CAUSAL HETEROGENEITY IN
ADHD: ARE THERE IMPLICATIONS
FOR CLINICAL PRACTICE?
EDMUND SONUGA-BARKE
D
B
BL
Developmental Brain-Behaviour Laboratory
School of Psychology
OVERVIEW
• DSM-IV ADHD subtypes – A successful way to handle
heterogeneity?
• New approaches to ADHD subtyping.
– Statistical refinement of the clinical phenotype.
– Towards translational taxonometrics.
• Neuropsychological markers of multiple causal pathways in
ADHD.
– Executive dysfunction
– Delay aversion
– Temporal processing
• Implications: Treatment tailoring to subtype targets?
DSM-IV ADHD SUBTYPES – A
SUCCESSFUL WAY TO HANDLE
HETEROGENEITY?
ADHD: THE CLINICAL REALITY
Patients present with a range of clinical profiles with
varying types and degrees of; (i) symptoms of
inattention, impulsivity/hyperactivity; (ii) comorbidity;
(iii) complicating factors; and (iv) impairment.
They may appear so different from one another that it is
sometimes difficult to see them as having the same
disorder.
THE DIAGNOSTIC REIFICATION
That this heterogeneity masks a core syndrome marked
by a cluster of symptoms which can be distinguished
from normality and from other related conditions and
abstracted from local complicating factors and types of
impairment.
HETEROGENEITY IN SYMPTOM PROFILE
INATTENTION
HYPER/IMPULSIVE
ATTENTION!
S
E
V
E
R
I
T
Y
Hyperactivity/Impulsivity
Inattention
ADHD: THE CLINICAL REALITY
Patients present with a range of clinical profiles with
varying types and degrees of; (i) symptoms of
inattention, impulsivity/hyperactivity; (ii) comorbidity;
(iii) complicating factors; and (iv) impairment.
They may appear so different from one another that it is
sometimes difficult to see them as having the same
disorder.
THE DIAGNOSTIC REIFICATION
Heterogeneity masks a core syndrome category marked
by a cluster of symptoms which can be distinguished
from normality and from other related conditions and
abstracted from local complicating factors and types of
impairment.
ADHD IS A DIAGNOSTIC ABSTRACTION
HANDLING HETEROGENEITY
IDENTIFYING SUBTYPES
THE CREDIBILITY OF THIS CATEGORICAL VIEW
DEPENDS ON OUR ABILITY TO PARTITION
HETEROGENEITY IN CLINICALLY PLAUSIBLE WAYS.
A number of approaches have been explored that address the
putative causes of heterogeneity.
(I)
Gender – Are there separate male and female ADHD?
(II) Severity and pervasiveness – ADHD vs HKD?
(III) Familiality – Is ADHD different if it runs in the family?
(IV) Onset and persistence – Is adult onset a valid ADHD type?
(V) Comorbidity – Is HK-CD a subtype or HKD with a comorbid condition?
(VI) Uneven symptom profile – Are differences between inattentive and
hyperactive/impulsive types of aetiological and clinical significance?
DSM-IV SUBTYPES
6 of 9 H/I &
6 of 9 IA
symptoms
Com Type
ADDITIONAL DIAGNOSTIC CRITERIA
Some symptoms/impairment before age 7 years; Some impairment in two or more
settings ;Clinically significant impairment; Not accounted for by another disorder
THE VALUE OF DSM-IV SUBTYPES
Hyp/Imp and Inatt are overlapping but separate
dimensions.
However subtypes....
not stable over time
 little genetic/familial specificity
 poor neuropsychological discrimination
 Little or no differential treatment response
Poor evidence for the validity of the ADHD subtypes.
HYP/IMP – PERHAPS A PRODROMAL FORM OF CT.
IA – PERHAPS SUB-THRESHOLD OR OTHER DISORDER.
Todd et al., 2008, McLoughlin et al 2007, Willcut et al, 2007, Gorman et al. 2006
THE FAILURE OF DSM-IV SUBTYPES: FUNDAMENTAL
QUESTIONS.
 Why ‘split’ rather than ‘lump’ anyway? To identify more
homogenous causal entities that can be targeted more
precisely -“get the right treatment to the right people”.
