what causes adhd? can science improve treatment? acamh ... · 18/09/2019 11 a translational model...
TRANSCRIPT
18/09/2019
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What causes ADHD?
Can science improve treatment?
ACAMH ADHD Masterclass 2019
Edmund Sonuga‐Barke
RUNNING ORDER
• Why we …..treat?…..research?…..label?
• Medical v Bio‐psycho‐social models as a basis for translational science?
• The state of ADHD science
• Aetiology Genes Environments GE interaction and correlation.
• Pathophysiology Heterogeneity & complexity
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WHY WE …..TREAT?
WHY WE …..TREAT?
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NASCENTEarly Acting Risk Processes Genetic, Environmental
& Biological Markers
CHARACTERISING ADHD DEVELOPMENTAL CONTINUITIES AND ESCALATIONS
NASCENT
PRODROME
Early Acting Risk Processes
Early Sub‐clinical Signs in Preschool
Genetic, Environmental& Biological Markers
High Activity, Speech/Motor Delay, Difficult Temperament
CHARACTERISING ADHD DEVELOPMENTAL CONTINUITIES AND ESCALATIONS
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NASCENT
PRODROME
FULL
Early Acting Risk Processes
Early Sub‐clinical Signs in Preschool
Clinical Condition in Middle Childhood
Genetic, Environmental& Biological Markers
High Activity, Speech/Motor Delay, Difficult Temperament
Diagnostic Criteria Met
CHARACTERISING ADHD DEVELOPMENTAL CONTINUITIES AND ESCALATIONS
NASCENT
PRODROME
FULL
COMPLEX
Early Acting Risk Processes
Early Sub‐clinical Signs in Preschool
Clinical Condition in Middle Childhood
Emergence of Comorbidity in Later Adolescence
Genetic, Environmental& Biological Markers
High Activity, Speech/Motor Delay, Difficult Temperament
Diagnostic Criteria Met
Conduct Disorder, Depression, Anxiety
CHARACTERISING ADHD DEVELOPMENTAL CONTINUITIES AND ESCALATIONS
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NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
Early Acting Risk Processes
Early Sub‐clinical Signs in Preschool
Clinical Condition in Middle Childhood
Emergence of Comorbidity in Later Adolescence
Spirals of Dysfunctionin Adulthood
Genetic, Environmental& Biological Markers
High Activity, Speech/Motor Delay, Difficult Temperament
Diagnostic Criteria Met
Conduct Disorder, Depression, Anxiety
Personality Disorders, Substance Abuse
CHARACTERISING ADHD DEVELOPMENTAL CONTINUITIES AND ESCALATIONS
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
ILLUSTRATING THE INCREMENTAL DEVELOPMENTAL BURDEN OF ADHD
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IMPAIRMENT
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
IMPAIRMENT
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
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IMPAIRMENT
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
IMPAIRMENT
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
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IMPAIRMENT
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
IMPAIRMENT
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
IMPAIRMENT
IMPACT ON FAMILY & COMMUNITY
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NASCENT
PRODROME
FULL
COMPLEX
ESCAL’TING
IMPAIRMENT
IMPACT ON FAMILY & COMMUNITY
ECONOMIC BURDEN HEALTH, EDUCATION & JUSTICE
WHY WE……RESEARCH?
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WHY WE……RESEARCH?
MEDICATION – EFFICACIOUS BUT LIMITED
o Medication is a pragmatic short‐term solution to a serious problem.
o Its efficacy is proven by countless RCTs ‐ but it has limitations
– normalization – rare
– Key functional outcomes untouched
– long term effects ‐ uncertain
– side effects – frequent
– resistance from parents, clinicians and governments – common
– societal concern about the increasing prescribing rates
o For all these reasons the development of effective non‐pharma treatments is an urgent priority.
o Especially as current approaches such a parent training, neurofeedback and cognitive training appear to lack solid evidence of efficacy.
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A translational model holds out the promise that therapeutic innovation
builds on scientific understanding about ADHD pathogenesis.
‐‐‐‐‐‐‐‐‐‐‐
If we can understand the causes of ADHD we can target them with new and
improved treatments.
BENCH TO BEDSIDE IN ADHD – MYTH OR REALITY
LabClinic
We wax lyrical about the reciprocal relationship between science and practice…
…but identifying the ways in basic science has affected clinical practice in relation to ADHD is a challenge!
We have evidence‐based medicine.Where is the science‐driven medicine?
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WHY WE …….LABEL
WHY WE …….LABEL
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Dear old thing ‐ these kids are suffering. If we are going to help them then we need to
clearly identify them.
Listen old chap ‐ the ADHD label is damaging ‐ it stigmatises,
undermines agency, distracts from socio‐economic reality –it’s big
pharma driven.
ADHD ‐ A(N UNNECESSARILY) POLARISING AND CONTROVERSIAL CONCEPTTHE REASONABLE DEBATE…….
….TYPICALLY DESCENDS INTO THE UNREASONABLE SCRAP!
Sonuga‐Barke
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WHAT DO WE MEAN BY SAYING SOMEONE SUFFERS A DISORDER?
o Boundaries and underlying structure of construct need to be characterised.
o Do problems of attention, impulse control and activity form a syndrome?
o Inattention, overactivity and impulsive behaviours do cluster and can be differentiated statistically and prognostically from other clusters of problems despite a degree of overlap between and heterogeneity within.
o Is the syndrome associated with suffering through distress/disability?
o developmentally inappropriate levels of severe/pervasive disorder can be greatly impairing, in both the short and long term – predictive of school failure, unemployment, criminality, mental health, addictions and relationships problems.
We will use the term “disorder” as a shorthand for this impairing cluster
LABELS ESSENTIAL BUT ALSO POTENTIALLY LIMITING
o Clinical science can only proceed if there is effective communication between scientists (& clinicians).
o Need precisely defined terms giving common reference points.
o Terms used systematically & consistently are essential for progress.
o But philosophers of science also warn us that shared terms have an insidious effect on science ‐ introducing non‐scientific assumptions to shape hypotheses.
o Unpacking these assumptions turns diagnoses into “working models” – an approximation of reality ‐ to be tested, updated and refined.
