What causes ADHD? Can science improve treatment? ACAMH ADHD - - PDF document

18/09/2019 1

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

1 2

18/09/2019 2

WHY WE …..TREAT? WHY WE …..TREAT?

3 4

18/09/2019 3

NASCENT

Early 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

5 6

18/09/2019 4

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

7 8

18/09/2019 5

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 Dysfunction in 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

9 10

18/09/2019 6

IMPAIRMENT

NASCENT PRODROME FULL COMPLEX ESCAL’TING

IMPAIRMENT

NASCENT PRODROME FULL COMPLEX ESCAL’TING

11 12

18/09/2019 7

IMPAIRMENT

NASCENT PRODROME FULL COMPLEX ESCAL’TING

IMPAIRMENT

NASCENT PRODROME FULL COMPLEX ESCAL’TING

13 14

18/09/2019 8

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 15 16

18/09/2019 9

NASCENT PRODROME FULL COMPLEX ESCAL’TING

IMPAIRMENT IMPACT ON FAMILY & COMMUNITY ECONOMIC BURDEN HEALTH, EDUCATION & JUSTICE

WHY WE……RESEARCH?

17 18

18/09/2019 10

WHY WE……RESEARCH? MEDICATION – EFFICACIOUS BUT LIMITED

• Medication is a pragmatic short‐term solution to a serious problem.
• 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

• For all these reasons the development of effective non‐pharma treatments is

an urgent priority.

• Especially as current approaches such a parent training, neurofeedback and

cognitive training appear to lack solid evidence of efficacy.

19 20

18/09/2019 11

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

Lab Clinic

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?

21 22

18/09/2019 12

WHY WE …….LABEL WHY WE …….LABEL

23 24

18/09/2019 13

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 CONCEPT THE REASONABLE DEBATE……. ….TYPICALLY DESCENDS INTO THE UNREASONABLE SCRAP!

Sonuga‐Barke

25 26

18/09/2019 14

WHAT DO WE MEAN BY SAYING SOMEONE SUFFERS A DISORDER?

• Boundaries and underlying structure of construct need to be characterised.
• Do problems of attention, impulse control and activity form a syndrome?
• 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.

• Is the syndrome associated with suffering through distress/disability?
• 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

• Clinical science can only proceed if there is effective communication between

scientists (& clinicians).

• Need precisely defined terms giving common reference points.
• Terms used systematically & consistently are essential for progress.
• But philosophers of science also warn us that shared terms have an insidious

effect on science ‐ introducing non‐scientific assumptions to shape hypotheses.

• Unpacking these assumptions turns diagnoses into “working models” – an

approximation of reality ‐ to be tested, updated and refined.

27 28

18/09/2019 15

MEDICAL V BIO‐PSYCHO‐SOCIAL MODELS AS A BASIS FOR TRANSLATIONAL SCIENCE?

• The original concept of ADHD has its roots in the medical model and still

carries a set of implicit assumptions

• ADHD as a discrete disease category
• qualitatively different from normality
• impairment inherent to the condition
• Resulting wholey from bio‐genetically determined dysfunction

within brain

• 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.

• 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

29 30

18/09/2019 16

• A bio‐psycho‐social perspective holds out considerable hope for

translational progress.

• It assumes.
• ADHD is a mismatch between extreme expression of continuous

temperamental traits and the social environment.

• Impairment depends on social context
• Results from complex developmental interplay between genes and the

social environment mediated by brain alterations.

• In principle this offers diverse possibilities for intervention.

