What causes ADHD? Can science improve treatment? ACAMH ... · 18/09/2019 11 A translational model holds out the promise that therapeutic innovation builds on scientific understanding

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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


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NASCENT

PRODROME

FULL



Clinical Condition in Middle Childhood



Diagnostic Criteria Met


NASCENT

PRODROME

FULL

COMPLEX




Emergence of Comorbidity in Later Adolescence




Conduct Disorder, Depression, Anxiety


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NASCENT

PRODROME

FULL

COMPLEX

ESCAL’TING




Emergence of Comorbidity in Later Adolescence

Spirals of Dysfunctionin Adulthood




Conduct Disorder, Depression, Anxiety

Personality Disorders, Substance Abuse


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))


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


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


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)



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


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


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


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


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


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


PROMOTINGRESILIENCE

G Euterine

E

Prenatal Postnatal


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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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PROMOTINGRESILIENCEPROMOTINGRESILIENCE

G Euterine

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

G Euterine

E

Prenatal Postnatal



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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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

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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



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



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



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


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


EF – 46%

DEL – 38%

EF – 21%

DEL – 36%

TIME – 44%

EF – 32%

TIME – 32%

REW – 4% DEL – 14%

EF – 36%

VAR – 54%



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EF PERFORMANCE HIGHLY VARIABLE ‐PERIODIC “DIPS” MAY BE MISINTERPRETED

AS FIXED DEFICITS.


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


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


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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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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CHILDREN WITH ADHD WAIT LESS THAN THEIR PEERS






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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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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PROCESSES REWARDING EVENTS

EXECUTIVE 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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EXECUTIVE CONTROL

DEFAULT MODE


REWARD/EVALUATION

SELF REFERENTIAL STATES

OFCOFC

NAccVMFC

OFC

Thal

DLPFC

Caud

ACCS/IPL

MTG LPCPCCMPFC



EXECUTIVE CONTROL

DEFAULT MODE


REWARD/EVALUATION


OFCOFC

NAccVMFC

OFC

Thal

DLPFC

Caud

ACCS/IPL

PCCMPFC

LPC

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EXECUTIVE CONTROL

DEFAULT MODE


REWARD/EVALUATION


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 AVERSIVE EVENTS

ATTENTIONAL CONTROL

DEFAULT MODE


REWARD/EVALUATION

PUNISHMENT


OFCOFC

NAccVMFC

OFC

Thal

DLPFC

Caud

ACCS/IPL

MPFCLPC

MTL

OFCOFC

VMFC

DLPFC

AmygTP

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ATTENTIONAL CONTROL

DEFAULT MODE


REWARD/EVALUATION

PUNISHMENT


OFCOFC

NAccVMFC

OFC

Thal

DLPFC

Caud

ACCS/IPL

MPFCLPC

MTL

AI

TP





ATTENTIONAL CONTROL

DEFAULT MODE


REWARD/EVALUATION

PUNISHMENT


OFCOFC

NAccVMFC

OFC

Thal

DLPFC

Caud

ACCS/IPL

MPFCLPC

MTL

AMYG

insula



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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


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.


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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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What causes ADHD? Can science improve treatment? ACAMH ... · 18/09/2019 11 A translational model holds out the promise that therapeutic innovation builds on scientific understanding

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