudinal approach. This effort highlights the feasibility of sleep task-free fMRI to identify neuronal signatures of autism that can eventually serve as predictive markers of later outcome.
ASD, DEV, IMAGS http://dx.doi.org/10.1016/j.jaac.2017.07.672
SYMPOSIUM 17 DEVELOPMENTAL PERSPECTIVES ON AGGRESSION AND DISRUPTIVE BEHAVIORS AND IMPLICATIONS FOR TREATMENT Jeffrey Newcorn, MD, Icahn School of Medicine at Mount Sinai, [email protected]; Iliyan Ivanov, MD, Icahn School of Medicine at Mount Sinai, [email protected]
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 56 NUMBER 10S OCTOBER 2017
Objectives: Aggression is a behavioral trait that is present from early development and may follow various developmental trajectories. Aggressive behaviors are robustly present in youth diagnosed with disruptive behavior disorders (DBD), such as ADHD, ODD, and conduct disorder (CD); moreover, the link between childhood DBDs and later antisocial personality disorder (ASPD) has been well documented. However, the underlying neurobiological mechanisms that may either facilitate or offer protective effects on the transition from childhood DBD to ASPD are poorly understood. This symposium will discuss new findings from naturalistic and experimental studies that have examined the neurobiological substrates of aggressive behaviors and related diagnoses and consider implications for treatment of this population. Methods: Participants in these studies include both children and adolescents who have been followed longitudinally or have participated in various clinical or neuroimaging protocols. Participants in the neuroimaging studies had comprehensive assessments followed by pharmacological challenge or ongoing treatment; fMRI scans were performed using different reward processing and inhibitory control tasks. Results: Findings indicate that low serotonergic reactivity in children with ADHD may predict later ASPD, and a variety of neuroregulatory deficits are present in youth with aggression and DBDs. This includes both volumetric abnormalities and aberrant functional connectivity linking prefrontal cortex, limbic structures, and striatum. Stimulant and nonstimulant medications can potentially have a role in treating aggression and DBDs in youth with ADHD, and the best predictive model highlights the inter-relationships among ADHD symptoms, aggression, and mood dysregulation. Conclusions: This symposium will present the results of several studies indicating the neurobiological basis of aggression and disruptive behavior disorders in youth with ADHD. Etiological factors relevant to the developmental trajectories of aggression, relations to adult psychopathology, and possible treatments for aggression will be discussed.
AGG, NEUROA, NECHEM http://dx.doi.org/10.1016/j.jaac.2017.07.674
17.1 SEROTONERGIC FUNCTION AND EARLY ADULTHOOD OUTCOMES IN CHILDREN WITH DISRUPTIVE BEHAVIOR DISORDERS Iliyan Ivanov, MD, Icahn School of Medicine at Mount Sinai, [email protected] Objectives: Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include ADHD and, more notably, comorbid ADHD and conduct disorder (CD). As independent studies have provided evidence for the purported role of abnormal serotonergic functions in aggressive youth and adults, little evidence exists on the role of serotonin on the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relationship between serotonergic functions in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood will predict the development of adult ASPD. Methods: We studied 40 adults (males ¼ 37, females ¼ 3; ages 23–26 years; mean age 24.57 years, SD 14.47) divided into two groups: participants with (n ¼ 21) and without ASPD (n ¼ 19). We used logistic regression to assess whether serotonergic measures in childhood (ages 7–11 years) assessed via prolactin and cortisol response to a fenfluramine challenge predicted the development of ASPD in early adulthood. Results: Logistic regression models showed that prolactin response in childhood was not a significant predictor of adult ASPD but was linked to strong sex effect (i.e., significantly elevated prolactin response in females). In contrast, low cortisol response (an indirect measure of central serotonin) significantly predicted adult ASPD (P ¼ 0.043) above and beyond CD, which was another independent predictor of ASPD. Conclusions: This report provides new evidence of the link between low serotonergic functions in childhood and adult psychopathology, particularly the development of ASPD. More specifically, this link seems to be prominent in boys diagnosed with ADHD who may also have comorbid CD. Clinical relevance is related to the development of new methods of assessment of
www.jaacap.org
S327