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Beyond the dual pathway model: Evidence for the dissociation of timing,

inhibitory and delay-related impairments in Attention Deficit/Hyperactivity

Disorder.

Edmund Sonuga-Barke PhD, Paraskevi Bitsakou PhD and Margaret Thompson MD

Professor Sonuga-Barke and Drs Bitsakou and Thompson are with the Developmental

Brain Behaviour Laboratory at the School of Psychology, University of Southampton.

Professor Sonuga-Barke is also with the Department of Experimental Clinical &

Health Psychology at Ghent University.

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

participants’ recruitment and administration of the PACS; Rebecca Barrett, Anna

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)

to Edmund Sonuga-Barke & Margaret Thompson for Paraskevi Bitsakou. Clinical

data from the participants included in this paper contributed to the IMAGE project

(Faraone; NIH grand R01 MH62873-01A1).

Correspondence to Edmund Sonuga-Barke, Institute for Disorder of Impulse and

Attention, School of Psychology, University of Southampton, Highfield,

Southampton, SO17 1BJ, UK, e-mail: [email protected]

1
 Abstract

Objectives: The dual pathway model explains neuro-psychological heterogeneity in

Attention Deficit/Hyperactivity Disorder (ADHD) in terms of dissociable cognitive

and motivational deficits each affecting some but not other patients. We explore

whether deficits in temporal processing might constitute a third dissociable

neuropsychological component of ADHD.

Method: Nine tasks designed to tap three domains (inhibitory control, delay aversion

and temporal processing) were administered to ADHD probands (n=71; ages 6 to 17

years), their siblings (n=71; 65 unaffected by ADHD) and a group of non-ADHD

controls (n=50). IQ and working memory were measured.

Results: Temporal processing, inhibitory control and delay-related deficits

represented independent neuropsychological components. ADHD children differed

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

with substantial groups of patients showing only one problem. Domain-specific

patterns of familial co-segregation provided evidence for the validity of

neuropsychological sub-groupings.

Conclusion: The current results illustrate the neuropsychological heterogeneity in

ADHD and initial support for a triple pathway model. The findings need to replicated

in larger samples.

Key words: ADHD, Delay Aversion, Heterogeneity, Inhibitory Control, Timing.

2
Neuropsychological studies of Attention Deficit/ Hyperactivity Disorder (ADHD)

implicate a broad range of processes. 1 These include executive dysfunction ((EDF 2)

e.g, inhibitory 3 and working memory (WM 4) deficits), non-executive deficits (e.g.

perception5; memory 6; timing 7) and alterations in motivational processes. 8 However,

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

neuropsychological heterogeneity in ADHD. 11 The dual pathway model 12-14 explains

this heterogeneity as two, more or less, independent patterns of deficit each affecting

some ADHD patients: One grounded in dorsal fronto-striatal dysregulation mediated

by inhibitory based EDF (I-EDF), the other underpinned by ventral fronto-striatal

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

represent a dissociable third neuropsychological ‘pathway’. This is biologically

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

confirms alterations within key components of temporal processing circuits in ADHD.

35

ADHD has a complex causal structure with both genetic and environmental

factors implicated. 36,37,10 Where they mediate genetic effects, neuropsychological

3
deficits (i.e., endophenotypes 38,39) will be correlated within families and levels of

deficits in unaffected family members will be intermediate between their ADHD

relatives and unrelated controls. Furthermore, if different endophenotypes mediate

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

explore this further.

We adopted a multivariate methodology with three tasks chosen for each

neuropsychological domain to improve measurement reliability and allow the

underlying latent structure of neuropsychological deficits to be explored.

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

discrimination, reproduction and motor synchronization. 45, 25 Our battery also

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

associated processes 47 (but see 48).

We predicted; (a) that neuropsychological domain will form independent

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

effects – neuropsychological deficits will breed true and; (e) neuropsychological

domains will show distinctive patterns of associations in terms of: IQ and oppositional

defiant disorder (ODD). Literacy was included because of the possibility of a

4
common role for the cerebellum in reading disorder and ADHD in children with TPD
49
(but see 50).

