Beyond The Dual Pathway Model Evidence For The Dissociation of Timing, Inhibitory and Delay-Related Impairments in Attention DeficitHyperactivity Disorder.
Beyond The Dual Pathway Model Evidence For The Dissociation of Timing, Inhibitory and Delay-Related Impairments in Attention DeficitHyperactivity Disorder.
Beyond The Dual Pathway Model Evidence For The Dissociation of Timing, Inhibitory and Delay-Related Impairments in Attention DeficitHyperactivity Disorder.
Beyond the dual pathway model: Evidence for the dissociation of timing,
Disorder.
Professor Sonuga-Barke and Drs Bitsakou and Thompson are with the Developmental
The authors would like to thank the families who participated in this project; Dr. L.
Psychogiou; Dr. A. Weeks, Dr. V. Fiske, Dr. J. Chan, and Dr. A. Shyam for help with
Maria Re, and Amanda Meliá De Alba for help with data entry and collection; Luke
Phillips for the construction of the tasks and his technical support. This research was
funded in part by an ESRC CASE Award (PTA-033-2003-00046 with Eli Lilley Ltd)
data from the participants included in this paper contributed to the IMAGE project
1
Abstract
and motivational deficits each affecting some but not other patients. We explore
Method: Nine tasks designed to tap three domains (inhibitory control, delay aversion
from controls on all factors. For ADHD patients the co-occurrence of inhibitory,
temporal processing and delay-related deficits was no greater than expected by chance
neuropsychological sub-groupings.
ADHD and initial support for a triple pathway model. The findings need to replicated
in larger samples.
2
Neuropsychological studies of Attention Deficit/ Hyperactivity Disorder (ADHD)
e.g, inhibitory 3 and working memory (WM 4) deficits), non-executive deficits (e.g.
even the most robust neuropsychological effects are only moderate in size (e.g. .3 to
.6 Cohen’s d; 2) and fall short of the level required for diagnosis. 9 For example, Nigg
et al. 10 found only 30% of patients with deficits on at least three tasks in a large EF
battery. This pattern of limited associations across distinct domains highlights the
this heterogeneity as two, more or less, independent patterns of deficit each affecting
circuits and linked to altered signalling of delayed rewards, manifest as delay aversion
(DAv 11,15). Clinical and pre-clinical studies provide support for this model 16-20 (but
see 21). However many patients appear unaffected by either DAv or I-EDF. 17 This
paper is the first to explore whether temporal processing deficits (TPD) in ADHD
plausible as MRI suggests that although TPD may share neural components (i.e.,
basal ganglia;22,23) with I-EDF and DAv, it is also distinctive in some ways (i.e.,
cerebellum 24). It is clinically plausible as ADHD children have shown TPD across a
range of timing tasks. 25-31 Results on motor timing are less consistent. 29, 32-34 fMRI
ADHD has a complex causal structure with both genetic and environmental
3
deficits (i.e., endophenotypes 38,39) will be correlated within families and levels of
specific pathways these familial effects should ‘breed true’ - e.g., siblings of ADHD
children with I-EDF should also show I-EDF. Evidence of familial correlation and
co-segregation has been reported for I-EDF 40,41, TPD 28,42,43 and DAv.15 Here we
Performance on the I-EDF tasks (i.e., Stop Signal, Go-No-Go and a Stroop like
response interference tasks) is inter-correlated and associated with ADHD. 3 For DAv
tasks (i.e., Maudsley Index of Delay Aversion; Delayed Frustration Task; Delayed
Reaction Time Task) correlations are smaller. 44 For TPD we assessed time
included a simple measure of WM (i.e., WISC digit span). Previous reports suggest
that TPD implicates WM problems 25 (but see 46) and I-EDF and WM are closely
principal components; (b) significant case-control differences in each domain; (c) sub-
groups of ADHD individuals affected by only one deficit; (d) domain specific familial
domains will show distinctive patterns of associations in terms of: IQ and oppositional
4
common role for the cerebellum in reading disorder and ADHD in children with TPD
49
(but see 50).