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MEDICAL V BIO‐PSYCHO‐SOCIAL MODELS AS A BASIS FOR TRANSLATIONAL SCIENCE?
o The original concept of ADHD has its roots in the medical model and still carries a set of implicit assumptionso ADHD as a discrete disease categoryo qualitatively different from normalityo impairment inherent to the conditiono Resulting wholey from bio‐genetically determined dysfunction
within brain o This has led researchers to focus on its genetic origins and to search for
a single core deficit in the minds or brains of the affected child. o This has hampered progress in the field and led to a focus on meds.
So much data now challenges these core assumptions – this has led to the beginning of a reconceptualization of ADHD.
THE WAY YOU THINK ABOUT ADHD WILL AFFECT THE WAY YOU RESEARCH IT AND TREAT IT!
DISORDER IN THE MEDICAL MODEL
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o A bio‐psycho‐social perspective holds out considerable hope for translational progress.
o It assumes.
o ADHD is a mismatch between extreme expression of continuous temperamental traits and the social environment.
o Impairment depends on social contexto Results from complex developmental interplay between genes and the
social environment mediated by brain alterations.
o In principle this offers diverse possibilities for intervention.
A BIO‐PSYCHO‐SOCIAL ALTERNATIVE
ADHD
Emo & Behproblems
SOCIAL
ENVIRONMEN
T
neuro‐cognitive impairment
secondaryneuro‐cognitive impairmentOFC
OFC
VMFC
DLPFC
Amyg
TP
sense of selfwho I am –
what can I do?
EARLY OPERATING GENE AND PRE‐ AND PER‐NATAL RISK INTERACT TO CREATE A SPECTRUM OF BIOLOGICAL RISK
CREATE DEVELOPMENTAL PATHWAYS MEDIATED BY NEURO‐COGNITIVE ALTERATIONS.
POSTNATAL ENVIRONMENT MAY MODERATE PATHWAYSTHAT ENVIRONMENT IS LIKELY CORRELATED WITH GENESAND EVOKED BY THE CHILD’S BEHAVIOR AND CHARACTERISTICSTOGETHER MAKE A CRITICAL AND UNDERMINING ENVIRONMENTCHILDREN’S WELLBEING IS INFLUENCED BY THE EMOTIONAL ATMOSPHERE
WITHIN THEIR FAMILYTHESE SECONDARY EFFECTS MEDIATED BY NEUROBIOLOGICAL ALTERATIONS
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ADHD
Emo & Behproblems
pre‐ perinatalG, E, GE, GxE
SOCIAL
ENVIRONMEN
T
originating causes
neuro‐cognitive impairment
secondaryneuro‐cognitive impairmentOFC
OFC
VMFC
DLPFC
Amyg
TP
sense of selfwho I am –
what can I do? Cognitive Training
Psycho‐therapy
NON‐PHARMA TREATMENTS COULD TARGET MULTIPLE LEVELS
Public Health
Education
Parenting Training & Family Therapy
o The concept of ADHD is evolving rapidly as the shift from a medical model to a bio‐psycho‐social perspective gathers pace ‐ promoted by scientific progress.
o This is creating new opportunities for non‐pharmacological intervention innovation.
o The evolving concept of ADHD has provided coherence and continuity that has made this body of work possible and will in the future promote improvements in clinical practice.
o While we should not underestimate some of the negative aspects of labelling and stigma ADHD itself is far more stigmatizing and harmful than the label.
ADHD AS AN EVOLVING CONCEPT
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THE STATE OF ADHD SCIENCE
AETIOLOGY
What are the necessary and sufficient conditions for ADHD?
How can we know who will develop ADHD?
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GENES & ENVIRONMENTS
THEIR INTERACTION AND CORRELATION
“ADHD IS SO HERITABLE – IT MUST BE ALL GENETIC!”
0 0.2 0.4 0.6 0.8 1 1.2
Matheny 1971Willerman 1973Goodman 1989
Gillis 1992Edelbrock 1992Stevenson 1992
Schmitz 1995Thapar 1995Gjone 1996
Silberg 1996Sherman 1997
Levy 1997Nadder 1998
Hudziak 2000Willcutt 2000Thapar 2000
Coolidge 2000Kuntsi 2001Martin 2002
Rietveld 2003Laarson 2004
Dick 2005Hudziak 2005
Derks 2007Polderman 2007
Spatola 2007Tuvblad 2009
Cole 2009Bornovalova 2010
Ilott 2010Lichtenstein 2010
Greven 2011Polderman 2011
Langner 2013Chang 2013
Chen 2016Rydell 2017
Heritability
Mean heritability across 37 studies = 74%
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ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
HOW CAN WE KNOW WHO WILL DEVELOP ADHD?
G
ITS SIMPLE ‐ ITS ALL IN THE GENES!
“WE WILL BE ABLE TO PREDICT WHO GETS ADHD WHEN WE HAVE THE GENE FOR ADHD”
ADHD
NOT ADHD
DEVELOPMENT
Prenatal Postnatal
INITIAL OPTIMISM FOR A SIMPLE SOULTION
CANDIDATE GENES STUDIES
o P
Initially assumed ADHD a small number of common variants of large effect would be implicated and these would be linked to neuro‐transmitter function – especially dopamine.
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Initially assumed ADHD a small number of common variants of large effect would be implicated and these would be linked to neuro‐transmitter function – especially dopamine.
Early success followed by failures to replicate ‐ genes accounting for an ever decreasing proportion of disorder variance (<1%).
DRD4Chromosome 11
DAT1chromosome5
INITIAL OPTIMISM FOR A SIMPLE SOULTION
CANDIDATE GENES STUDIES
• Realisation that many small effect variants involved in ADHD (many not predicted) meant new strategy was required.
• New high through‐put methods ‐ arrays of 100,000s of single nucleotide polymorphisms (SNPs) could be tested quickly/cheaply. Hypothesis free approaches now feasible.
• A shift from biological to statistical genetics.
• Need for correction for multiple tests ‐ very large samples required.