Methods

Participants

Seventy-one families with an ADHD child participated in the Southampton arm of

IMAGE. 51 Seventy-one ADHD probands with a combined type diagnosis (M = 12.03

years, SD = 2.34 years), 65 unaffected siblings (M = 11.46 years, SD = 3.19 years)

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-

structured clinical interview (inter-rater reliability ranging from .79 to .96) 53 A

standardized algorithm was applied to derive the 18 DSM-IV ADHD items. To

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

the hyperactive/impulsive and inattentive domains (i.e., a rating of 2 or 3) on the

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

borderline cut-offs for hyperactivity/impulsivity and were excluded. This left a

5
preponderance of females controls (gender χ2(1) = 9.37, p < .01). Table 1 reports the

background and clinical characteristics for the three groups. .

Insert Table 1 about here

Tasks & Measures

For more detailed descriptions see Bitsakou et al. 3,44

A) I-EDF tasks

i) Stop-Signal Task 54 : On six blocks (the first 2 blocks were practice) of 32 trials

participants responded to ‘go’ stimuli by pressing a response button and inhibited

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

response time in each block.

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

indicating the direction of a green left or right-pointing arrow respectively and

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

of the GNG task.

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

the dependent variable (MStroop).

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

made is the dependent variable (MIDA).

ii) Delay Frustration (DeFT 57): A series of simple math questions (55 trials) were

presented on a computer. Participants selected from four possible answers by pressing

buttons on a box. On most trials response was immediately followed by the next trial.

On a minority of trials access to the next question was delayed by 20 seconds (8

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

delay (see 44 for details).

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

estimate full scale IQ. 62

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

efficiency) was used as a reading ability index.

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

ethics committee. Participants and parents gave written informed consent.

9
Analytical strategy

(i) Principal components factor analysis was used to examine the structure

of associations between the tasks. We chose an exploratory over a confirmatory

approach because this was the first analysis of its kind in the literature. To

maximize statistical power and allow a common metric by which controls,

probands and siblings could be compared all participants were included. Given

the correlation between age and performance (8 out of 9 were significant; r > -

.24), test scores were age-adjusted using standard regression procedures.

(ii) Factor scores (item to factor loadings as weightings) were calculated

and used to estimate case-control differences using ANOVA. We checked

whether case-control differences were due to group differences in IQ and ODD.

(iii) The number of ADHD patients (including affected siblings) with a

deficit in each of the neuropsychological domains identified in the factor analysis

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

showed one and not another types of deficit.

(iv) The association between these neuropsychological groupings in the

ADHD and comorbid psychiatric problems, IQ and literacy was examined using

multiple regression.

(v) Familiality was examined through inter-sibling correlations and

comparisons of; (i) probands, unaffected siblings and controls and (ii) unaffected

siblings of probands with and without domain specific deficit.

Insert Table 2 and Table 3 about here

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

poorer DRT performance, increased DeFT responding and premature responding

during time anticipation. A preference for the large delayed reward (MIDA), reduced

DRT and better WM loaded on a fourth component (2.68% of the variance) –

suggesting the productive use of delay. Given their differential loadings these

components were labelled Delay-Negative and Delay-Positive respectively.

Insert Table 4 about here

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

significant controlling for IQ (Inhibition: F(1,116) = 17.53, p<.001; Delay Negative:

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;

Delay-Positive: F(1,67) = 0.001, p=.99).

Insert Figure 1 about here

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

neither cognitive outcomes (p>.3). No deficit predicted the presence of comorbid

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.

In contrast proband-sibling correlations were significant only for Inhibition (r=.31,

p=.01) and Timing (r=.34, p=.005; Delay-Negative- r=-.08, p=.48; 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.

Furthermore, siblings of probands with Inhibition deficits were more impaired on

Inhibition themselves than siblings of probands without Inhibition deficits

(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

(t(63) = -2.17, p<.05) but not Inhibition, Delay-Negative or Delay Positive

(t(63)=0.14, p=.88; t(63)=-0.46, p=.64; t(63)=-.025, p=.80 respectively). No specific

familial effects were evident for the delay factors (Table 5).

Insert Table 5 about here

Discussion

ADHD is neuropsychologically heterogeneous, with different individuals affected to

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

evidence of co-segregation. Finally, there was a degree of domain specific

association. Timing was associated with reading problems. Delay problems were

associated with low IQ and reading problems - though reading effects were mediated

by IQ.