Methods
Participants
and 50 non-ADHD controls (M = 12.15 years, SD = 2.25 years) were included in the
key analyses. Six siblings had ADHD and were excluded from the case-control and
familiality analyses. Cases (aged between 6 and 17 years) with an existing full clinical
diagnosis of ADHD were included in IMAGE if they also fulfilled criteria for a
research diagnosis (see below) and had an IQ of at least 70. Patients were excluded if
they had a history of clinically significant depression and anxiety or other major
mental health problems (e.g., autism, epilepsy). ODD or CD was not an exclusion
criteria. The research diagnostic protocol is described in detail elsewhere (see 51).
Probands and those siblings with T scores > 63 on the Conners’ ADHD subscales
were administered the Parental Account of Childhood Symptoms (PACS 52): a semi-
receive a research diagnosis, children had to; (i) have sufficient PACS symptoms, (ii)
meet the PACS criteria for impairment and (iii) display at least one symptom in both
Conners. Control children attended local schools. Parent and teacher versions of the
SDQ 53 confirmed that 15 of the 65 controls initially recruited, scored above the
5
preponderance of females controls (gender χ2(1) = 9.37, p < .01). Table 1 reports the
A) I-EDF tasks
i) Stop-Signal Task 54 : On six blocks (the first 2 blocks were practice) of 32 trials
their response when a auditory stop signal was presented (25% of trials). The go task
consisted of “X” and “O”, presented in the centre of the screen for 1000ms (ISI
2500ms). The interval between the go signal and stop tone varied to ensure
approximately a 50% success rate. The stop signal reaction time (SSRT) was
estimated by subtracting the mean stop signal latency from the mean correct go
ii) Go/No-Go task (GNG): On 100 trials participants responded as fast and accurately
as they could to “go” stimuli by pressing the left or right computer mouse button
inhibited their response when a double headed arrow (“no-go” stimulus) was
presented (25 % of trials). The probability of a correct inhibition was the main index
iii) Modified Stroop Task (MStroop 55). 100 trials of congruent or incongruent stimuli
were presented. Congruent stimuli (75 % of trial) were green left or right pointing
arrows) and participants had to press a left or right computer mouse button indicating
the direction of the green arrows. Incongruent stimuli (25% of trials) were red, left or
right pointing arrows and participants had to press the opposite mouse button to that
6
indicated by the red arrows. Probability of inhibitions on the incongruent trials was
B) DAv tasks
i) Maudsley’s Index of Childhood Delay Aversion (MIDA 56): This is a game like
computer-based choice delay task. 12 Individuals choose to either wait for 2 seconds
and shoot one spaceship (1 point) or to wait for 30 seconds to shoot two spaceships (2
points). There was no post-reward delay period. There were 15 trials. Children were
told that they would get either one or two rewards based on their performance,
although the specific cut-off was not revealed. Rewards were stationary items chosen
by participants at the end of the session. The percentage of large delayed choices
ii) Delay Frustration (DeFT 57): A series of simple math questions (55 trials) were
buttons on a box. On most trials response was immediately followed by the next trial.
trials). On eight distractor trials the delay period varied from 3 to 10 seconds. The
mean total duration of responding per second of delay in the 20 second trials was the
dependent variable. For the present analysis we used responses during the first 10
seconds as analysis showed that participants’ responses during these two periods may
be reflect different processes (i.e. early responses frustration and later responses
persistence).
iii) Delay Reaction Time (DRT 58): On 12 trials (and 4 practice trials) a stimulus (either
a left or a right green arrow) appeared on the centre of the computer screen for either 3
or 20 seconds. The screen then turned blank and the participants responded as quickly
and accurately as possible to the disappearance of the stimulus, by pressing the left or
7
right mouse button. A DRT index was calculated by subtracting the mean RT score for
the two delay levels of the DRT task from the RT on a simple RT condition with no
C) TPD tasks
i) Tapping 45: This is an auditory computerised task. An auditory tone was presented
every 1200 ms and the child had to tap along at the same pace by pressing a response
button (15 cued trials). In 41 uncued trials, in which the tone was not present, the child
was asked to continue tapping at the previously cued rate. The main index of the task is
the variability of tapping on uncued trials - calculated as the within subject standard
deviation.