REALITY CHECK
GENOMEWIDE ASSOCIATION STUDIES
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PGC ADHD/IPSYCH‐SSI‐BROAD COLLABORATION106 MEMBERS, 14 COUNTRIES, 5 CONTINENTS
Demontis et al., 2018
SNP heritabilty = 0.22
20,183 CASES 35,191 CONTROLS, 8,151,190 GENETIC MARKERS
12 genome‐wide significant loci
Demontis et al., 2018
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Associated with ……
• Impaired speech production, grammar defects. articulatory impairment
• Abnormal activation in motor‐related areas during word repetition (PET)
• Reduced volume/significantly less grey matter bilaterally in caudate nucleus.
• Abnormal activation of Broca’s area and putamen (fMRI)
• Moderate intellectual disability
• Cognitive and motor developmental delays.
Expressed in……
• striatum, cerebral cortex, cerebellum, substantia nigra, thalamus, ventral tegmental area.
• cortical projection neurons, dopaminergic neurons, medium spiny neurons, pyramidal neurons
FOXP2 CLINICAL PHENOTYPES & EXPRESSION (Bacon & Rappold, Human Genetics, 2012))
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
“SO ITS NOT AS SIMPLE AS THAT!”MULTIPLE COMMON AND RARE GENETIC VARIANTS APPEAR TO ACT TOGETHER
GGG1 G2
G3 G4
G5 G6
Prenatal Postnatal
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• As well as common variants genes there are also rare variants characterised by large scale duplications, deletions or inversions across genes in chromosomes.
• These essentially denovo mutations.
• Such effects long known to cause certain rare diseases – but thought to be more generally a low burden to the general population.
• The advent of whole genome sequencing shows such variants affect many people – associated with psychiatric disorders.
THE NEXT LEVEL OF COMPLEXITY
RARE COPY NUMBER VARIANTS
0 0.05 0.1 0.15 0.2
Willliams 2010
Williams 2011
Stergiakouli 2012
Mick 2012
Yang 2012
Lionel 2011
Elia 2012
Average Number of CNVs per Subject
Control ADHD
N=410N=1156
P=.0009
N=2455N=896
N=5081N=727
N=735
N=2357
P=.02
N=969
N=1844
N=898
N=248
N=8220N=2488
P=.39
P=.32
P=.25
P=.74
P=.03
BURDEN OF LARGE RARE COPY NUMBER VARIANTS IN ADHD
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P = 4.38 × 10–10
PATHWAY ANALYSIS OF CNVs: GLUTAMATE SYSTEM (Elia et al., Nature Genetics, 2011)
G
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
“SO ITS NOT AS SIMPLE AS THAT!”MULTIPLE COMMON AND RARE GENETIC VARIANTS APPEAR TO ACT TOGETHER
G1 G2
G3 G4
G5 G6
Prenatal Postnatal
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G
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
“SO WHY NOT JUST ADD GENES TOGETHER TO KNOW WHO GETS IT”
A GENETIC RISK SCORE ‐ “MORE RISK GENES = MORE ADHD”
G1 G2
G3 G4
G5 G6
Prenatal Postnatal
“SO WHY NOT JUST ADD GENES TOGETHER TO KNOW WHO GETS IT”
A GENETIC RISK SCORE ‐ “MORE RISK GENES = MORE ADHD”
• Polygenic risk score = number of ADHD risk SNPs carried by an individual.
• Some SNPs will be true risk but many false positives.
• Statistical significance of PGRS proves it captures many true positives.
• It confirms many common variants associated with ADHD.
– could mean hundreds, thousands or more.
– cannot tell us which variants are true ADHD genes.
• Between 30‐40% of ADHD’s heritability is due to common DNA variants.
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-0.41-0.54-0.54
0.26430.4455
-0.2830.2657
0.3040.258
0.2850.2690.275
0.320.338
0.2540.160
0.2160.1846
-0.21670.1592
0.4780.451
-0.3440.39
0.36810.5488
-0.61230.4212
-0.432-0.2978
-0.3762
-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8
CHILDHOOD IQ (P = 1.24E-6)
EDUCATIONAL ATTAINMENT (P = 6.02E-80)
COLLEGE COMPLETION P = 3.30E-31)
NEUROTICISM (P = 1.02E-08)
DEPRESSIVE SYMPTOMS (P = 7.00E-19)
SUBJECTIVE WELL BEING (P = 3.73E-09)
PGC CROSS-DISORDER ANALYSIS (P = 5.58E-09)
WAIST-TO-HIP RATIO (P = 1.16E-17)
BODY MASS INDEX (P = 1.68E-15)
OBESITY CLASS 1 (P = 1.81E-15)
WAIST CIRCUMFERENCE (P = 2.20E-15)
OVERWEIGHT (P = 1.73E-14)
OBESITY CLASS 2 (P = 5.10E-12)
OBESITY CLASS 3 (P = 4.05E-07)
EXTREME BMI (P = 9.31E-07)
HIP CIRCUMFERENCE (P = 2.13E-06)
CHILDHOOD OBESITY (P = 3.29E-06)
TYPE 2 DIABETES (P = 7.80E-05)
HDL CHOLESTEROL (P = 2.44E-07)
TRIGLYCERIDES (P = 6.49E-05)
EVER VS NEVER SMOKED (P = 4.33E-16)
CIGARETTES SMOKED PER DAY (P = 1.07E-05)
FORMER VS CURRENT SMOKER (P = 6.74E-05)
LUNG CANCER (P = 6.35E-10)
LUNG CANCER (ALL) (P = 2.53E-07)
SQUAMOUS CELL LUNG CANCER (P = 4.57E-05)
AGE OF FIRST BIRTH (P = 3.70E-61)
NUMBER OF CHILDREN EVER BORN (P = 8.51E-17)
MOTHERS AGE AT DEATH (P = 6.48E-07)
FATHERS AGE AT DEATH (P = 7.19E-06)
PARENTS AGE AT DEATH (P = 3.51E-05)
ADHD PGRI CORRELATES WITH IMPORTANT HEALTH OUTCOMES
G
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
“BUT ITS STILL NOT AS SIMPLE AS THAT” “PRENATAL ENVIRONMENT SEEMS ALSO TO BE IMPORTANT”
G Euterine
E
Prenatal Postnatal
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• Maternal life style during pregnancy
Smoking – (Thaper et al., 2003)Drinking – (Knopik et al., 2005)Diet ‐ Oily fish intake – (Gale et al. 2016). Stress – (Rodriguez et al., 2005). Drugs of abuse (Mick et al., 2002)
• Prematurity ‐ x2 relative risk: (Bhutta et al., 2002)
• Birth weight ‐ Lighter twin had 13% higher ADHD symptom score (Hultman et al., 2007).