A BIO‐PSYCHO‐SOCIAL ALTERNATIVE

ADHD Emo & Beh problems SOCIAL ENVIRONMENT neuro‐cognitive impairment secondary neuro‐cognitive impairment

O F C O F C

VMFC DLPFC Amyg TP

sense of self who 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 PATHWAYS THAT ENVIRONMENT IS LIKELY CORRELATED WITH GENES AND EVOKED BY THE CHILD’S BEHAVIOR AND CHARACTERISTICS TOGETHER MAKE A CRITICAL AND UNDERMINING ENVIRONMENT CHILDREN’S WELLBEING IS INFLUENCED BY THE EMOTIONAL ATMOSPHERE WITHIN THEIR FAMILY THESE SECONDARY EFFECTS MEDIATED BY NEUROBIOLOGICAL ALTERATIONS

31 32

18/09/2019 17

ADHD Emo & Beh problems pre‐ perinatal G, E, GE, GxE SOCIAL ENVIRONMENT

• riginating

causes neuro‐cognitive impairment secondary neuro‐cognitive impairment

O F C O F C

VMFC DLPFC Amyg TP

sense of self who I am – what can I do?

Cognitive Training Psycho‐ therapy

NON‐PHARMA TREATMENTS COULD TARGET MULTIPLE LEVELS

Public Health Education Parenting Training & Family Therapy

• 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.

• This is creating new opportunities for non‐pharmacological intervention

innovation.

• 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.

• 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

33 34

18/09/2019 18

THE STATE OF ADHD SCIENCE AETIOLOGY What are the necessary and sufficient conditions for ADHD? How can we know who will develop ADHD?

35 36

18/09/2019 19

GENES & ENVIRONMENTS THEIR INTERACTION AND CORRELATION “ADHD IS SO HERITABLE – IT MUST BE ALL GENETIC!”

0.2 0.4 0.6 0.8 1 1.2

Matheny 1971 Willerman 1973 Goodman 1989 Gillis 1992 Edelbrock 1992 Stevenson 1992 Schmitz 1995 Thapar 1995 Gjone 1996 Silberg 1996 Sherman 1997 Levy 1997 Nadder 1998 Hudziak 2000 Willcutt 2000 Thapar 2000 Coolidge 2000 Kuntsi 2001 Martin 2002 Rietveld 2003 Laarson 2004 Dick 2005 Hudziak 2005 Derks 2007 Polderman 2007 Spatola 2007 Tuvblad 2009 Cole 2009 Bornovalova 2010 Ilott 2010 Lichtenstein 2010 Greven 2011 Polderman 2011 Langner 2013 Chang 2013 Chen 2016 Rydell 2017

Heritability

Mean heritability across 37 studies = 74%

37 38

18/09/2019 20

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

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

• 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.

39 40

18/09/2019 21

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%).

DRD4

Chromosome 11

DAT1

chromosome5

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

41 42

18/09/2019 22

PGC ADHD/IPSYCH‐SSI‐BROAD COLLABORATION 106 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

43 44

18/09/2019 23 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))

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

“SO ITS NOT AS SIMPLE AS THAT!”

MULTIPLE COMMON AND RARE GENETIC VARIANTS APPEAR TO ACT TOGETHER

G

G

G1 G2 G3 G4 G5 G6

Prenatal Postnatal

45 46

18/09/2019 24

• 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

0.05 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=410 N=1156

P=.0009

N=2455 N=896 N=5081 N=727 N=735 N=2357

P=.02

N=969 N=1844 N=898 N=248 N=8220 N=2488

P=.39 P=.32 P=.25 P=.74 P=.03

BURDEN OF LARGE RARE COPY NUMBER VARIANTS IN ADHD

47 48

18/09/2019 25

P = 4.38 × 10–10

PATHWAY ANALYSIS OF CNVs: GLUTAMATE SYSTEM

(Elia et al., Nature Genetics, 2011)

G

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

“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

49 50

18/09/2019 26

G

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

“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.