ii) Duration Discrimination 25: Participants were presented with two unfilled intervals
(target and comparison), each defined by two brief tones (50ms, 1000Hz) at the
beginning and end. The target interval of 400ms was randomly presented as either the
first or second duration. The comparison interval was always longer than 400ms and
was adjusted up or down in 10ms increments depending upon the accuracy of the
participant’s responses. The target and comparison interval were separated by 800 ms
and the inter-trial interval was 1000 ms. Participants were instructed to press the left
button on a response box if they thought the first tone was longer and the right button of
a response box if they thought the second tone was longer. An up-down-transformed-
response adaptive procedure was used to track 80% accuracy. 59 The procedure stopped
after 6 reversals of direction. The average of the last 5 reversal values was the
dependent measure. 25
iii) Time anticipation 45: In this game like task participants anticipated when a visual
stimulus would reappear. The child beamed oxygen over to a spaceship to save the
crew. In block 1 the anticipation interval was 400ms and in the block 2 it was 2000ms.
8
In each block the ally spaceship was visible for the first 10 trials and for the remaining
16 trials participants were asked to press a button to anticipate when it would arrive
(i.e., 400 or 2000ms). The participant was given feedback after every trial. The mean
percentage of total early responses (i.e., made before the ally arrived) was the
dependent measure.
Other measures
Working memory: Forward and backward digit span subscales from the WISC-III 60
were administered. The level at which the participant failed to correctly repeat numbers
on two consecutive trials at one level of difficulty was the dependent measure.
IQ: The vocabulary and block design subtests from the WISC-III 61 were used to
Reading: The TOWRE test of word reading efficiency 61 was administered. The
combined score from the two sub-scales (sight word efficiency and phonetic decoding
Procedure
Children with ADHD were off-medication at least 48 hours before testing. Probands
and siblings were tested by different researchers. Full testing took between 2 to 2 1/2
hours. The tasks within each neuropsychological domain (e.g., MIDA, DeFT and
DRT for DAv) were administered in the same order. The three neuropsychological
constructs (i.e., DAv, I-EDF, TPD) were presented in counterbalanced order. Children
rested during short breaks. The experimenter remained with each child throughout the
task. At the end of the session all children received a £5 voucher for participation in
addition to any MIDA rewards. Ethical approval was received from the University of
Southampton, School of Psychology ethics committee and the local NHS medical
9
Analytical strategy
(i) Principal components factor analysis was used to examine the structure
approach because this was the first analysis of its kind in the literature. To
probands and siblings could be compared all participants were included. Given
the correlation between age and performance (8 out of 9 were significant; r > -
was calculated using cut-offs based on the lowest 10 percent of scores in the
control group (11). We then examined the frequency with which individuals
ADHD and comorbid psychiatric problems, IQ and literacy was examined using
multiple regression.
