Probabilistic epigenesis of externalizing disorders in children and adolescents

Probabilisticepigenesisof externalizingdisordersin children and adolescents David Cohen Service de Psychiatrie de l’Enfant et de l’Adolescent GH Pitié-Salpêtrière – Paris Université Pierre et Marie Curie Laboratoire CNRS ˝Institut des Systèmes Intelligents et Robotiques˝ http://speapsl.aphp.fr

The categorialapproach Oppositional Defiant Disorder (ODD) Collection of negative and provocative behaviors, including being disobedient and hostile towards those in a position of authority. ConductDisorder Collectionof repetitive and persistent behaviors that go against the fundamental rights of others and the societal norms and rules ADHD et HKD Repetitivebehaviorsthatconsists of (i) lack of attentiveness, (ii) hyperactivity, and (iii) impulsiveness Borderline Personalitysubtypes Cohen & Marcelli, 2009

The dimensionalapproach(i) Clinicalassessment Hyperactivity or hyperkinesia Physical aggressiveness Impulsiveness Opposition - verbal aggressiveness Anti-social dimension Anxiety Emotional dysregulation Depression, manicdefense

Dimensions psychologiques pertinentes The dimensionalapproach(ii) Psychologicalassessment Attention and executive functions (in particular the failure to use inhibitory skills) Self esteem and narcissistic personality disorder Disorganized and insecure attachment styles Attribution disorders Callous-unemotional traits The absence of moral and sentimental development or access to guilt

Developmental view of externalized disorders ODD CD ASP  ADHD Child Adolescent Young Adult Modified from Loeber et al, JAACAP. 2000

5-year stability of ADHD subtypes Low diagnostic stability at 5 years Unless for the severe combined subtype 35 % Todd et al, JAACAP. 2008

The genetic vulnerability model DNA VULNERABILITY PHENOTYPE Stress Adaptative factors Life events

Metatheoritical model of probabilistic epigenesis[≠ predetermined epigenesis] ENVIRONMENT Physical – Social – Cultural BEHAVIOR and CONDUCT NEURAL LEVEL GENETIC LEVEL BI-DIRECTIONAL Early interaction Adolescence Individual development Modified from Goetlieb, Dev Science, 2007

Arguments to support this modelPlan of the talk • Theoritical arguments related to neural network modelisation • The lack of direct genetic determinism contributing to externalizing disorders • The contribution of environmental variables to externalizing disorders • The contribution of animal models to understand consequences of stress on development • Towards a probabilistic epigenetic model Cohen, Neurosciences BioBehavioral Review, 2010

Probabilistic automata as a model for epigenesis of cellular networks (i) Probabilistic programming is more efficient than deterministic to account for the generation of complex networks (high number of cells, diversity of interactions) (ii) Probabilistic automata have self-organizing properties that make them adequate to account for non-directed learning at cellular and multicellular levels (iii) in particular, changes in the structure of a network can come about in the results of its functioning. E.g. Immune system – Central nervous system Milgram & Atlan, J Theor Biol, 1983

Accuracy  but N of states  Accuracy is easily achieved if redundant structure Accuracy vs. Complexity Accuracy is more easily achieved if complex structure Accuracy  but N of states 

MOTHERESE SOCIAL INTERACTION JOINT ATTENTION Exaggerates acoustic cues for phonemes Increases attention and arousal, which results in more robust and durable learning Assists detection of object-sound correspondences SOCIALISATION Universal language speech perception Language-specific perception Sensory learning •  of nonnative • consonants • perception • of native consonants perception Recognition of language-specific combined sounds PERCEPTION PROBABILISTIC LEARNING Infant discriminate phonetic units universally Vowels-specific perception Detection of specific patterns in the word Time (months) 0 2 4 6 8 10 12 Infant produces non-speech sounds Babbling First words PRODUCTION Language-specific speech production Infant produces vowels sounds Sensory-motor learning Language-specific speech production Universal language speech production Khul, 2009