• Peri‐natal complications ‐ Ben Amor (2005).
“BUT ITS NOT AS SIMPLE AS THAT” PRENATAL ENVIRONMENT SEEMS ALSO TO BE IMPORTANT
G Euterine
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
“BUT ARE WE SURE THE ACTUAL EXPOSURE IS CREATING THE RISK”TAKING ACCOUNT OF PASSIVE GENE ENVIRONMENT CORRELATION
MATERNAL SMOKING DURING PREGNANCY
IN ANMIAL MODELS NICOTINE IN UTERO LEADS TO A RANGE OF
BRAIN ALTERATIONS.
SO IT IS A PLAUSIBLE CAUSAL FACTOR.
IT IS CORRELATED WITH ADHD
G Euterine
E
Prenatal Postnatal
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G Euterine
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
G Euterine
E
MATERNAL SMOKING DURING PREGNANCY
IN ANIMAL MODELS NICOTINE IN UTERO LEADS TO A RANGE OF
BRAIN ALTERATIONS.
SO IT IS A PLAUSIBLE CAUSAL FACTOR.
IT IS CORRELATED WITH ADHD
Prenatal Postnatal
“BUT ARE WE SURE THE ACTUAL EXPOSURE IS CREATING THE RISK”TAKING ACCOUNT OF PASSIVE GENE ENVIRONMENT CORRELATION
• Genetically related who smoked v genetically unrelated who didn’t smoked.
• Isolate prenatal exposure to smoking from genetic confounds.
• If maternal smoking is causal ‐ not matter if child is genetically related or unrelated to mother
Genetically Related
Mothers (N=546):Homologous, sperm donation, surrogacyFathers (N=531): Homologous, egg donation, surrogacy
Genetically UnrelatedMothers (N=160): Egg and embryo donationFathers (N=173): Sperm and embryo donation
CAN WE DISENTANGLE ACTUAL EFFECTS OF EXPOSURE ON ADHD AND GE CORRELATIONS?
Cardiff In Vitro Fertilization Study(An Adoption at Conception Design)
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NO ASSOCIATION BETWEEN SMOKING AND ADHD IN GENETICALLY UNRELATED DYADS
Lower birthweight
ADHD
EnvironmentalPathway
Thapar et al, 2009, Biol Psychiatry.
Genetically Related Only
Genetically Related and Unrelated
G Euterine
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
“GENES MAY ALSO MODERATE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT
G Euterine
E
Prenatal Postnatal
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G Euterine
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
G Euterine
E
Prenatal Postnatal
“GENES MAY ALSO DETERIMINE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT
G Euterine
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCE
G Euterine
E
Prenatal Postnatal
“GENES MAY ALSO DETERIMINE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT
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“GENES MAY ALSO DETERIMINE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT
DEVELOPMENTAL PERSPECTIVE ON ADHD CAUSESCAUSE AS A NON‐DETERMINISTIC PROCESS
DEVELOPMENT
ADHD
NOT ADHD
Prenatal Postnatal
Euterine
EG
DURING EARLY DEVELOPMENT MULTIPLE G AND E FACTORS ACT TOGETHER TO ALTER BRAIN ‐ CREATING A SPECTRUM ADHD LIABILITY
Euterine
EG
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ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCEPROMOTINGRESILIENCE
G Euterine
“OK – AT LEAST ITS SET BY BIRTH SURELY”“RIGHT?”
G Euterine
E
Prenatal Postnatal
ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCEPROMOTINGRESILIENCE
G Euterine
“NO – ITS NOT THAT SIMPLE”“POST‐NATAL FACTORS ALSO CREATE NEW/MODERATE ESTABLISHED RISK”
PROVIDING PROTECTION
CREATINGNEW RISK
Eearly
BUT THESE EFFECTS MIGHT ALSO BE THE RESULT OF PASSIVE GE!
G Euterine
E
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ESTABLISHINGVULNERABILITY
PROMOTINGRESILIENCEPROMOTINGRESILIENCE
G Euterine
PROVIDING PROTECTION
CREATINGNEW RISK
Eearly
STUDIES OF ADOPTED CHILDREN PREVIOUSLY EXPOSED TO RISK ENVIRONMENTS CAN HELP TEASE THIS OUT
G Euterine
E
ADOPTION OF PROFOUNDLY DEPRIVED INFANTS FROM THE ROMANIAN ORPHANAGES PRE‐1990’s
SEVERELY RESTRICTED DIET AND LITTLE SOCIAL OR COGNITIVE STIMULATION
1 TO 43 MONTHS
NURTURING, SUPPORTIVE FAMILY
22 TO 25 YEARS
ADOPTION
RADICAL AND PRECISELY TIMED CHANGE
ENGLISH & ROMANIAN ADOPTEES STUDYA UNIQUE NATURAL EXPERIMENT OF THE EFFECTS OF EARLY DEPRIVATION ON DEVELOPMENT
• Deprivation duration likely un‐confounded with genetic risk• Children placed in institutions in early infancy/ Adopted at regime fall• No reason why most deprived would also be most at risk genetically
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REMISSION OF COGNITIVE IMPAIRMENT BUT PERSISTENCE OF OTHER DISORDERS
DEPRIVATION‐RELATED ADHD
Is there persistence and continuity in deprivation‐related ADHD?
Is there a distinctive pattern of subtype/comorbidity/sex ratio/impairment?