 Can subtypes be refined to facilitate better treatment or
should they be scrapped?
Can the clinical subtype be mapped more closely onto (i) the
‘causes’ of ADHD and (ii) treatment response?
 Do we need to integrate ‘causal’ processes into subtypes?
 Can this improve treatment?
REFINE THE CLINICAL PHENOTYPE OR GO
“DEEPER”?
NEW APPROACHES TO ADHD SUBTYPING.
1, STATISTICAL REFINEMENT OF THE
CLINICAL PHENOTYPE
2. TOWARDS TRANSLATIONAL
TAXONOMETRICS
REFINING THE CLINICAL PHENOTPYE
-LATENT CLASS ANALYSIS
Models the latent structure of the disorder on
the basis of the manifest characteristics of
ADHD patients..
…..to identify clusters of patients with
distinctive clinical profiles…..
…on the basis of (i) similarity of symptom
endorsement and (ii) class prevalence.
Dr Richard Todd PhD MD
2/17/1951-8/22/2008
Pioneer of latent class approaches
to ADHD subtypes.
Rasmussen
et al 2004
3samples:
Missouri
Females
Australian
Females
Australian
Males
95% C.I.
DSM-IV SUBTYPES
6 of 9 H/I &
6 of 9 IA
symptoms
Com Type
ADDITIONAL DIAGNOSTIC CRITERIA
Some symptoms/impairment before age 7 years; Some impairment in two or more
settings ;Clinically significant impairment; Not accounted for by another disorder
LATENT CLASS REFINEMENT
Few symptoms
Mild Inattentive
Talkative Impulsive
Inattentive/Impulsive
Severe
Hyper/Impulsive
Severe
Inattentive
Combined
Severe
Rasmussen et al 2004
THE VALUE OF LATENT CLASS SUBTYPES
 Replicable and robust (Rasmussen et al., 2004).
 Identify previously overlooked types (mild CT; Volk et al., 2006).
 Are systematically/differentially related to impairment – severe IA, severe CT, moderate
CT are most impaired (Volk et al., 2006).
 A little more stable over time than DSM-IV types (Todd et al., 2008).
 Is stable across informants (Alhoff et al., 2006).
 May help us to understand the overlap with comorbid conditions.
 ODD/CD (Acosta et al., 2008)
Autism (Reiersen et al., 2007)
 Developmental Co-ordination Disorder (Reiersen et al., 2008).
 Can be operationalised as simple diagnostic rules (Volk et al., 2009) .
 May be more aetiologically homogenous – map clinical phenotype more closely on
causal pathways.
 More heritable (Todd et al., 2001).
 Linked to specific measured genes and environments (Neuman et al., 2007).
CAN WORKING ONLY AT THE LEVEL OF THE
CLINICAL PHENOTYPE EVER ALLOW US TO
IDENTIFY HOMOGENEOUS CAUSAL ENTITIES?
LATENT CLASS REFINEMENT OF CLINICAL
PHENOTYPE
Mild Inattentive
Talkative Impulsive
Inattentive/Impulsive
Severe
Hyper/Impulsive
Severe
Inattentive
Combined
Severe
Rasmussen et al 2004
SIMPLE CLINICAL PHENOTYPE CAUSE MODEL
If you can refine the clinical phenotype sufficiently you
will produce a 1:1 map to cause.
Cause X
Cause Y
Cause Z
COMPLEX CLINICAL PHENOTYPE-CAUSE MODEL
Causes remote from clinical phenotype. Equi-finality and
multi-finality in causal pathways. 1:1 match between
clinical phenotype and cause impossible.
Cause X
Cause Y
Cause Z
INTEGRATING CAUSAL FACTORS INTO SUBTYPE MODELS
TOWARDS TRANSLATIONAL TAXOMETRICS
Shifts the focus from manifest variables
(exophenotype) to markers of neuro-biological
processes (endophenotype)…
…to identify subgroups of patients whose ADHD have
distinctive “causes”…
…which can promote the tailoring of new treatments to
new treatment targets.