Four dimensions of inheritance: an evolutionary perspective • Genetic inheritance • Epigenetic inheritance • Behavioural inheritance • Symbol-based / cultural inheritance environment Jablonka & Lamb, BBS, 2006 • Culture (Nurture) - Hobbes • Development - Lorenz • Behaviorallearning - Bandura • Nature - Rousseau Learning

Modified from Caspi & Moffitt, Nat Rev Neurosci. 2006 gene Genes for autism & MR Disorder gene endophenotype DR2impulsiveness alcohol dependance Disorder environt Alcoholism & aldehyde deshydroase Disorder modulation gene Canabis/COMT/SCZ Maltreatment/MAOA/CD Stress/5HTTrans/MDE G x E Disorder environt environt epigenesis Disorder? Stress & non genomic transmission of behaviors modulation gene Enriched environts & animal models of CNS disorders Disorder?

gene Genes for autism & MR Disorder Behavioral phenotype: e.g. Autism spectrum disorder Examples of atypical phenotypes that usually are autistic but were not and vis et versa

X-linked borderline MR with major CD: Evidence for implication of MAOA Dutch family, agressive and impulsive behaviors (rape, arson) Locus = Xp11-21 MAOA lod score= 3.69 Affected males had disturbances of monoamine metabolism and normal MAOB activity Brunner et al, Am J Hum Genet. 1993

gene endophenotype DR2impulsiveness alcohol dependance Disorder Endophenotype In this case, genetic determinism is carried through a variable known as an endophenotype, which is directly linked to the disorders. Poor empathy / Extreme callous-emotional traits

Reduced amygdala response to fearful expressions in youths with callous unemotional traits and disruptive behaviors Marsh et al. Am J Psy 2008

Evidence for substantial genetic risk for extreme callous-unemotional traits (CU) in 7-year-old is associated with antisocial behavior (AB) TEDS (3687 twin pairs) with extreme CU (N=612) at 7-year-old with extreme AB (N=444)at 7-year-old Strong genetic influence Low shared environment influence Low genetic influence Strong shared environment influence Viding et al, JCPP. 2005

environt Alcoholism & aldehyde deshydroase Disorder modulation Effects of alcohol / cigarette consumption during pregnancy on the child development Modulation of the risk of ADHD by DAT polymorphism

Genetic modulation of alcohol/cigarette consumption during pregnancy and child development Prospective study 6 to 60 months N=160 Hyperactivity Inattention Opposition Conners’ parent RS Kahn et al, J Pediatr. 2003

Examples gene x environment interaction for depression, schizophrenia and conduct disorder Genes may be COMT, MAOA, 5HTTrans, Huntington Environment may be stressful life events, maltreatment, early life adversity, family with deviant communication gene Canabis/COMT/SCZ Maltreatment/MAOA/CD Stress/5HTTrans/MDE G x E Disorder environt

Environmental risk, genetic liability & conduct disorder Jaffee et al., Dev Psychopathol, 2005 Twin study – E-risk study N=1116 same sex twin pairs Highest genetic risk=MZ has co-twin with the diagnosis High genetic risk=DZ has co-twin with the diagnosis Highest genetic risk=DZ has co-twin with no diagnosis Lowest genetic risk=MZ has co-twin with no diagnosis Conduct problem and maltreatment Gene-environment interaction in vulnerability to CD

Environmental risk, genetic liability & conduct disorder Caspi et al, Science, 2002 Dunedin MHDS Prospective study N = 442 boys, from birth to 26 y CD, violence and ASP at follow-up Maltreatment groups did not differ on MAOA activity MAOA activity moderates the impact of early maltreatment on the developement of violence Maltreatment experienced < 11 years severe maltreatment probable maltreatment no maltreatment