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0
5
10
15
20
25
30
35
low risk (n=108) high risk (n=85) low risk (n=85) high risk (n=60)
% C
AS
ES
AGE 15 YOUNG ADULT
2=8.48
2=17.46
1 : 3.9 1 : 7.7
ADOLESCENT & YOUNG ADULT COMPARISON
2 = 10.56(p=.001)
LoRisk
(n=79)
HiRisk
ADHD‐
(n=41)
ADHD+
(n=17)
LoR vs ADHD+ ADHD‐ vs ADHD+
DSE 0.1 (0.63) 1.0 (1.58) 1.6 (1.84) t=‐3.32, p=.004 t=‐1.29, p=.20
AUTISM 1.3 (2.14) 1.8 (2.45) 5.3 (4.18) t=‐3.82, p=.001 t=‐3.89, p<.001
IQ 102.7 (16.09) 96.0 (13.11) 93.3 (10.62) t=1.88, p=.06 t=0.62, p=.54
CD 46.4 (10.78) 48.4 (13.45) 51.4 (11.16) t=‐1.42, p=.16 t=‐0.64, p=.52
CU 26.0 (7.0) 26.7 (7.91) 35.8 (6.30) t=‐5.05, p<.001 t=‐3.97, p<.001
Depression 54.3 (13.96) 58.2 (14.97) 65.0 (12.60) t=‐2.40, p=.02 t=‐1.34, p=.19
Anxiety 54.1 (13.63) 58.0 (14.03) 62.7 (11.86) t=‐2.00, p=.05 t=‐0.99, p=.33
COMORBIDITIES
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2 = 10.56(p=.001)
TREATED WITH MPHTREATMENT AND IMPAIRMENT
++
ADHD MEDICATION
G Euterine
Eearly
BUT THERE IS A SECOND SORT OF (EVOCATIVE) GE THAT MIGHT BE IMPORTANT DURING THE POST‐ADOPTION PERIOD.
Elate
ADOPTION CREATINGSECONDARY PROTECTION
Euterine
EG
Prenatal Pre‐adoption Post‐adoption
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G Euterine
Eearly
Elate
CHILD BEHAVIOUR EVOKING NEGATIVE
PARENTING CREATINGSECONDARY RISK
Euterine
EG
Prenatal Pre‐adoption Post‐adoption
BUT THERE IS A SECOND SORT OF (EVOCATIVE) GE THAT MIGHT BE IMPORTANT DURING THE POST‐ADOPTION PERIOD.
INTERGENERATIONAL TRANSMISSION
BIOLOGICAL V ADOPTIVE MOTHER‐CHILD PROCESSES
Sample
561 sets “at birth” adopted children, adoptive parents, and birth parents assessed at child age 9‐, 18‐, 27‐months of age; ongoing assessments at 4.5 years, 6 years, 7 years, 8 years, 9 years.
Measures
Birth Mother ADHD
Child Impulsivity
Child Activation: Drive, Reward Responsiveness, and Fun Seeking scales of BIS/BAS
Adoptive Mother‐to‐Child Hostility, Adoptive Mother Depression
Child ADHD and Conduct Problems: Conner’s Parent Questionnaire
Harold et al, 2017
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Birth Mother
ADHD
Symptoms
Child Impulsivity
and Activation
Adoptive
Mother
Hostility
Adoptive
Mother
Depression
Child ADHD
Symptoms (Father
Report)
Child Conduct
Problems (Father
Report)
Genetically Related Genetically Unrelated
.15*
.01
..42**+
.12*
.02
.01
.19*.14*
.32**
18 mths – 4.5 yrs 4.5 years 6 years
.22*+ .30**
CHILD ADHD AND CONDUCT PROBLEMS
PATHOPHYSIOLOGY
MULTIPLE NEUROBIOLOGICAL PATHWAYS
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G Euterine
Gearly
Eearly G
late Elate
CAUSE AS A PROCESS NOT A SINGLE EVENT
Euterine
EEuterine
EG G G
ADHD?G E
uterine
Euterine
EG
ORIGINATINGCAUSES
WHAT IS THE CORE BRAIN DEFICIT IN ADHD?
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CITATIONS PER YEAR (GOOGLE SCHOLAR)
IN 1997 PERHAPS THE MOST INFLUENTIAL ADHD PAPER EVER PROPOSED AN ANSWER
ADHDINHIBITORY‐BASE
EXECUTIVEDYSFUNCTION
inhibitionflexibility WM
G Euterine
Euterine
EG
ORIGINATINGCAUSES
EF DEFICITS ARE A NECESSARY AND SUFFICIENT EXPLANATION FOR THE RANGE OF ADHD IMPAIRMENTS
81
82
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ADHDINHIBITORY‐BASE
EXECUTIVEDYSFUNCTION
DLPFC
Caud
ACC
S/IPL
inhibitionflexibility WM
G Euterine
Euterine
EG
EF DEFICITS ARE A NECESSARY AND SUFFICIENT EXPLANATION FOR THE RANGE OF ADHD IMPAIRMENTS
G Euterine
Euterine
EG
ORIGINATINGCAUSES
Willcutt et al 2009
ADHDINHIBITORY‐BASE
EXECUTIVEDYSFUNCTION
DLPFC
Caud
ACC
S/IPL
EF DEFICITS EXTREMELY COMMON IN ADHD
G Euterine
Euterine
EGG Euterine
Euterine
EG
ORIGINATINGCAUSES
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Willcutt et al 2009
ADHDINHIBITORY‐BASE
EXECUTIVEDYSFUNCTION
DLPFC
Caud
ACC
S/IPL
EF DEFICITS EXTREMELY COMMON IN ADHD
G Euterine
Euterine
EGG Euterine
Euterine
EG
ORIGINATINGCAUSES
Nakayo et al 2011
AND HYPOTHESIZED BRAIN STRCUTURES ARE AFFECTED
BRAIN STRUCTURE
Hart et al 2013
BRAIN FUNCTION
EF DEFICITS EXTREMELY COMMON IN ADHDRECENT MEGA‐ANALYSIS HIGHLIGHTS ROLE OF BASAL GANGLIA
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EF IS NOT THE CORE DEFICIT IN MOST CASES.PERFORMANCE IS HIGHLY VARIABLE ‐ PERIODIC DIPS MAYBE MISINTERPRETED AS
DEFICITS.
