Attention Deficit Hyperactivity Disorder:
Neurodevelopmental Perspectives on
Current Research and Treatment
Development
JJeffreyy M. Halperin,
p , Ph.D.
Department of Psychology
Queens College, City University of New York
Department of Psychiatry
The Mount Sinai School of Medicine
Outline






Neurodevelopmental Perspectives on ADHD
Re--thinking the Neural Substrates of ADHD
Re
from a Lifespan Perspective
Queens College Preschool Project (QCPP)
Relations between neuropsychological and
behavioral functioning over time
Implications for understanding ADHD
Implications for Treatment and Future Research
ADHD Across the Lifespan
Adults
Adolescents
School-age
Preschoolers
1
What Causes ADHD?

Genetic Determinants
Environmental Factors

Brain Dysfunction

Hypothesized Neural Anomalies in
ADHD




Prefrontal (PFC)/Executive Impairments?
Subcortical state regulation anomalies?
Dopaminergic insufficiencies?
Poor alpha 2a receptor functioning?

Behavioral and neurocognitive heterogeneity
suggest that it may not be the same in all with the
disorder

ADHD is a developmental disorder, but most
models do not consider development!
2
ADHD is Likely Related to Catecholaminergic
Innervation of the Frontal Lobe and Basal Ganglia
Developmental Considerations

PFC and the EFs it mediates develop relatively
late in ontogeny
Synaptic pruning: 5 – 16 years
years--old
Myelination:: through early adulthood
Myelination
 EFs develop into at least early adulthood




Yet ADHD is always present in early childhood
ADHD tends to get better with age
Developmental trajectories of behavioral deficits
associated with ADHD and early frontal lobe lesions
ADHD
Early PFC
Lesion*
Preschool
Later in
Childhood
Present in
Childhood
Always
Sometimes
Adolescent
Trajectory
Improve or remain the
same
Worsen
Onset of Symptoms
*Anderson et al. 1999; Trauner et al. 2001
3
Corresponding trajectories for A) the remission of ADHD, B) the development of
EFs, and C) the maturation of white matter in the DLPFC. Figures from A) Hill
& Schoener, 1996; B) Paus, 2005; and C) Barnea-Goraly et al., 2005.
Note: FA = fractional anisotrophy; SSRT = Stop-signal reaction time.
A Developmental Model of ADHD
Pathophysiology*




Distinct neural and cognitive mechanisms are involved
in the etiology of and recovery from ADHD
ADHD is due to non-cortical neural dysfunction that is
present early in ontogeny and remains static throughout
the lifetime
PFC circuitry is not linked to the cause of ADHD, but
is involved in recovery
The diminution of symptoms with age is accounted for
by the degree to which the development of the
PFC/EFs are able to compensate through the
implementation of ‘top down’ regulatory control.
*Halperin & Schulz (2006). Psychological Bulletin.
Predictions from Model

Improvements in behavior over time should be
differentially linked to distinct types of
neurocognitive functioning

M
Measures
off hi
higher
h cortical
ti l ““recovery”” mechanisms
h i
should parallel later status; effortful/goal
effortful/goal--directed

Measures of subcortical “causal” mechanisms persist
irrespective of later clinical status; less conscious
control/stimulus--driven
control/stimulus
4
Preliminary Support from Longitudinal Study
of Adolescents with Childhood ADHD



Irrespective of followfollow-up status, those with childhood
ADHD are impaired on less consciously controlled
measures (e.g., RTSD, ankle movements)1,2
ADHD--p
ADHD
persisters are most impaired
p
on measures
requiring effortful control (e.g., working memory, CPT
errors, conflict resolution) 1,2
Prefrontal activation obtained during effortful
processing (i.e., conflict resolution), parallels severity of
adult symptomatology 3,4
1Halperin
3Schulz
2 Bedard
4Schulz
et al. (2008) JCPP.
et al., In review.
et al. (2005a) Neuropsychology
et al. (2005b) JAACAP
Longitudinal Study of Urban Youth with
ADHD: Baseline Assessment