51 52

18/09/2019 27

• 0.41
• 0.54
• 0.54

0.2643 0.4455

• 0.283

0.2657 0.304 0.258 0.285 0.269 0.275 0.32 0.338 0.254 0.160 0.216 0.1846

• 0.2167

0.1592 0.478 0.451

• 0.344

0.39 0.3681 0.5488

• 0.6123

0.4212

• 0.432
• 0.2978
• 0.3762
• 0.8
• 0.6
• 0.4
• 0.2

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

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

“BUT ITS STILL NOT AS SIMPLE AS THAT” “PRENATAL ENVIRONMENT SEEMS ALSO TO BE IMPORTANT”

G

E

uterine

E

Prenatal Postnatal

53 54

18/09/2019 28

• 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 E

uterine

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

“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

E

uterine

E

Prenatal Postnatal

55 56

18/09/2019 29

G E

uterine

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

G

E

uterine

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, surrogacy Fathers (N=531): Homologous, egg donation, surrogacy Genetically Unrelated Mothers (N=160): Egg and embryo donation Fathers (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)

57 58

18/09/2019 30

NO ASSOCIATION BETWEEN SMOKING AND ADHD IN GENETICALLY UNRELATED DYADS

Lower birth weight

ADHD Environmental Pathway

Thapar et al, 2009, Biol Psychiatry.

Genetically Related Only Genetically Related and Unrelated

G E

uterine

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

“GENES MAY ALSO MODERATE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT

G

E

uterine

E

Prenatal Postnatal

59 60

18/09/2019 31

G E

uterine

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

G

E

uterine

E

Prenatal Postnatal

“GENES MAY ALSO DETERIMINE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT

G E

uterine

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE

G

E

uterine

E

Prenatal Postnatal

“GENES MAY ALSO DETERIMINE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT

61 62

18/09/2019 32

“GENES MAY ALSO DETERIMINE THE EFFECTS OF THE ENVIRONMENT” MAKING SOME SUSCEPTIBLE TO THEIR EFFECTS AND OTHERS RESILIENT DEVELOPMENTAL PERSPECTIVE ON ADHD CAUSES CAUSE AS A NON‐DETERMINISTIC PROCESS

DEVELOPMENT ADHD NOT ADHD

Prenatal Postnatal

E

uterine

E G

DURING EARLY DEVELOPMENT MULTIPLE G AND E FACTORS ACT TOGETHER TO ALTER BRAIN ‐ CREATING A SPECTRUM ADHD LIABILITY

E

uterine

E G

63 64

18/09/2019 33

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE PROMOTING RESILIENCE

G E

uterine

“OK – AT LEAST ITS SET BY BIRTH SURELY” “RIGHT?”

G

E

uterine

E

Prenatal Postnatal

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE PROMOTING RESILIENCE

G E

uterine

“NO – ITS NOT THAT SIMPLE” “POST‐NATAL FACTORS ALSO CREATE NEW/MODERATE ESTABLISHED RISK”

PROVIDING PROTECTION CREATING NEW RISK

E

early

BUT THESE EFFECTS MIGHT ALSO BE THE RESULT OF PASSIVE GE!

G

E

uterine

E

65 66

18/09/2019 34

ESTABLISHING VULNERABILITY PROMOTING RESILIENCE PROMOTING RESILIENCE

G E

uterine

PROVIDING PROTECTION CREATING NEW RISK

E

early

STUDIES OF ADOPTED CHILDREN PREVIOUSLY EXPOSED TO RISK ENVIRONMENTS CAN HELP TEASE THIS OUT

G

E

uterine

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 STUDY

A 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

67 68

18/09/2019 35

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?

69 70

18/09/2019 36

5 10 15 20 25 30 35 low risk (n=108) high risk (n=85) low risk (n=85) high risk (n=60)

% CASES 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

71 72

18/09/2019 37

2 = 10.56(p=.001)

TREATED WITH MPH

TREATMENT AND IMPAIRMENT + +

ADHD MEDICATION

G E

uterine

E

early

BUT THERE IS A SECOND SORT OF (EVOCATIVE) GE THAT MIGHT BE IMPORTANT DURING THE POST‐ADOPTION PERIOD.