HETEROGENEITY
INTER‐ & INTRA‐ INDIVIDUAL
ADHDINHIBITORY‐BASE
EXECUTIVEDYSFUNCTION
DLPFC
Caud
ACC
S/IPL
IT IS NOT AS SIMPLE AS THAT
G Euterine
Euterine
EGG Euterine
Euterine
EG
ORIGINATINGCAUSES
THESIS
ADHD IS AN EXECUTIVE DYSFUNCTION DISORDER – EF DEFICITS ARE UBIQUITOUS, STABLE, NECESSARY AND
SUFFICIENT.
ADHD NEUROSCIENCE – THESIS AND ANTITHESIS
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THESIS
ADHD IS AN EXECUTIVE DYSFUNCTION DISORDER – EF DEFICITS ARE UBIQUITOUS, STABLE, NECESSARY AND
SUFFICIENT.
ANTI‐THESIS
ADHD IS HETEROGENEOUS WITH VARIATION IN EF BETWEEN, AND FLUCTUATIONS WITHIN PATIENTS.
ADHD NEUROSCIENCE – THESIS AND ANTITHESIS
EF IS NOT THE CORE DEFICIT FOR ALL INDIVIDUALS WITH ADHD
HETEROGENEITY – WHAT HAVE WE LEARNT?
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AT MOST ONLY 50% OF ADHD PARTICIPANTS HAD AN EF DEFICIT
HETEROGENEITY – WHAT HAVE WE LEARNT?
Solanto et al., 2001
EF – 46%
DEL – 38%
THEN THERE WERE TWO…NO, I MEAN THREE…..ACTUALLY SIX
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Sonuga‐Barke et al., 2010
Sjowall et al. 2013de Zeeuw et al. 2012
Solanto et al., 2001
EF – 46%
DEL – 38%
EF – 21%
DEL – 36%
TIME – 44%
EF – 32%
TIME – 32%
REW – 4% DEL – 14%
EF – 36%
VAR – 54%
THEN THERE WERE TWO…NO, I MEAN THREE…..ACTUALLY SIX
THEN THERE WERE TWO…NO, I MEAN THREE…..ACTUALLY SIX
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EF PERFORMANCE HIGHLY VARIABLE ‐PERIODIC “DIPS” MAY BE MISINTERPRETED
AS FIXED DEFICITS.
HETEROGENEITY – WHAT HAVE WE LEARNT?
SPONTANEOUS FLUCTATIONS
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SPONTANEOUS FLUCTATIONS
SPONTANEOUS FLUCTATIONS
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0
5000
10000
15000
20000
25000
30000
35000
40000
1
AUC F
requ
ency
Ban
d .0
2-.0
7 H
z
Baseline placebo low MPH med MPH high MPH
CONTROLS ADHD
SPONTANEOUS FLUCTATIONS
DEFICIENT EF PERFORMANCE COULD BE (I) A CORE FIXED PROBLEM OR (II) A PERIOD OR CONTEXT SPECIFIC DIP DUE TO SOME
OTHER PROBLEM.
Sonuga‐Barke et al., 2010
Sjowall et al. 2013de Zeeuw et al. 2012
Solanto et al., 2001
EF – 46%
DEL – 38%
EF – 21%
DEL – 36%
TIME – 44%
EF – 32%
TIME – 32%
REW – 4% DEL – 14%
EF – 36%
VAR – 54%
CORE EF DEFICIT
% ?
SPONTENEOUS OR INDUCED
PERFORMANCE DIP
% ?
INTER‐ AND INTRA‐INDIVIDUAL VARIABILITY IN TASK PERFORMANCE
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ADHDINHIBITORY‐BASE
EXECUTIVEDYSFUNCTION
DLPFC
Caud
ACC
S/IPL
IT IS NOT AS SIMPLE AS THAT (x2)
G Euterine
Euterine
EGG Euterine
Euterine
EG
ORIGINATINGCAUSES
COMPLEXITY
MULTIPLE BRAIN NETWORKS
ADHD PATHOPHYSIOLOGY IS HIGHLY COMPLEX WITH MULTIPLE BRAIN SYSTEMS INTERACTING TO PRODUCE EVEN SIMPLE ADHD IMPAIRMENTS.
COMPLEXITY THESIS & ANTI‐THESIS
THESIS
ADHD IS PATHOPHYSIOLOGICALLY SIMPLE ‐ DRIVEN PRIMARILY BY DYSFUNCTION IN ONE SYSTEM.
ANTI‐THESIS
EVEN WITHIN SPECIFIC SUB‐GROUPS OF PATIENTS ADHD INVOLVES THE INTERACTION BETWEEN MULTIPLE BRAIN SYSTEMS AND COGNITIVE
PROCESSES.
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IMPULSIVE CHOICE IN ADHD
A SIMPLE BEHAVIOUR WITH A COMPLEX NEURAL ARCHITECTURE
• In every day life, where our resources are finite, we have often to choose between lager later (LL) over smaller sooner (SS) rewards to act effectively.
• Self control is tested if the SS option is especially tempting.
• Some of us can resist this temptation and choose LL.
• Some can’t and choose SS – This has been called waiting impulsivity.
• Individuals with ADHD find it very difficult.
IMPULSIVE CHOICE
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• In every day life, where our resources are finite, we have often to choose between lager later (LL) over smaller sooner (SS) rewards to act effectively.
• Self control is tested if the SS option is especially tempting.
• Some of us can resist this temptation and choose LL.
• Some can’t and choose SS – This has been called waiting impulsivity.
• Individuals with ADHD find it very difficult.
CHILDREN WITH ADHD WAIT LESS THAN THEIR PEERS
• In every day life, where our resources are finite, we have often to choose between lager later (LL) over smaller sooner (SS) rewards to act effectively.
• Self control is tested if the SS option is especially tempting.
• Some of us can resist this temptation and choose LL.
• Some can’t and choose SS – This has been called waiting impulsivity.
• Individuals with ADHD find it very difficult.