comparisons of; (i) probands, unaffected siblings and controls and (ii) unaffected
10
Results
Correlations (Table 2) were in general larger within domains (Mean r =.22) than
between domains ( Mean r =.11). Correlation between putative I-EDF and TPD
measures were moderate. Correlations between putative DAv measures were weak
and non-specific. WM was associated with TPD measures and DRT and MStroop. For
the principle components analysis there were four factors with eigen values greater
than one (Table 3). Component one (17.25% variance) had high loadings for SSRT,
GNG and MStroop only (factor labelled Inhibition). Component two (14.68%) had
high loadings for TPD items and WM (factor labelled Timing). The third and fourth
components both implicated delay-related tasks. Component three appeared to tap the
negative effect of imposed delay (12.95% of the variance) and was associated with
during time anticipation. A preference for the large delayed reward (MIDA), reduced
suggesting the productive use of delay. Given their differential loadings these
Children with ADHD had poorer scores on all components (Table 4). No gender or
effects were found. The effects sizes (Cohen’s d) were .76 for Inhibition; .79 for
Delay-Negative; .67 for Timing and .51 for Delay Positive. Effects remained
F(1,116) = 6.67, p<.05; Delay Positive: F(1,116) = 4.18, p<.05) except for Timing
11
(F(1,116) = 3.60, p=.06). The presence of ODD had no effect (Inhibition: F(1,67) =
3.24, p=.07; Timing: F(1,67) = 0.30, p=.86; Delay-Negative: F(1,67) = 0.07, p=.78;
Figure 1 presents a Venn diagram showing the proportion of ADHD cases who met
threshold for deficits in the Timing, Inhibition and the Delay domains. In order to
simplify the presentation of this categorical data we added those who met threshold
for Delay-Positive and Delay-Negative and included them in one group. Seventy one
percent of cases displayed some neuropsychological deficit. Timing was the most
common deficit and Inhibition the least. Overlap between the different deficits was
uncommon and never greater than expected by chance (Inhibition and Delay –
χ2=0.14; p=.91; Inhibition and Timing - χ2=2.75; p=.10; Timing and Delay - χ2=1.00;
p=.32) with over 70 percent of those affected showing just one deficit. Inhibition
showed the smallest proportion of ‘pure’ cases (31% compared to 56% for Timing
and 60% for any Delay). The three deficit categories were introduced as predictors
into multiple regression models with IQ, ODD and literacy as outcomes. Delay
deficits were associated with IQ (β=-.28; p=.012) and literacy (β=-.33; p=.002) while
Timing was significantly associated with literacy only (β=-.40; p<0.001). When IQ
was added as a predictor the effects of Delay (β=-.17; p=.11) but not Timing on
literacy (β=-.30; p=.004) were significantly reduced. Inhibition was associated with
ODD (p>.3).
12
The unaffected sibling scores were intermediate between probands and controls scores
(Table 4). Probands and siblings were impaired compared to controls on Timing,
Delay-Negative and Delay Positive. For Inhibition probands were more impaired than
both unaffected siblings and controls. Trends analysis suggested that siblings’ were
intermediate relative to ADHD probands and control cases except for Delay-Positive.
r=.009, p=.94). Multiple regressions with proband scores in the four domains as the
predictor and sibling scores on each domain as the outcome (forward stepwise
procedure) showed that these associations were homotypic in nature; i.e., sibling
domain scores were specifically predicted only by probands’ scores for Inhibition (R2
=.09; F(1,63)=6.94; p<.05) and Timing (R2 =.11; F(1,63)=8.46; p<.01) respectively.
(t(63)=2.71, p<.01) but showed no other deficits (Timing; t(63)=0.04, p=.96; Delay-
Negative; t(63)=-1.21, p=.23; Delay Negative t(63)=0.36, p=.71; Table 5). Likewise,
siblings whose probands had Timing deficits had higher levels of these themselves
familial effects were evident for the delay factors (Table 5).
Discussion
different degrees in different domains. 12,21 These results extend and refine the dual
13
pathway model of ADHD heterogeneity. 12-14 Our data provides the first evidence that
Timing, Inhibition and Delay deficits in ADHD are dissociable from each other and
that substantial sub-groups of patients are affected in only one domain. The results
therefore run counter to a recent suggestion that timing deficits may be the underlying
core of the diverse range of problems seen in ADHD. 35 The strongest evidence for
familial effects came for Inhibition 63-67,40 and Timing. 41-43,28 Indeed siblings of
probands with impairment in one of these domain also tended also to have problems
in these domains: Inhibition and Timing deficits in ADHD breed true. Consistent with
the previous inconsistent literature 68,69,63 evidence was much weaker for the familial
basis of the Delay components: While levels of sibling impairment were intermediate
between controls and probands, sibling correlations were weak and there was no
association. Timing was associated with reading problems. Delay problems were
associated with low IQ and reading problems - though reading effects were mediated
by IQ.