TOXIC AND PER NATAL FACTORS that impact brain development either during pregnancy and/or infancy) MICRO-ENVIRONMENTAL VARIABLESthat impact the child and his/her family in a proximal way Low socioeconomic status, Early separation, Single/disrupted parent (father absence), Large number of siblings, Individual handicap or poor social skills, Sexual and/or physical abuse, Family violence and/or alcoholism, Mentally ill parent, Parental use of punishment as opposed to reward MACRO-ENVIRONMENTAL VARIABLESthat impact at a more general societal level Urban residency, TV exposure, Minority, Rejection from school, Inclusion in at-risk pro-social alternatives (peer grouping: e.g., ganging; drug abuse), Competitive and violent culture epigenesis environt Stress & non genomic transmission of behaviors Disorder Mealey L, BBS. 1995 Cohen, Neuroscience BioBehav Rev 2010

Maltreatment and antisocial behaviors: e.g. MICRO 7 years 5 years Jaffee et al, J Abnorm Psychol. 2004 Twin study – E-risk study - N=1116 same sex twin pairs Physical maltreatment plays a causal role in the development of children’s antisocial behavior

Maternaldepressionand antisocial behaviors: e.g. MICRO Kim-Cohen et al. Arch Gen Psy 2005 Twin study – E-risk study N=1116 same sex twin pairs Post natal maternal depression predicted antisocial behaviors at age 7: -with a ”dose effect” -after controlling for mother’s and father’s ASPD -with additive effects -with high heritability

Intergenerational transmission of childhood conduct problems: a twin study D’Onofrio et al. 2007 Arch Gen Psy High-risk sample – 889 twin families – N=2554 Australia Using the number of conduct disorder symtoms, there was a significant intergenerational transmission for all offsprings (male>female) In male, largely mediated by environmental variables In female, not the same. A common genetic liability accounted for the intergenerational relations

Affiliation to an antisocial group during adolescence: e.g. MACRO 1 Getting inside the group of ASB Leaving the group  of ASB Two trajectories regarding admission to a group: Early-adolescence then mid adolescence Lacourse et al. Dev Psych 2006

Ealy stress, inproper maternal care, stress during gestation influence development through non genomic transmissions of behaviors in animal models Victor Denenberg (1970) – Michael Meaney (2000) environt epigenesis Stress & non genomic transmission of behaviors Disorder

Early experiences and epigenetic programming Early experiences have long-term effects on behavioral and biological systems: e.g. handling (pup/mother separation) Denenberg et al, Science, 1967; Liu et al., Science, 1997 Early experiences affect future generation providing a non-genomic mechanism for the transmission of behavioral traits Denenberg & Whimbey, Science, 1963; Francis et al., Science, 1999 The uterine environment affects development through environmental factors rather than genetic ones Denenberg et al, Neuroreport, 1998; Francis et al., Nat Neurosci, 2003

Maternal care impacts development through behavioral programming and responses to stress in adulthood… Maternal care (pup licking/grooming and arched back nursing) influences: - Hypothalamic-Pituitary-Adrenal responses to stress in offsprings Liu et al. Science, 1997 - Hippocampal synaptogenesis, plasticity and spatial learning and memory Liu et al. Nat Neurosci, 2000; Mirescu et al. Nat Neurosci, 2004 - The offspring epigenome in the hippocampus; and reversal occurs when (1) cross-fostering is proposed; (2) histone deacetylase is infused in early post natal Weaver et al. Nat Neurosci, 2004

Rats models implicate epigenetic regulation of hippocampal glucocorticoid R expression in mediationg the effects of early life experience on adult behaviorHow adversity gets under the skin? Hyman et al. Nat Neurosc 2009

Familycontext, early interactions and antisocial behaviors: e.g. MICRO Caspi et al. Dev Psychopathol, 2004 Twin study – E-risk study N=565 MZ twin pairs The twin receiving more maternal negative emotional expression and less warmth at age 5 had more antisocial behaviors at age 7 Jaffee et al. Child Dev, 2003 Twin study – E-risk study – N=1116 twin pairs The less time father with low antisocial behaviors lived with their children, the more conduct problems their children had receiving When father engaged in high levels of antisocial behavior, the more time they lived with their children, the more conduct problems their children had