CHILDREN WITH ADHD WAIT LESS THAN THEIR PEERS
MIDA/CDT ‐ 1 PT AFTER 2 SECS VERSUS 2 PTS AFTER 30 SECONDS
Ivo Marx
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IMPULSIVE CHOICE IN ADHD
A SIMPLE BEHAVIOUR WITH A COMPLEX NEURAL ARCHITECTURE
IMPULSIVE CHOICE IN ADHD
A SIMPLE BEHAVIOUR WITH A COMPLEX NEURAL ARCHITECTURE
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FOUR INTERRELATED BRAIN CIRCUITSALTERED IN ADHD – ASSOCIATED WITH IC?
EXECUTIVE CONTROL
UNDERPINS SELF CONTROL
DLPFC
Caud
ACCS/IPL
EF DEFICITS EXTREMELY COMMON IN ADHDRECENT MEGA‐ANALYSIS HIGHLIGHTS ROLE OF BASAL GANGLIA
DLPFC
Caud
ACCS/IPL
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COULD EXECUTIVE DYSFUNCTION CONTRIBUTE
TO IC IN ADHD?
EF BRAIN NETWORKS ASSOCIATED WITH IC
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FOUR INTERRELATED BRAIN CIRCUITSALTERED IN ADHD – ASSOCIATED WITH IC?
PROCESSES REWARDING EVENTS
EXECUTIVE CONTROL
UNDERPINS SELF CONTROL
REWARD/EVALUATION
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
EF DEFICITS EXTREMELY COMMON IN ADHDRECENT VBM MEGA‐ANALYSIS HIGHLIGHTS ALTERATIONS IN REWARD NETWORKS
NAccVMFC
OFC
Thal
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STUDIES WITH MONETARY INCENTIVE DELAY TASK
p<0.0001
Controls ADHD
SCHERES ET AL, 2006
STROHLE ET AL, 2008
Controls ADHD
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COULD ALTERED REWARD RESPONSIVITY CONTRIBUTE
TO IC IN ADHD?
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FOUR INTERRELATED BRAIN CIRCUITSALTERED IN ADHD – ASSOCIATED WITH IC?
PROCESSES REWARDING EVENTS
EXECUTIVE CONTROL
DEFAULT MODE
UNDERPINS SELF CONTROL
REWARD/EVALUATION
SELF REFERENTIAL STATES
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
MTG LPCPCCMPFC
FOUR INTERRELATED BRAIN CIRCUITSALTERED IN ADHD – ASSOCIATED WITH IC?
PROCESSES REWARDING EVENTS
EXECUTIVE CONTROL
DEFAULT MODE
UNDERPINS SELF CONTROL
REWARD/EVALUATION
SELF REFERENTIAL STATES
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
PCCMPFC
LPC
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FOUR INTERRELATED BRAIN CIRCUITSALTERED IN ADHD – ASSOCIATED WITH IC?
PROCESSES REWARDING EVENTS
EXECUTIVE CONTROL
DEFAULT MODE
UNDERPINS SELF CONTROL
REWARD/EVALUATION
SELF REFERENTIAL STATES
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
MPFCLPC
MTL
HUMAN BRAIN IS INTRINSICALLY ORGANIZED INTO DYNAMIC, ANTICORRELATED FUNCTIONAL NETWORKS
Fox et al., 2005 – PNAS
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WHAT ROLE COULD DMN PLAY IN IC?
A DOUBLE EDGED SWORD
PROSPECTION PROMOTES FUTURE ORIENTATED ECONOMIC THOUGHT
problems arise due to periodic lapses, the result of spontaneous intrusions of unattenuated DMN neuronal oscillations during task performance.
UNMODULATED ACTIVATION DURING TASKS DISRUPTS ATTENTION
DMN‐RELATED PROSPECTION REDUCES IMPULSIVE CHOICE
A DOUBLE EDGED SWORD
The Journal of Neuroscience, May 4, 2011 • 31(18):6771– 6779 • 6771
MPFC activation predicted more future oriented choice which was moderated by reward size
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WAITING IS AN EMOTIONALLY PUNISHING EXPERIENCE FOR INDIVIDUALS WITH ADHD
COULD THIS CONTRIBUTE TOIC IN ADHD?
FOUR INTERRELATED BRAIN CIRCUITS
ALTERED IN ADHD – ASSOCIATED WITH IC?
PROCESSES REWARDING EVENTS
PROCESSES AVERSIVE EVENTS
ATTENTIONAL CONTROL
DEFAULT MODE
UNDERPINS SELF CONTROL
REWARD/EVALUATION
PUNISHMENT
SELF REFERENTIAL STATES
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
MPFCLPC
MTL
OFCOFC
VMFC
DLPFC
AmygTP
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PROCESSES REWARDING EVENTS
PROCESSES AVERSIVE EVENTS
ATTENTIONAL CONTROL
DEFAULT MODE
UNDERPINS SELF CONTROL
REWARD/EVALUATION
PUNISHMENT
SELF REFERENTIAL STATES
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
MPFCLPC
MTL
AI
TP
FOUR INTERRELATED BRAIN CIRCUITS
ALTERED IN ADHD – ASSOCIATED WITH IC?
PROCESSES REWARDING EVENTS
PROCESSES AVERSIVE EVENTS
ATTENTIONAL CONTROL
DEFAULT MODE
UNDERPINS SELF CONTROL
REWARD/EVALUATION
PUNISHMENT
SELF REFERENTIAL STATES
OFCOFC
NAccVMFC
OFC
Thal
DLPFC
Caud
ACCS/IPL
MPFCLPC
MTL
AMYG
insula
FOUR INTERRELATED BRAIN CIRCUITS
ALTERED IN ADHD – ASSOCIATED WITH IC?
