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Probabilistic epigenesis
of externalizing disorders
in 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 categorial approach
Oppositional Defiant Disorder (ODD)
Collection of negative and provocative behaviors,
including being disobedient and hostile towards those in
a position of authority.
Conduct Disorder
Collection of repetitive and persistent behaviors that go
against the fundamental rights of others and the societal
norms and rules
ADHD et HKD
Repetitive behaviors that consists of (i) lack of
attentiveness, (ii) hyperactivity, and (iii) impulsiveness
Borderline
Personality subtypes
Cohen & Marcelli, 2009
The dimensional approach
(i) Clinical assessment
Hyperactivity or hyperkinesia
Physical aggressiveness
Impulsiveness
Opposition - verbal aggressiveness
Anti-social dimension
Anxiety
Emotional dysregulation
Depression, manic defense
The dimensional
approach
Dimensions
psychologiques
pertinentes
(ii) Psychological assessment
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
Stress
Adaptative
factors
Life events
PHENOTYPE
Metatheoritical model of probabilistic epigenesis
[≠ predetermined epigenesis]
ENVIRONMENT
Physical – Social – Cultural
Individual development
BI-DIRECTIONAL
BEHAVIOR and CONDUCT
NEURAL LEVEL
GENETIC LEVEL
Early
interaction
Adolescence
Modified from Goetlieb, Dev Science, 2007
Arguments to support this model
Plan 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 
Minimum number of necessary states
Deterministic automaton
x
n (D)
x
n (P)1
x
n (P)2
Accuracy is easily
achieved if redundant
structure
δ1
Accuracy
vs.
Complexity
δ2
Probabilistic automaton
Accuracy is more easily
achieved if complex
structure
Accuracy  but N of states 
SOCIALISATION
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
Universal language speech perception
Language-specific perception
PERCEPTION
Sensory learning
PROBABILISTIC LEARNING
Infant discriminate
phonetic units
universally
0
PRODUCTION
 of nonnative
consonants
perception
Recognition of language-specific
combined sounds
2
Vowels-specific
perception
4
Infant produces
non-speech sounds
Infant produces vowels sounds
 of native
consonants
perception
Detection of specific
patterns in the word
6
8
Babbling
10
Time
(months)
12
First words
Language-specific speech production
Sensory-motor learning
Universal language speech production
Language-specific speech production
Khul, 2009
Arguments to support this model
Plan 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
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
Behavioral learning - Bandura
Nature - Rousseau
Learning
Modified from Caspi & Moffitt, Nat Rev Neurosci. 2006
gene
Disorder
Genes for autism & MR
Disorder
DR2impulsiveness
alcohol dependance
Disorder
Alcoholism &
aldehyde deshydroase
gene
endophenotype
environt
modulation
gene
environt
GxE
Disorder
Canabis/COMT/SCZ
Maltreatment/MAOA/CD
Stress/5HTTrans/MDE
environt
epigenesis
Disorder?
Stress & non genomic
transmission of behaviors
modulation
gene
Enriched environts & animal
Disorder?
models of CNS disorders
gene
Disorder
Genes for autism & MR
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
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
Dutch family,
agressive and
impulsive
behaviors (rape,
arson)
gene
endophenotype
Disorder
DR2impulsiveness
alcohol dependance
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
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
Transformed
MZ co-twin
Transformed
DZ co-twin
Heritability
Extreme CU
.73
.39
.67
Extreme AB
with CU
.76
.36
.81
Extreme AB
without CU
.64
.49
.3
Strong genetic influence
Low shared environment influence
Low genetic influence
Strong shared environment influence
Viding et al, JCPP. 2005
environt
Disorder
Alcoholism &
aldehyde deshydroase
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
Conners’ parent RS
Opposition
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
environt
GxE
Disorder
Canabis/COMT/SCZ
Maltreatment/MAOA/CD
Stress/5HTTrans/MDE
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 followup
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
Arguments to support this model
Plan 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
TOXIC AND PER NATAL FACTORS that impact brain
development either during pregnancy and/or infancy)
MICRO-ENVIRONMENTAL VARIABLES that 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 VARIABLES that 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
environt
epigenesis
Cohen, Neuroscience BioBehav Rev 2010
Disorder
Stress & non genomic
transmission of behaviors
Mealey L, BBS. 1995
Maltreatment and antisocial behaviors: e.g. MICRO
5 years
7 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
Maternal depression and 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
Arguments to support this model
Plan 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
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
Disorder
Stress & non genomic
transmission of behaviors
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 nongenomic 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 behavior
How adversity
gets under the
skin?
Hyman et al. Nat Neurosc 2009
Family context, 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 Disorders
in Romanian Preschool Children
Zeanah et al, Am J Psy. 2009
Institutional Rearing and Psychiatric Disorders
in Romanian Preschool Children
Children with any history of institutional rearing had
more psychiatric disorders 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
disorders than children who 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
Arguments to support this model
Plan 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
Developmental view of externalizing disorders
Protective factors
Cultural factors
Psychosocial factors
Hostile parenting
Early life adversities
Toxic factors
Genetic factors
Biological factors
Family factors
Psychosocial factors
Peer grouping
Drug abuse
School exclusion
ODD
ADHD
Child
CD
ASP
Impulsivity
Aggressiveness
Hyperactivity
Empathy/Callous-unemotional traits
Narcissism/Self-esteem
Insecure attachment
Manic defense
Adolescent
Young Adult
Modified from Loeber et al, JAACAP. 2000
Metatheoritical model of probabilistic epigenesis
[≠ predetermined epigenesis]
ENVIRONMENT
Physical – Social – Cultural
Individual development
BI-DIRECTIONAL
BEHAVIOR and CONDUCT
NEURAL LEVEL
GENETIC LEVEL
Early
interaction
Adolescence
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
Motherreared
Carence
précoce
Modulation
génétique
Barr et al, Biol Psy. 2004
Axe
corticotrope
Peerreared
Consommation
d’alcool
Barr et al, Arch Gen Psy. 2004
Epigenetic regulation of the glucocorticoid R
in human brain associates
with childhood abuse and suicide
McGowan et al. Nat Neurosci 2009
Hippocampal glucocorticoid R expression
(a) total GR; (b) GR 1F
Increased cytosine
methylation of the NR3C1
promoter in the
hippocampus of abused
individuals who suicide
McGowan et al. Nat Neurosci 2009
As clinician, let’s work within a developmental
framework, a dimensional assessment and an
integrative approach
Organic
Psycho
Social
Familial
Psychodynamic
SUBJET
Cognitive
Clinical