Reversibility of adverse rearing condition consequences by restoring normal family rearing Adoption study N=144 Romanian (≤42 months)adoptees reared in very depriving institutions vs. 52 UK born (≤6 months) adoptees At entry, cognitive impairment was associated with institutional deprivation and with its duration At follow-up (6 years of age): - There was a remarkable degree of recovery after restoration of normal family rearing -Major deficits persisted in a substantial minority: General Cognitive Index was 25 points lower in those who entered the UK after 2 years vs. those who entered before 6 months whatever the degree of malnutrition Rutter et al, Dev Psychol. 2004

Institutional Rearing and Psychiatric Disordersin RomanianPreschoolChildren Zeanah et al, Am J Psy. 2009

Institutional Rearing and Psychiatric Disordersin RomanianPreschoolChildren Children with any history of institutional rearinghad more psychiatricdisorders than children without such a history (53.2% vs. 22.0%) Children removed from institutions and placed in foster families were less likely to have internalizing disordersthanchildrenwho continued with care as usual (22.0% vs. 44.2%) Boys were more symptomatic than girls regardless of their caregiving environment Unlike girls, boys had no reduction in total psychiatric symptoms following foster placement Zeanah et al, Am J Psy. 2009

Timing of intervention affects brain electrical activity in children exposed to severe psychosocial neglect Scalp topography of alpha power Mean alpha power across sites Children exposed to PS neglect (institution) and cared as usual, N=48 Children exposed to PS neglect (institution) and placed in foster care after 24 months, N=28 Children exposed to PS neglect (institution) and placed in foster care before 24 months, N=25 Children never institutionalized, N=42 Vanderwert et al, PlosOne. 2010

Association of exposure to peer verbal abuse with elevated psychiatric symptom scores Teicher et al, Am J Psy. 2010

Association of exposure to peer verbal abuse with corpus callosum abnormalities N=63 No history of sexual abuse No history of physical abuse Peer verbal abuse score > 30 % Teicher et al, Am J Psy. 2010

Developmental view of externalizing disorders Family factors Psychosocial factors Peer grouping Drug abuse School exclusion Protective factors ODD CD ASP Cultural factors Psychosocial factors Hostile parenting Early life adversities Toxic factors Genetic factors Biological factors  Impulsivity Aggressiveness Hyperactivity Empathy/Callous-unemotional traits Narcissism/Self-esteem Insecure attachment Manic defense ADHD Child Adolescent Young Adult Modified from Loeber et al, JAACAP. 2000

Metatheoritical model of probabilistic epigenesis[≠ predetermined epigenesis] ENVIRONMENT Physical – Social – Cultural BEHAVIOR and CONDUCT NEURAL LEVEL GENETIC LEVEL BI-DIRECTIONAL Early interaction Adolescence Individual development In this view, neural (and other) structures begin to function before they are fully mature, and this activity, whether intrinsically derived or extrinsically stimulated plays a significant role in the developmental process. Since the coordination of formative functional and structural influences within and between all levels of analysis is not perfect, a probabilistic element is introduced in all developing systems and their outcome. Some tension may occur (e.g. early life, culture, CU traits) Modified from Goetlieb, Dev Science, 2007

Rearing condition, 5HTT polymorphism and (i) response to stress or (ii) alcohol preference from Caspi and Moffitt, Nat Rev Neurosci. 2006 Mother- reared Peer- reared Carence précoce Modulation génétique Consommation d’alcool Axe corticotrope Barr et al, Biol Psy. 2004 Barr et al, Arch Gen Psy. 2004

Epigenetic regulation of the glucocorticoid Rin human brain associateswith childhood abuse and suicide McGowan et al. Nat Neurosci 2009

Probabilistic epigenesis of externalizing disorders in children and adolescents