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o For ADHD children the experience of waiting during the delay before outcomes or events is especially aversive.
o delay imposition is a negative reinforcer and delay escape a potent reinforcer.
o ADHD is a functional expression of this aversion to delay –associated with the escape or avoidance of delay.
o It is hypothesized to emerge during development
THE DELAY AVERSION HYPOTHESIS OF IC IN ADHD
ATTEMPTS TO AVOID DELAY‐REATED EMOTIONS
DELAY AVERSION
REQUIRED TO WAIT
EXTERNALLY MEDIATED(CENSURE)
INTERNALLY MEDIATED(SHAME)
CAN’T WAIT
THE DELAY AVERSION HYPOTHESIS OF IC IN ADHD
CHOOSELEAST DELAYED
OPTION
SPEED UP THE PASSAGE OF TIME
DELAY ESCAPE POSSIBLE
DELAY ESCAPE IMPOSSIBLE
IMPULSIVE BEAHVIOURS
INATTENTIONEXCESS ACTIVITYDISRUPTIVENESS
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TIME IS A PSYCHOLOGICALLY MALEABLE THING!
A Watched Pot
EXPERIMENTS SHOW THAT YOU CAN MAKE TIME PASS MORE QUICKLY BY SWITCHING ATTENTIONAL FOCUS OR INCREASING ENVIRONMENTAL
STIMULATION.
o For ADHD children the experience of waiting during the delay before outcomes or events is especially aversive.
o delay imposition is a negative reinforcer and delay escape a potent reinforcer.
o ADHD is a functional expression of this aversion to delay –associated with the escape or avoidance of delay.
o It is hypothesized to emerge during development as a secondary consequence of the negative feelings and experiences associated with WI.
Predictionso Behavioural: IC exacerbated when SS choices help delay
escape: o Neurobiological: Cues of delay elicit activation within the
brain’s emotional circuits which mediates delay aversion and WI.
THE DELAY AVERSION HYPOTHESIS OF IC IN ADHD
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DELAY AVERSION – QUICK DELAY QUESTIONNAIRE
not at all like th
em
very mu
ch like
them
1 will not give up, even if they have to wait a long time for something important. 1 2 3 4 5
2 is usually calm when they have to wait in queues. 1 2 3 4 5
3will often choose a task which helps me in the long term even if they don’t get anything from it right away.
1 2 3 4 5
4 are calm when waiting for things. 1 2 3 4 5
5 often give up on things that they cannot have straight away. 1 2 3 4 5
6 hate waiting for things. 1 2 3 4 5
7try to avoid tasks that will only give them something in the long term and not straight away.
1 2 3 4 5
8feel annoyed when they have to wait for someone else to be ready before I can do something.
1 2 3 4 5
9 Having to wait for things makes them feel stressed and tense. 1 2 3 4 5
10The future is not important for them. They only consider the instant outcomes of their actions.
1 2 3 4 5
Quick Delay Questionnaire – Parent and Teacher form
Name/ID: ____________________ Age: ___________ School Year: ________Birth Date: _____/_____/______ Today’s Date: _____/_____/_____ Gender: M F
Day Month Year Day Month Year (Please circle one)
THE EDI (ESCAPE DELAY INCENTIVE TASK)
IS AMYGDALA HYPER‐RESPONSIVE TO DELAY CUES?
TARGET
DELAY CONSEQUENCE (2,6 or 14 secs)
CUE FEEDBACK
NO DELAY CONSEQUENCE (0
secs)
CERTAIN DELAY TRIALNO DELAY TRIAL
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CERTAIN DELAY VERSUS NO DELAY
ASSOCIATION BETWEEN BRAIN RESPONSE AND SELF ASESSMENT OF DELAY AVERSION IN EVERYDAY LIFE
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DAY DREAMERS LOOSE TRACK OF TIME
COULD MIND WANDERING BE A WAY OF COPING WITH DAv BY CHANGING HOW TIME IS EXPERIENCED?
DELAY MINIMIZATION
CHOOSELEAST DELAYED
OPTION
SPEED UP THE PASSAGE OF TIME
DELAY ESCAPE POSSIBLE
DELAY ESCAPE IMPOSSIBLE
IMPULSIVE BEAHVIOURS
INATTENTIONEXCESS ACTIVITYDISRUPTIVENESS
MINDWANDERING
COULD EXCESS DMN BE FUNCTIONAL RATHER THAN DYSFUNCTIONAL?INTERNAL SELF‐DISTRACTION FOR COPING WITH UNPLEASENT EMOTIONS AND SITUATIONS?
IF SO WE WOULD PREDICT THAT ‐
ADHD CHILDREN WON’T ATTENUATE DMN ACTIVITY WHEN WAITING
DMN ACTIVITY WOULD BE CORRELATED WITH SELF‐RATED DELAY
AVERSION.
WE COMPARED RESTING AND WAITING LOW FREQUENCY BRAIN
ACTIVITY IN ADHD.
COULD EXCESSIVE DMN ACTIVITY DURING WAITING BE AN INTERNALISED
EXPRESSION OF DELAY AVERSION?
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WHAT HAPPENS TO THE DEFAULT MODE WHEN WE ARE ACTUALLY WAITING?
IS IT ATTENUATED TO HELP COMPLETE THE WAITING TASK?IS IT ACTIVATED AS ONE EITHER PROSPECTS ABOUT THE OUTCOME
OR DISTRACTS ONSELF THROUGH MIND WANDERING?
restforced
to wait
workchoose
to wait
EEG ANALYSES OF LOW FREUENCY OSCILLATION IN DMN
Chia‐Fen Hsu
6.00
7.00
8.00
9.00
10.00
11.00
Control ADHD
Rest
2CRT
CW
FW
8.50
9.00
9.50
10.00
10.50
11.00
11.50
Control ADHD
LFO IN ADHD DURING WAITING WERE CORRELATED WITH DELAY AVERSION
SUMMARY
o Highly heritable, but specific common risk variants challenging to find.
o G likely to interact with pre‐ & perinatal E risks – but genuine G effects need to be distinguished from those due to shared genetics ?
o Adoption studies highlight power of post‐natal adversity and evocative GE effects.
o Neuropsychological and neuroimaging date combine to suggest that multiple brain networks and associated cognitive processes mediate ADHD risk pathways (complexity) to different degrees in different individuals (heterogeneity).
o Context dependent and dynamic – not fixed.
oWhat are the implications for treatment?
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