BUILT ON CAUSAL PATHWAY MODELS OF ADHD
NEUROPSYCHOLOGICAL MARKERS OF
MULTIPLE CAUSAL PATHWAYS IN ADHD
EXECUTIVE DYSFUNCTION
DELAY AVERSION
TEMPORAL PROCESSING
THE BIO-MEDICAL MODEL HAS PROMOTED A
MODEL OF CAUSAL HOMOGENEITY
A reified disease-based notion of disorder is
insufficiently grounded in the reality of the patient
population.
Mental Disorders are: discrete
dysfunctional/endogenous/trait-like/homogenous
Where is the fixed-common core dysfunction in the
brains/minds of ADHD children that ‘causes’ the
disorder?
WHAT IS THE CORE DEFIT?
Originating
Causes
Neurobiological
Alteration
Neuropsychological
deficit
Disorder
EXECUTIVE DYSFUNCTION MODEL
A Simple Cognitive
Deficit Model
Executive Circuit
Thalamo-cortico-striatal loop
PRIMARY
MOTOR
AREA
EXECUTIVE CIRCUIT
DISTURBANCE
NE
DA
DLPFC
GENERALISED
EXECUTIVE
DEFICITS
THALAMUS
Caudate
Nucleus
ADHD
Adapted from Barkley, 1997
DORSAL
STRIATUM
Adapted from Alexander, 1986
THE NOTION OF A STABLE CORE DEFICIT IS A
SCIENTIFIC RED HERRING
Solid evidence base
Links EDF and its neural substrate & ADHD.
• Deficits in working memory, attentional flexibility, planning
• Inhibitory deficits may be a precursor
• Evidence implicating...
– pre-fronto-striatal networks
– dopamine, norepinephrine (Genes, Drugs)
Executive dysfunction is not the common core fixed
deficit that ‘causes’ ADHD.
Not the Holy Grail for which we have been searching.
EXECUTIVE DYSFUNCTION: A NECESSARY &
SUFFICIENT CONDITION FOR ADHD?
•
But…
– only a proportion of children with ADHD have EDF.
– many children without ADHD have EDF.
– EDF in ADHD nearly always presents in partial and fragmented
way.
IF NOT EXECUTIVE DYSFUNCTION WHAT THEN?
EXECUTIVE
DYSFUNCTION
OTHER
• Most children with
ADHD don’t show
executive dysfunction.
32%
?
• What ‘causes’ ADHD
in these other cases?
68%
Proportion of ADHD children with a broadbased
EF deficit (equivalent to 10 percent controls)
DO TEMPORAL PROCESSING DEFICITS AND DELAY
AVERSION REPRESENT ADDITIONAL ‘CAUSES’
WHICH ARE DISSOCIABLE FROM EXECUTIVE
DYSFUNTION?
DISSECTING HETEROGENEITY IN ADHD: DELAY
SENSITIVITY, EXECUTIVE FUNCTIONING AND
TEMPORAL PROCESSING.
Bitsakou, Temporal Sonuga-Barke (submitted)
To examine the independence and overlap of temporal
processing, executive function and delay aversion
components to ADHD.
ADHD
CONTROLS
7-12 years
>12 years
7-12 years
>12 years
Male
44
19
17
15
Female
10
4
12
5
NINE NEUROPSYCHOLOGICAL TASKS
INHIBITORY CONTROL
Stop Signal
Adjusted to 50% correct
SSRT
Go-NoGo
G – left or right arrow
NG – double headed arrow
Probability of inhibition
DELAY SENSITIVITY
MIDA
1pt – 2-s:: 2pt – 30-s
No post reward delay
Choice of LL
Delay Frustration
55 simple problems
8 x 20-s.imposed delay
Responses during to delay
Stroop-like
Compatible – green arrows
Conflict – red arrows
Probability of inhibition
Delayed Response
Press when arrow disappears
No delay
Delay 3-s and 20-s
(RT delay – RT immediate)
TEMPORAL PROCESSING
Discrimination
Target 400ms tone
Comparator adjusted by 10 ms
Average time difference
between tones
Reproduction
Target interval signalled
Target invisible not signalled
RT non-signal trials
Tapping
Tap to regular tone (1200ms)
Tap no tone
Variability on no tone trials
Working memory (digit span) and IQ also collected
RESULTS
LATENT STRUCTURE
Construct
Delay
Aversion
Inhibitory
Control
Temporal
Processing
Working
Memory
Measures
Component
Inhibitory
Executive
Dysfunction
Temporal
Processing
Deficit
Negative Effect of
Imposed Delay
Productive
Use of
Delay
MIDA
.16
.003
.09
.76
DRT
.02
-.06
.56
-.58
DeFT
-.25
-.01
.70
.17
SSRT
-.56
.21
-.20
-.10
GNGI
.81
-.03
-.22
-.08
MStroop
.77
-.05
-.18
.18
Tapping
-.16
.68
-.16
.06
Discrimination
-.11
.66
.20
-.05
Anticipation
.05
.51
.52
-.06
Digit Span
.00
-.48
.08
.49
Eigenvalue
1.72
1.46
1.29
1.26
% Variance
17.25
14.68
12.95
12.68
FACTOR SCORE (STANDARIDZED)
ALL 4 DOMIANS ARE ASSOCIATED WITH ADHD.