Initially recruited 1990 – 1997
Clinically--referred sample
Clinically
Age
g at initial assessment 7 – 11 yyears
Teacher ratings: IOWA Conners
Parent ratings: CBCL
Parent Interview: DISC
Comorbidity in Childhood
Diagnosis
N = 98
% ODD
49.0
% CD
32.7
% Anxiety
31.6
% Mood
10.2
5
Adolescent Characteristics of Probands
and Matched Control Group
Childhood ADHD
N
Mean Age
(years)
Mean WAISWAISIII FSIQ
% Male
Controls
98
85
18.4
18.5
93.3
96.8
88.8
87.1
Axis I Diagnoses in patients with childhood
ADHD and never-ADHD controls
ADHD
Controls
ADHD (%)
49.5
0
<.001
Depression (%)
4.7
.001
Anxiety (%)
21.6
19 6
19.6
82
8.2
< 05
<.05
ODD (%)
CD (%)
22.7
26.8
1.2
1.3
<.001
<.001
Alcohol Abuse/Dep. (%)
15.5
7.1
Drug Abuse/Dep. (%)
44.3
27.1
.08
<.05
Adolescents Diagnosed with ADHD
During Childhood
35
ADHD
D-RS
30
25
20
Controls
Remitters
Persisters
15
10
5
0
Parent*
Self*
*All groups differ, p < .05
6
Working Memory and ADHD Outcome*
Controls (n=85)
ADHD (n=98)
Remitters (n=29)
100
100
WAIS-III WM
MI
Controls (n=85)
Persisters (n=44)
95
95
90
90
85
85
80
Controls vs. ADHD: p=.007; d=.41
80
Controls vs. Remit: p>.30; d=.20
Controls vs. Persist: p=.03; d=.43
*Halperin et al. 2008
Perceptual Inhibition
Never‐ADHD ADHD‐partial remitters ADHD‐persisters
190
550
SDR
RT (ms)
Mean RT (ms)
650
450
160
130
100
350
70
Compatible
Incompatible
Compatible Incompatible
Main effect Condition: p < .001
Main effect Group: p = .004
GxC Interaction: p = .04
Main effect Condition: p < .001
Main effect Group: p = .08
GxC Interaction: p > .10
Bedard et al. In Review.
Continuous Performance Test (CPT(CPT-IP)
Errors, which reflect effortful processing,
processing, as a
Function of Adolescent/Adult Status
16
80
14
78
12
76
10
74
Controls
Remitters
Persisters
72
8
Controls
Remitters
Persisters
6
70
4
68
2
0
66
Percent Hits*
Percent False
Alarms*
*Controls differ from Persisters, p < .05
Halperin et al. 2008
7
Less Conscious Reaction Time Measures
as a Function of ADHD Persistence
Controls
Remitters
Persisters
250
650
600
550
200
500
450
150
400
350
100
300
250
200
Hit RT (in msec.)*
*Persisters < Controls, p = .045
50
RT SD (in msec.)**
**Persisters = Remitters > Controls, p < .001
Activity Level in Adolescents as a
Function of Persistence of ADHD
Persisters
100
90
80
70
60
50
40
30
20
10
0
Ankle*
Remitters
Controls
Waist
*Persisters = Remitters > Controls
Halperin et al. 2008
Activation During Go/No
Go/No--go Task
Schulz et al. 2005; JAACAP
8
Stimulus and Response Conflict Task
BLOCKED DESIGN
Location
Control
+
+
0
30
Stimulus
Characteristic
+
90
60
Prepotent
Motor
Response
Control
+
+
150
120
Time (seconds)
180
Combined
+
210
240
270
Block 1
Control A
Block 2
+
Location
TRIALS
+
+
C
+
Control B
+
+
Block 4
Block 3
Stimulus
Characteristic
c
+
Prepotent
Motor
Response
C
+
C
+
Block 5
Block 6
Combined
C
+
C
+
+
C
0
1500
Time (milliseconds)
2000
Activation During Conflict Task
Schulz et al. 2005; Neuropsychology
The Preschooler
9
Queens College Preschool Project
(QCPP)
Overview of Methodology

Gather parent and teacher ADHD ratings on a
g sample
p of 3 and 4 yearyear
y -old children
large

Comprehensive inin-lab assessment of identified
children/parents
Semi--annual parent and teacher behavior ratings
Semi
In--lab reIn
re-evaluation annually



Identify “at risk” and “control” children
QCPP: Classification Criteria

At Risk (AR) Group:


At least 6 Hyperactivity/Impulsivity or Inattention
symptoms rated 2 or greater (0 – 3 scale) by parent,
teacher,, or a combination of the two
Typically--developing (TD) Group
Typically
Group::

Fewer than 3 Hyperactivity/Impulsivity and
Inattention symptoms rated 2 or greater by both
parent and teacher
QCPP: Sample Characteristics
TD
(N=76)
At--Risk
At
(N=140)
t
p
Age (in years)
4.20 (.48)
4.36 (.46)
2.46
<.05
% Boys
B
67 1
67.1
75 7
75.7
1.84*
1 84* > .10
10
WPPSI FSIQ
112.63 (12.0) 101.96 (12.8) 5.96
ADHD--RSADHD
RS-P
8.74 (4.9)
27.6 9 (10.9) 17.57 < .001
ADHD--RSADHD
RS-T
4.63 (4.3)
30.32 (13.5)
<.001
20.64 < .001
*Chi Square
10
ADHD and ODD Diagnoses in AtAt-Risk Group
(N = 140)
Primary Measures (for this presentation)