processes in ADHD are seen as a single overarching construct. In fact, in the present
study, two components were found. The first associated with negative performance in
the face of imposed delay (i.e., DRT and DeFT), including time anticipation. The
second was associated with performance that depended on a commitment to wait for a
desired outcome or persist in a task even when this was not imposed (e.g., MIDA and
working memory). Clearly much more work is required to establish these as separate
DAv single factor consisting of loosely associated test scores. When set alongside
14
tasks tapping other domains, it becomes clear that the situation is more complex than
originally thought.
The current study had a number of limitations. First, the sample used was small for
the examination of sub-groups and in future much larger studies using measures from
multiple domains are required to replicate these findings. The current analysis should
deficits as both moderators of treatment effects and novel putative treatment targets.
In terms of (i), assuming they can be replicated in larger samples and validated using
clinical outcomes the current results would provide some support for the
between, for instance, Inhibitory and Timing ADHD subtypes. In terms of (ii), recent
studies suggest that cognitive training on executive tasks may have efficacy as a
treatment for ADHD. 71 The current results highlight the possibility that such training
will be more effective if it is targeted and tailored for children with problems in the
executive domain (e.g., I-EDF), while training that strengthens temporal processing or
delay-related functions might be more effective for patients with these types of
deficits.
15
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Table 1: Sample and clinical characteristics of ADHD probands, their unaffected siblings and typical control cases by age.
N = 48 N = 23 N = 40 N = 25 N = 29 N = 21
Male % 85.4 82.6 55 48 58.6 76.2 16.40e <.001c
Age 10.69 (1.41) 14.81 (1.09) 9.45 (2.23) 14.68 (1.22) 10.90 (2.12) 13.89 (0.83) 1.16 .31
WISC-III N = 48 N = 23 N = 40 N = 25 N = 29 N = 21
Vocabulary 8.77 (2.85) 8.61 (2.33) 9.00 (2.78) 8.68 (2.61) 10.31 (3.56) 9.14 (3.30) 2.30 .10
Block Design 9.42 (2.79) 9.13 (1.91) 9.85 (3.15) 9.40 (2.21) 10.97 (2.32) 9.81 (2.80) 2.85 .06
Full 94.60 (13.66) 93.21 (9.53) 96.51 (14.42) 94.24 (11.45) 103.91 (14.31) 96.85 (15.74) 3.90 <.05b
TOWRE N = 46 N = 22 N = 38 N = 23 N = 24 N = 21
Total 96.22 (21.40) 88.45 (17.13) 100.61 (20.76) 99.61 (21.93) 108..25 (16.81) 96.29 (14.32) 3.91 <.02b
Parent SDQ N = 48 N = 23 N = 40 N = 25 N = 29 N = 21
Hyperactivity 8.31 (1.74) 8.26 (2.05) 3.13 (3.05) 2.20 (2.04) 2.14 (1.72) 1.76 (1.64) 164.45 <.001c
Total 23.27 (6.55) 20.61 (5.68) 10.53 (8.71) 8.64 (7.59) 6.66 (4.79) 6.00 (3.91) 101.04 <.001c,d
Teacher SDQ N = 38 N = 18 N = 36 N = 16 N = 24 N = 13
Hyperactivity 6.74 (2.86) 6.94 (2.36) 3.11 (2.42) 4.50 (2.73) 1.29 (1.51) 1.46 (1.05) 63.82 <.001c,d
Total 14.61 (7.27) 15.56 (7.26) 6.64 (5.48) 11.31 (8.17) 3.63 (3.62) 3.69 (2.68) 38.79 <.001c,d
25
b = ADHD probands were significantly different from Controls
c = ADHD probands were significantly different from Siblings and Controls
d = Siblings were significantly different from Controls
e = χ2
26
Table 2: Correlations between putative Inhibitory Control, Delay Aversion, Temporal Processing and
Working Memory indices (age adjusted)
1 2 3 4 5 6 7 8 9
Delay related measures
1 MIDA
2 DeFT .01
3 DRT -.18* .17*
Inhibitory control measures
4 SSRT -.11 .08 .05
5 GNG -.01 -.21** -.08 -.29***
6 MStroop .20** -.22** -.12 -.19** .56***
Temporal processing measures
7 Tapping -.05 .01 -.02 .14* -.07 -.16*
8 Discrimination -.14 .18* .08 .20* -.16* -.13 .23**
9 Anticipation -.04 .12 .19* .03 -.14 -.14 .15* .26**
Working memory measures
10 Digit Span .13 .07 -.16* -.09 .03 .14* -.15* -.23** -.13
Note: DeFT = Delay Frustration Task; DRT = Delay Reaction Time; GNG = Go-No-Go; MIDA =
Maudsley’s Index of Delay Aversion; MStroop = Modified Stroop; SSRT = Stop Signal Reaction
Time; *=p<.05; **=p<.01; ***=p<.001.