I-EDF
TPD
NEID
PUD
PROPORTIONS WITH DEFICIT AND OVERLAP
DELAY n=25
15 (19.5%)
1 (1.6%)
EF n=16
NO
DEFICIT n=22
5 (6.5%)
4 (5.2%)
5 (6.4%)
6 (7.8%)
19 (24.%)
TIME n=34
Based on 10% cut in normals
A TRIPLE PATHWAY
HYPOTHESIS
CORTICO-VENTRAL
STRIATAL
LOOP
DISTURBANCE
IMPAIRED
SIGNAL
DELAYED
REWARD
CORTICO-DORSAL
STRIATAL
LOOP
DISTURBANCE
INHIBITORY
DEFICITS
CORTICOCEREBELLAR
LOOP
DISTURBANCE
SIMPLIFIED
FUNCTIONAL
NEUROANATOMY
OFC
MOTOR
CORTICES
ANTERIOR
CINGULATE
DLPFC
TEMPOROSENSORYMOTOR
INTEGRATI’N
DEFICITS
THALAMUS
AMYGDALA
DELAY
AVERSION
EXECUTIVE
DEFICITS
ADHD
MOTOR
ASYNCHRONY
VENTRAL
STRIATUM
DORSAL
STRIATUM
Nucleus
Accumbens
Caudate
Nucleus
NEO
CEREBELLUM
IMPLICATIONS FOR PRACTICE
• DIAGNOSTIC IMPLICATIONS: SHOULD THERE BE CAUSAL
SUBTYPES MARKED BY NEUROPSYCHOLOGICAL DEFICITS?
• EDF, DEL & TD ..
SHOULD WE MODEL PHENOTYPIC AND
ENDOPHENOTYPIC HETEROGENEITY
SIMULTANEOUSLY?
SHOULD WE MODEL PHENOTYPIC AND
ENDOPHENOTYPIC HETEROGENEITY
SIMULTANEOUSLY?
Impulsive
/Inattentive
Timing
Impulsive/
Inattentive
Executive
ImpulsiveInattentive
Delay Averse.
Combined
Severe Timing
Combined
Severe Executive
Combined
Severe – Delay
Averse
OR SHOULD WE SEE DEFICITS AS EXTENDED ACROSS DISORDER
TYPES?: A COMPLICATION RATHER THAN A SUB-TYPE
EDf
DAv
TimD
OR SHOULD WE SEE DEFICITS AS EXTENDED ACROSS DISORDER
TYPES?: A COMPLICATION RATHER THAN A SUB-TYPE
EDf
DAv
ADHD
TimD
OR SHOULD WE SEE DEFICITS AS EXTENDED ACROSS DISORDER
TYPES?: A COMPLICATION RATHER THAN A SUB-TYPE
PDD
ODD/CD
EDf
DAv
ADHD
TimD
Dyslexia/LD
IMPLICATIONS FOR PRACTICE
• DIAGNOSTIC IMPLICATIONS: SHOULD THERE BE
NEUROPSYCHOLOGICAL SUBTYPES?
• EDF, DEL & TD ..