Parent and Teacher Ratings



ADHD-RS ((DuPaul
ADHDDuPaul et al. 1998)
Children’s Problem Checklist (CPC; Healey et al.
2008)
NEPSY
Attention/Executive Function
Language
 Sensorimotor
 Visuospatial
 Memory


QCPP: Solid State Actigraph
Recordings
Ankle*
Waist*
1400
600
1200
500
1000
400
800
300
600
400
200
200
0
100
Boys
Controls
Girls
At-risk
0
Boys
Girls
*Main Effect Group, p < .001
11
QCPP: NEPSY Domain Scores
(Baseline)*
Typically-developing
At-risk
115
110
105
100
95
90
85
80
75
70
Exec/Att
Lang.
Sen/Mot
Vis/Sp
Mem
* All p < .001
NEPSY Subtest Scores in Hyperactive
Preschoolers
Typically-developing
At-risk
on
Ph
Bo
dy
Pa
r
t*
Pr
oc
Co
m
p.
D
es
.C
op
Bl
.
k.
C
on
.
Vi
s.
At
t.
St
a
I m t ue
.H
an
d
Vi
sm
N
ot
ar
.M
em
Se
.
nt
.R
ep
.
13
12
11
10
9
8
7
6
*p > .05
QCPP Timeline
ADHD-RS
CPC
NEPSY
ADHD-RS
CPC
NEPSY
ADHD-RS
ADHD
RS
CPC
0
6
12
ADHD-RS
ADHD
RS
CPC
ADHD-RS
CPC
NEPSY
18
24
ADHD-RS
ADHD
RS
CPC
30
Time in Months
12
Are Changes in ADHD Severity Over
Time Related to Improved
Neuropsychological Functioning in AtAt
Risk Children?
ADHD severity assessed via a single
latent variable
Symptoms
Impairment
Parent
ADHD-RS
Parent
CPC
ADHD
Severity
Teacher
ADHD-RS
Teacher
CPC
Individual Trajectories for ADHD Severity in
At--Risk Children
At
3.0
ADHD factor z-score
2.0
1.0
0
-1.0
-2.0
-3.0
0
6
12
18
24
30
Time in months
13
Change in Neuropsychological Functioning
Assessed via a Single Latent Variable
(Baseline to 24 Month)
Attention/
Executive
Memory
Change in
Neuropsych.
Functioning
Visuospatial
Language
Sensorimotor
Distribution of NEPSY Change Scores
Mean = -0.07
SD = 1.00
N = 101
Change in NEPSY Associated with improved
ADHD trajectory
1.0
<20%ile (n=21, 91% ADHD dx at 24m)
20-40%ile (n=19, 68% ADHD dx at 24m)
40-60%ile (n=20, 75% ADHD dx at 24m)
ADHD factor zz-score
60-80%ile (n=21, 57% ADHD dx at 24m)
0.5
Fixed Effects:
Intercept: p=.058
p p
p=.007
Linear Slope:
Quadratic Slope: p=.54
>80%ile (n=20, 45% ADHD dx at 24m)
0
-0.5
-1.0
0
6
12
18
24
30
Time in months
14
Percentage of Cases Meeting Criteria for ADHD at
24--month Follow
24
Follow--up as a Function of Change in
NEPSY Score
Less improvement
More improvement
Chi Square = 11.18, p = .025
Do Changes in ADHD Severity Over
Time Precede or Follow Changes in
Neuropsychological Functioning?
At-risk children
N-1
N-2
.24*
N-3
.99*
N-4
N-5
N-1
.21
.20*
NeuroPsychological
Functioning
Baseline
N-2
.34***
.59***
.99*
N-3
.52***
N-4
N-5
.20*
.42**
ADHD
parent
.21*
ADHD
teacher
.42***
CPC
parent
.19*
CPC
teacher
ADHD
parent
N-5
.27*
-.19
-.40**
Attention
Deficit &
Impairment
at Time 2
.82***
N-4
.66***
NeuroPsychological
Functioning
at Time 3
.99***
-.07
.76
N-3
48**
-.02
Attention
Deficit &
Impairment
Baseline
N-2
.49** .52***
NeuroPsychological
Functioning
at Time 2
.33*
N-1
.63***
.15*
.34**
ADHD
teacher
Attention
Deficit &
Impairment
at Time 3
.81***
.99***
.56***
CPC
parent
CPC
teacher
ADHD
parent
.38*
.65***
ADHD
teacher
CPC
parent
.21*
CPC
teacher
15
Typically-developing children
N-1
56**
N-2
.40**
N-3
99**
N-4
.99**
N-5
N-1
.37**
NeuroPsychological
Functioning
Baseline
.55***
N-2
N-3
.49*** .74***
N-4
.67***
N-5
NeuroPsychological
Functioning
at Time 2
.60
N-1
.25**
ADHD
parent
.16**
ADHD
teacher
.14*
.13*
CPC
parent
CPC
teacher
ADHD
parent
N-5
.58***
-.08*
Attention
Deficit &
Impairment
at Time 2
.73***
N-4
.68***
-.17
-0.04
.73
N-3
.46**
NeuroPsychological
Functioning
at Time 3
87***
-0.19
Attention
Deficit &
Impairment
Baseline
N-2
.49**
.66***
.54***
.57**
ADHD
teacher
.49*
CPC
parent
Attention
Deficit &
Impairment
At Time 3
.72**
.43***
CPC
teacher
.87**
ADHD
parent
.75***
ADHD
teacher
.94***
CPC
parent
.63***
CPC
teacher
RMSEA = .067; 90% CI, .061-.072; CFI = .78
Summary of Preschool Data