E

late

ADOPTION CREATING SECONDARY PROTECTION

E

uterine

E G

Prenatal Pre‐adoption Post‐adoption

73 74

18/09/2019 38

G E

uterine

E

early

E

late

CHILD BEHAVIOUR EVOKING NEGATIVE PARENTING CREATING SECONDARY RISK

E

uterine

E G

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

75 76

18/09/2019 39

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

77 78

18/09/2019 40

G E

uterine

G

early

E

early

G

late

E

late

CAUSE AS A PROCESS NOT A SINGLE EVENT

E

uterine

E

E

uterine

E G G G

ADHD

?

G E

uterine

E

uterine

E G

ORIGINATING CAUSES

WHAT IS THE CORE BRAIN DEFICIT IN ADHD?

79 80

18/09/2019 41

CITATIONS PER YEAR (GOOGLE SCHOLAR)

IN 1997 PERHAPS THE MOST INFLUENTIAL ADHD PAPER EVER PROPOSED AN ANSWER

ADHD

INHIBITORY‐BASE EXECUTIVE DYSFUNCTION

inhibition

flexibility WM

G E

uterine

E

uterine

E G

ORIGINATING CAUSES

EF DEFICITS ARE A NECESSARY AND SUFFICIENT EXPLANATION FOR THE RANGE OF ADHD IMPAIRMENTS

81 82

18/09/2019 42

ADHD

INHIBITORY‐BASE EXECUTIVE DYSFUNCTION

DLPFC Caud ACC S/IPL

inhibition

flexibility WM

G E

uterine

E

uterine

E G

EF DEFICITS ARE A NECESSARY AND SUFFICIENT EXPLANATION FOR THE RANGE OF ADHD IMPAIRMENTS

G E

uterine

E

uterine

E G

ORIGINATING CAUSES

Willcutt et al 2009

ADHD

INHIBITORY‐BASE EXECUTIVE DYSFUNCTION

DLPFC Caud ACC S/IPL

EF DEFICITS EXTREMELY COMMON IN ADHD

G E

uterine

E

uterine

E G

G E

uterine

E

uterine

E G

ORIGINATING CAUSES

83 84

18/09/2019 43

Willcutt et al 2009

ADHD

INHIBITORY‐BASE EXECUTIVE DYSFUNCTION

DLPFC Caud ACC S/IPL

EF DEFICITS EXTREMELY COMMON IN ADHD

G E

uterine

E

uterine

E G

G E

uterine

E

uterine

E G

ORIGINATING CAUSES

Nakayo et al 2011

AND HYPOTHESIZED BRAIN STRCUTURES ARE AFFECTED

BRAIN STRUCTURE Hart et al 2013 BRAIN FUNCTION

EF DEFICITS EXTREMELY COMMON IN ADHD

RECENT MEGA‐ANALYSIS HIGHLIGHTS ROLE OF BASAL GANGLIA

85 86

18/09/2019 44

EF IS NOT THE CORE DEFICIT IN MOST CASES. PERFORMANCE IS HIGHLY VARIABLE ‐ PERIODIC DIPS MAYBE MISINTERPRETED AS DEFICITS.

HETEROGENEITY INTER‐ & INTRA‐ INDIVIDUAL

ADHD

INHIBITORY‐BASE EXECUTIVE DYSFUNCTION

DLPFC Caud ACC S/IPL

IT IS NOT AS SIMPLE AS THAT

G E

uterine

E

uterine

E G

G E

uterine

E

uterine

E G

ORIGINATING CAUSES

THESIS ADHD IS AN EXECUTIVE DYSFUNCTION DISORDER – EF DEFICITS ARE UBIQUITOUS, STABLE, NECESSARY AND SUFFICIENT. ADHD NEUROSCIENCE – THESIS AND ANTITHESIS

87 88

18/09/2019 45

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?