• as epiphenomenon
• as subtypes of disorder
• as complication & comorbidity
TREATMENT IMPLICATIONS CAN WE DEVELOP NEW
TREATMENTS TO TARGET SPECIFIC ‘CAUSAL’ SUBTYPES.
– Treatment
– Develop new treatments to target specific pathways.
– Pharmacological
– Psychological
– Target/tailor treatments more effectively.
– Assessment
– Biological/psychological markers
– The role of context
MEDIATORS OF SPECIFIC PATHWAYS ARE
POTENTIAL THERAPEUTIC TARGETS
Originating
Causes
G, E, GxE
Neurobiological
alteration
Neuropsychological
deficit
Disorder
IDENTIFYING SUCH DEFICITS SHOULD BE A
STIMULUS FOR PHARMACO-THERAPEUTIC INNOVATION
Originating
Causes
G, E, GxE
Altered
circuits
Deficits
Disorder
Medication
MAJOR DOPAMINE &
NOREPINEPHRINE
BRANCHES
OFC
DLPFC
VENTRAL
STRIATUM
DORSAL
STRIATUM
Nucleus
Accumbens
Caudate
Nucleus
MOTOR
CORTICES
NEO
CEREBELLUM
MEDIATORS OF DISEASE PROCESSES REPRESENT
POTENTIAL THERAPEUTIC TARGETS
Originating
Causes
G, E, GxE
Neurobiological
alteration
Neuropsychological
deficit
Disorder
IDENTIFYING SUCH PROCESSES SHOULD BE A
STIMULUS FOR PSYCHO-THERAPEUTIC INNOVATION
Originating
Causes
G, E, GxE
Neurobiological
alteration
Neuropsychological
deficit
Training
Disorder
Level 1: randomized controlled trials with concealed
allocation
Level 2: quasi-experimental (without randomization) studies
Level 3: controlled observational (cohort or
case–control studies) studies
PROGRM
DESIGN
LEVEL
COGNITIVE
CHANGES
SYMPTOM
CHANGES
Karatekin 2006
Antisaccade
training
NonRCT
1 sess
2
Reduced saccadic
RT
No report
Kerns et al. 1999
Pay
Attention!
RCT
16 sessions
1
Improved
attention/inhibition
Teacher ratings only
Kiingberg et al.
2002
Robomemo
RCT
20-30 sess
1
Improved WM/IQ
Head movements
reduced
Klingberg et al.,
2005
Robomemo
RCT
20-30 sess
1
Improved WM IQ
Parent ratings only
Kotwaletal. 1996
Captain’s
log
Case study
35 sess
3
Academic
perfomance
Parent rating only
O'Connell et al.
2006
Attention
Training
Feasibility
Study
-
Reduce commission
errors
No data
SemrudClikeman et al.
1999
Attention
Training
Non-RCT
32 sess
2
Improved Attention
No data
Shalev et al.
2007 [31]
Attenton
Training
RCT
1
Academic test
improvement
Parent only
CAN WE TARGET EXECUTIVE DEFICITS IN ADHD
USING COMPUTERISED TRAINING?
Computerized Training of Working Memory in Children with ADHD
Klingberg, T (MD, PhD)1, Unit of Neuropediatrics, Dept. Women and Children’s Health,
Karolinska Institute, Stockholm, Sweden
WM TRAINING CAN IMPROVE WM IN THOSE
WITH WM DEFICITS AND WITH ADHD
Holmes et al., 2009
Klingberg et al., 2005
BUT MANY REMAIN TO
BE CONVINCED THAT
IT HAS EFFICACY AS A
TREATMENT FOR
ADHD?
RATINGS OF ATTENTION
20
18
16
14
12
10
8
6
4
2
0
ns
*
PARENT
PRE
POST
TEACHER
Klingberg et al., 2005
DOES WM TRAINING CHANGE THE
BRAIN:ACTIVATION
Plasticity in neural systems
underlying WM
• Right middle frontal
gyrus
• Right inferior parietal
cortex
• Intraparietal cortex
Olesen et al. Nature Neurosci 2004
DOES WM TRAINING CHANGE THE BRAIN:
NEUROCHEMISTRY
– 14 hours training,
– Improved WM
– Inverse relationship to D1
receptor BP in WM regions
– Decrease in the density of
prefrontal and parietal
dopamine D1 receptors
– Changes in WM correlate
with changes in D1 activity/
Mc Nab et al. Science 2009
“THE FINDINGS, ALTHOUGH
ENCOURAGING, DO NOT AT
PRESENT PROVIDE CONCLUSIVE
EVIDENCE FOR
THE EFFICACY OF PROCESSSPECIFIC TRAINING AS AN
INTERVENTION FOR ADHD.”