Behavioral impairment related to ADHD
symptoms is clearly apparent during the
preschool years
Behavioral difficulties are accompanied
p
by a
wide array of cognitive deficits
Improved behavioral functioning is related to
and may be preceded by improved
neuropsychological functioning
Implications for Conceptualizing ADHD



ADHD is a lifespan disorder that must be
conceptualized within the context of a
developmental framework
Within the framework of o
ourr model
model, ADHD
might have a unitary cause; behavioral and
cognitive heterogeneity should increase with age
Although we might not be able to “cure”
ADHD, the trajectory should be susceptible to
positive and negative influences
16
Implications for Treatment



If ADHD is due to subcortical disorder that is relatively
permanent, can we develop lasting treatments?
Must take advantage of early cortical
neurodevelopment, that may be linked to
clinical/behavioral
/b
improvement across the lifespan.
f
Perhaps, environmental manipulations targeted at
facilitating experience
experience--dependent neurodevelopmental
processes such as synaptic pruning, dendritic
arborization and mylenation could be employed to
facilitate recovery
TEAMS
Training Executive, Attention and
Motor Skills
TEAMS is based on these ideas:
1) ADHD is associated with deficient neural networks that:
• affect a wide array of neurocognitive and behavioral processes
• may not be identical in all children with the disorder;
2) Neurodevelopment is sensitive to and can be positively affected by
appropriate environmental influences;
3) Effective environmental stimulation will be best achieved within a
social context;
4) Core activities of the treatment must be intrinsically rewarding (i.e.,
fun) rather than extrinsically reinforced (e.g., parental praise or
tokens). This will:
• facilitate self-imposed continuation of the intervention
• lead to generalization over time and across
settings.
17
How Do We Think TEAMS Will
Work?
• ‘Exercise the brain’ using game-like
activities which employ neurocognitive
and motor skills.
• Small group setting (4-5 children)
• Parent
P
t education
d
ti about
b t ADHD and
d
support
• Encourage parents to engage their
children in these game-like and exercise
activities at home.
Directions for Future Research


Need to develop and apply better measures of
stimulus--driven or “bottomstimulus
“bottom-up” processes
Need to add neuroimaging to the mix in
developmental studies
st dies

Does cognitive/behavioral improvement relate to
measurable changes in brain structure and function?

Do genes moderate ADHD trajectory?
Development of interventions to alter the
trajectory over the lifespan

Preschool Studies

Acknowledgements













David Marks, Ph.D.
Dione Healey, Ph.D.
Olga Berwid
Berwid,, Ph.D.
Elizabeth Kera,
Kera, Ph.D.
Amita Santra
Santra,, Ph.D.
Chaya Gopin
A i k Mlodnicka
Agnieszka
Ml d i k
Beth Rabinovitz
Katya Staikova
Michelle Bubnik
Katia Castelli
Bipasha Basu
NIMH




Adolescent Studies








Jeffrey Newcorn,
Newcorn, M.D.
Carlin Miller, Ph.D.
Joey Trampush
Virginia Fresiello
Seth Harty
Tobey Busch
Dana Barowsky
Neuroimaging




Kurt Schulz, Ph.D.
Jin Fan. Ph.D.
Chuck Tang, Ph.D.
Suzanne Clerkin,
Clerkin, Ph.D
RO1 MH060698
RO1 MH068286
1R21MH085898
18
Thank you.
you
19