27
Table 3: Component Structure of Inhibitory Control, Delay Aversion, and Temporal Processing
measures
Construct Measures Component
Inhibition Timing Delay-Negative Delay-Positive
Note: DeFT = Delay Frustration Task; DRT = Delay Reaction Time; GNG = Go-No-Go; MIDA =
Maudsley’s Index of Delay Aversion; MStroop = Modified Stroop; SSRT = Stop Signal Reaction
Time.
28
Table 4: Inhibition, Timing and Delay-related factor scores comparison between ADHD probands vs. unaffected siblings vs. control cases
ANOVA ANOVA
ADHD probands Unaffected Siblings Controls ADHD vs. Controls ADHD vs. Siblings vs. Controls Trends (p-va
Male Female Male Female Male Female Status (S) Gender (G) S x G S G SxG Post-hoca Linear Q
N=60 N=11 N=34 N=31 N=33 N=17
Inhibition F(1,117) F(1,117) F(1,117) F(2,180) F(1,180) F(2,180)
-0.29 (0.97) -0.46 (1.08) 0.32 (1.15) -0.28 (0.90) 0.22 (1.03) 0.83 (0.81) 17.74*** 1.00 3.24 9.47*** 0.53 2.28 1 > 2, 3 .000
Timing F(1,117) F(1,117) F(1,117) F(2,180) F(1,180) F(2,180)
0.30 (1.20) -0.20 (0.82) 0.15 (1.04) -0.10 (0.87) -0.32 (0.61) -0.55 (0.55) 5.30* 3.03 0.42 3.85* 4.19* 0.26 1, 2 > 3 .001
DN F(1,117) F(1,117) F(1,117) F(2,180) F(1,180) F(2,180)
0.30 (1.11) 0.006 (0.87) 0.12 (0.85) 0.04 (0.93) -0.40 (0.59) -0.47 (0.57) 8.71** 0.84 0.32 4.62* 4.03* 1.06 1, 2 > 3 .000
DP F(1,117) F(1,117) F(1,117) F(2,180) F(1,180) F(2,180)
-0.03 (0.93) -0.32 (0.92) 0.05 (1.06) -0.37 (0.92) 0.37 (0.90) 0.46 (0.90) 8.51** 0.23 0.86 5.93** 1.71 1.03 1, 2 > 3 .007
Note: DN = Delay Negative; DP = Delay Positive; S.D. = Standard Deviation; 1 = Proband; 2 = Sibling; 3 = Control
* = p < .05; ** = p < .01; *** = p < .001
a
> indicates that the group(s) on the left of the symbol had worse performance
29
Table 5: Specificity of familial effects – Comparison between siblings of probands with and without
neuropsychological impairment in each domain.
30
Figure 1: The proportion of ADHD cases (N=77) with Inhibiton, Timing and delay-
related problems and their degree of co-occurrence.
31