Markomicali et al, 2009
WHY IT MAY BE TOO LATE BY EIGHT
Over time •
•
•
•
complicated problems more resistant
behavioural habits reinforced over time
parental response “hardened”
neural plasticity reduced
THE EARLY PRE-SCHOOL PERIOD CAN PROVIDE
THE OPTIMUM PERIOD FOR COGNITIVE
TRAINING
ARE COMPUTERS THE BEST MEDIUM IN THE
PRESCHOOL PERIOD
THE SOCIAL BASIS OF PSYCHOLOGICAL
DEVELOPMENT AND EARLY INTERVENTION
Normal interactions between parents and young children
represent a …
…..crucial forum for the internalisation of cognition
and development of self regulation
….and a potential therapeutic opening for the
implementation and integration of cognitive training into
the everyday lives of children at risk of ADHD.
Vygotsky, Luria, Baumrind, Cole
REVISED NEW FOREST PARENTING
PROGRAMME
A second-generation parenting intervention for preschool ADHD.
•
•
•
•
Margaret Thompson
Cathy Laver-Bradbury
Ann Weekes
David Daley
GENERAL
GOALS
TREATMENT
TARGETS
PSYCHOEDUCATIO
N
Week 1
Parent
only
IMPROVE
PARENTAL
STYLE
understanding
ADHD
parenting and
ADHD
constructive
parent
positive parent
selforganisation
HELP
PARENTS
COMMUNICATE
listening skills
authoritative
talk
clarity and
consistency
IMPROVE
MANAGE
OF ODD
behavioural
principles
preventative
strategies
reward and
sanctions
consistency
IMPROVE
REGULATION
THROUGH
INTERACTION
 joint play
and
interaction
reciprocity
turn taking
scaffolding
Week 2
Parent only
PARENT-CHILD PLAY
Week 3
Parent &
Child
Week 4
Parent &
Child
MAJOR
REVIEW
Week 5
Parent only
PARENT-CHILD TASK
Week 6
Parent & Child
Week 7
Parent & Child
FINAL
REVIEW
Week 8
Parent only
DISTINCTIVE CORE GOAL
 increase constructive parenting and the effectiveness
of parents as facilitators of their child's development enhance home as a context for learning selfcontrol/behavioral regulation.
 teach parents to change their child's experience
(training/practice), to address areas of neuropsychological weakness (self regulation, delay
tolerance and organisational skills).
CONSTRUCTIVE PARENTING
Work within the children zone of proximal development
…to gradually increase their child self organisational
skills, delay tolerance and working memory during
episodes of everyday reciprocal interaction and
mother-child play using (a) organised games and (b)
identifying teachable moments by
… (a) scoping current levels of ability, identifying
appropriate and realistic developmental goals, (b)
providing the necessary support and encouragement
to achieve those goals (i.e. scaffolding) and (c)
consolidating through practice those developmental
gains and (d) rescoping.
WLC v NFPP
(SONUGA-BARKE ET
AL., 2001)
NFPP v TAU
(THOMPSON ET AL.,
2009)
0.6
0.4
0.2
WLC AD/HD
WLC CP
SC AD/HD
SC CP
0
-0.2
-0.4
-0.6
-0.8
-1
T1
T2
T3
SUMMARY
• ADHD is a multiply heterogeneous disorder.
• Subtyping aims to reduce heterogeneity – map better to
cause and treatment response.
• DSM-IV subtypes don’t work.
• Statistical refinement valuable in many ways.
• Translational taxometrics will integrate endo- and clinical
phenotype - more causally homogeneous subtypes and
promote treatment targeting and therapeutic innovation.
• Much more research needed on
•
clinical significance of neuropsychological deficits
•
how to integrate them into refined clinical subtype.
•
treatment targeting and tailoring .