89 90

18/09/2019 46

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

91 92

18/09/2019 47

Sonuga‐Barke et al., 2010 Sjowall et al. 2013 de 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

93 94

18/09/2019 48

EF PERFORMANCE HIGHLY VARIABLE ‐ PERIODIC “DIPS” MAY BE MISINTERPRETED AS FIXED DEFICITS. HETEROGENEITY – WHAT HAVE WE LEARNT? SPONTANEOUS FLUCTATIONS

95 96

18/09/2019 49

SPONTANEOUS FLUCTATIONS SPONTANEOUS FLUCTATIONS

97 98

18/09/2019 50

5000 10000 15000 20000 25000 30000 35000 40000

1

A U C F r e q u e n c y B a n 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. 2013 de 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

99 100

18/09/2019 51

ADHD

INHIBITORY‐BASE EXECUTIVE DYSFUNCTION

DLPFC Caud ACC S/IPL

IT IS NOT AS SIMPLE AS THAT (x2)

G E

uterine

E

uterine

E G

G E

uterine

E

uterine

E G

ORIGINATING CAUSES 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.

101 102

18/09/2019 52

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

103 104

18/09/2019 53

• 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

105 106

18/09/2019 54

IMPULSIVE CHOICE IN ADHD A SIMPLE BEHAVIOUR WITH A

COMPLEX NEURAL ARCHITECTURE

IMPULSIVE CHOICE IN ADHD A SIMPLE BEHAVIOUR WITH A COMPLEX NEURAL ARCHITECTURE

107 108

18/09/2019 55

FOUR INTERRELATED BRAIN CIRCUITS

ALTERED IN ADHD – ASSOCIATED WITH IC?

EXECUTIVE CONTROL UNDERPINS SELF CONTROL

DLPFC Caud ACC S/IPL

EF DEFICITS EXTREMELY COMMON IN ADHD

RECENT MEGA‐ANALYSIS HIGHLIGHTS ROLE OF BASAL GANGLIA

DLPFC Caud ACC S/IPL 109 110

18/09/2019 56

COULD EXECUTIVE DYSFUNCTION CONTRIBUTE TO IC IN ADHD? EF BRAIN NETWORKS ASSOCIATED WITH IC

111 112

18/09/2019 57

FOUR INTERRELATED BRAIN CIRCUITS

ALTERED IN ADHD – ASSOCIATED WITH IC?

PROCESSES REWARDING EVENTS EXECUTIVE CONTROL UNDERPINS SELF CONTROL REWARD/EVALUATION

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL

EF DEFICITS EXTREMELY COMMON IN ADHD

RECENT VBM MEGA‐ANALYSIS HIGHLIGHTS ALTERATIONS IN REWARD NETWORKS

NAcc VMFC OFC Thal

113 114

18/09/2019 58

STUDIES WITH MONETARY INCENTIVE DELAY TASK

p<0.0001 Controls ADHD SCHERES ET AL, 2006 STROHLE ET AL, 2008 Controls ADHD

115 116

18/09/2019 59

COULD ALTERED REWARD RESPONSIVITY CONTRIBUTE TO IC IN ADHD?

117 118

18/09/2019 60

FOUR INTERRELATED BRAIN CIRCUITS

ALTERED IN ADHD – ASSOCIATED WITH IC?

PROCESSES REWARDING EVENTS EXECUTIVE CONTROL DEFAULT MODE UNDERPINS SELF CONTROL REWARD/EVALUATION SELF REFERENTIAL STATES

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL

MTG LPC

PCC MPFC

FOUR INTERRELATED BRAIN CIRCUITS

ALTERED IN ADHD – ASSOCIATED WITH IC?

PROCESSES REWARDING EVENTS EXECUTIVE CONTROL DEFAULT MODE UNDERPINS SELF CONTROL REWARD/EVALUATION SELF REFERENTIAL STATES

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL PCC MPFC LPC

119 120

18/09/2019 61

FOUR INTERRELATED BRAIN CIRCUITS

ALTERED IN ADHD – ASSOCIATED WITH IC?

PROCESSES REWARDING EVENTS EXECUTIVE CONTROL DEFAULT MODE UNDERPINS SELF CONTROL REWARD/EVALUATION SELF REFERENTIAL STATES

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL MPFC LPC MTL

HUMAN BRAIN IS INTRINSICALLY ORGANIZED INTO DYNAMIC, ANTICORRELATED FUNCTIONAL NETWORKS

Fox et al., 2005 – PNAS

121 122

18/09/2019 62

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 123 124

18/09/2019 63

WAITING IS AN EMOTIONALLY PUNISHING EXPERIENCE FOR INDIVIDUALS WITH ADHD COULD THIS CONTRIBUTE TO IC 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

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL MPFC LPC MTL

OF C OF C

VMFC DLPFC Amyg TP

125 126

18/09/2019 64

PROCESSES REWARDING EVENTS PROCESSES AVERSIVE EVENTS ATTENTIONAL CONTROL DEFAULT MODE UNDERPINS SELF CONTROL REWARD/EVALUATION PUNISHMENT SELF REFERENTIAL STATES

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL MPFC LPC 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

OFC OFC

NAcc VMFC OFC Thal DLPFC Caud ACC S/IPL MPFC LPC MTL AMYG insula

FOUR INTERRELATED BRAIN CIRCUITS

ALTERED IN ADHD – ASSOCIATED WITH IC?

127 128

18/09/2019 65

• For ADHD children the experience of waiting during the delay

before outcomes or events is especially aversive.

• delay imposition is a negative reinforcer and delay escape a

potent reinforcer.

• ADHD is a functional expression of this aversion to delay –

associated with the escape or avoidance of delay.

• 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

CHOOSE LEAST DELAYED OPTION SPEED UP THE PASSAGE OF TIME DELAY ESCAPE POSSIBLE DELAY ESCAPE IMPOSSIBLE IMPULSIVE BEAHVIOURS INATTENTION EXCESS ACTIVITY DISRUPTIVENESS

129 130

18/09/2019 66

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.

• For ADHD children the experience of waiting during the delay

before outcomes or events is especially aversive.

• delay imposition is a negative reinforcer and delay escape a

potent reinforcer.

• ADHD is a functional expression of this aversion to delay –

associated with the escape or avoidance of delay.

• It is hypothesized to emerge during development as a

secondary consequence of the negative feelings and experiences associated with WI.

Predictions

• Behavioural: IC exacerbated when SS choices help delay

escape:

• 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

131 132

18/09/2019 67

DELAY AVERSION – QUICK DELAY QUESTIONNAIRE

not at all like them very much 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 3 will 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

• ften 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 7 try to avoid tasks that will only give them something in the long term and not straight away. 1 2 3 4 5 8 feel 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 10 The 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 TRIAL NO DELAY TRIAL

133 134

18/09/2019 68

CERTAIN DELAY VERSUS NO DELAY ASSOCIATION BETWEEN BRAIN RESPONSE AND SELF ASESSMENT OF DELAY AVERSION IN EVERYDAY LIFE

135 136

18/09/2019 69

DAY DREAMERS LOOSE TRACK OF TIME COULD MIND WANDERING BE A WAY OF COPING WITH DAv BY CHANGING HOW TIME IS EXPERIENCED?

DELAY MINIMIZATION

CHOOSE LEAST DELAYED OPTION SPEED UP THE PASSAGE OF TIME DELAY ESCAPE POSSIBLE DELAY ESCAPE IMPOSSIBLE IMPULSIVE BEAHVIOURS INATTENTION EXCESS ACTIVITY DISRUPTIVENESS 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?

137 138

18/09/2019 70

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? rest forced to wait work choose 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

• Highly heritable, but specific common risk variants challenging to find.
• G likely to interact with pre‐ & perinatal E risks – but genuine G effects need to

be distinguished from those due to shared genetics ?

• Adoption studies highlight power of post‐natal adversity and evocative GE

effects.

• 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).

• Context dependent and dynamic – not fixed.
• What are the implications for treatment?

139 140