Our findings challenge the delay aversion model 70 in which delay-related

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

components. Our prior analysis of performance on the “DAv” tasks 44 supported a

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

be seen as exploratory and illustrative. Second, measurement of working memory and

intelligence was limited.

From a clinical perspective highlighting the neuropsychological heterogeneity of

ADHD encourages us to explore; (i) the possibility of the existence of

neuropsychological subtypes and (ii) the significance of specific neuropsychological

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

establishment of neuropsychological sub-types in ADHD with distinctions drawn

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
References

1. Nigg J T. Neuropsychologic theory and findings in attention-

deficit/hyperactivity disorder: the stat of the field and salient challenges for the

coming decade. Biol Psychiatry. 2005;57:1424-1435.

2. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the

executive function theory of attention-deficit/hyperactivity disorder: a meta-

analytic review. Biol Psychiatry. 2005;57:1336-1346.

3. Bitsakou P, Psychogiou L, Thompson M, Sonuga-Barke E. Inhibitory Deficits

in Attention Deficit Hyperactivity Disorder are Independent of Basic

Processing Efficiency and IQ. J Neur Trans. 2008;115:261-268.

4. Rapport MD, Bolden J, Kofler MJ, Sarver DE, Raiker JS, Alderson RM.

Hyperactivity in boys with attention-deficit/hyperactivity disorder (ADHD): a

ubiquitous core symptom or manifestation of working memory deficits? J Abn

Child Psychol. 2009;37: 521-534.

5. Banaschewski T, Ruppert S, Tannock R, Albrecht B, Becker A, Uebel H,

Sergeant JA, Rothenberger A. Colour perception in ADHD. J Child Psychol

Psychiatry. 2006;47: 568-572.

6. Coghill DR, Rhodes SM, Matthews K: The neuropsychological effects of

chronic methylphenidate on drug-naïve boys with attention-

deficit/hyperactivity disorder. Biol Psychiatry. 2007;62: 954-962.

7. Toplak ME, Dockstader C Tannock R. Temporal information processing in

ADHD: findings to date and new methods. J Neurosci Methods. 2006;151:15-

29.

16
8. Luman M, Oosterlaan J, Sergeant, J A. The impact of reinforcement

contingencies on AD/HD: a review and theoretical appraisal. Clin Psychol

Rev. 2005;25:183-213.

9. Sergeant JA, Willcutt E, Nigg J. How clinically functional are executive

function measures of ADHD? In Shaffer D, Leibenluft E, Rohde LA,

Sirovatka P, Regier DA, editors. Externalizing Disorders of Childhood:

Refining the Research Agenda for DSM-V. Arlington, VA: Am Psychiatric

Assoc; 2007.

10. Nigg JT, Willcutt EG, Doyle AE, Sonuga-Barke EJS. Causal heterogeneity in

attention-deficit/hyperactivity disorder: Do we need neuropsychologically

impaired subtypes? Biol Psychiatry. 2005;57:1224-1230.

11. Sonuga-Barke EJ, Sergeant J, Nigg J., Willcutt E. Executive dysfunction and

delay aversion in ADHD: Nosological and diagnostic implications. Child

Adolesc Psychiatr Clin N Am. 2008;17:367-384.

12. Sonuga-Barke EJ. Psychological heterogeneity in AD/HD - a dual pathway

model of behaviour and cognition. Behav Brain Research. 2002;130:29-36.

13. Sonuga-Barke EJ. The dual pathway model of AD/HD: an elaboration of

neuro-developmental characteristics. Neurosci Biobehav Rev. 2003;27:593-

604.

14. Sonuga-Barke EJ. Causal models of Attention-Deficit/Hyperactiviy Disorder:

from common simple deficits to multiple developmental pathways. Biol

Psychiatry. 2005;57:1231-1238.

15. Marco R, Miranda A, Schlotz W, Melia A, Mulligan A, Müller U, et al. Delay

and choice in ADHD: A test of the delay aversion hypothesis. Neuropsychol.

2009;23:367-380.

17
16. Solanto MV, Abikoff H, Sonuga-Barke E, Schachar R, Logan GD, Wigal T, et

al. The ecological validity of delay aversion and response inhibition as

measures of impulsivity in AD/HD: a supplement to the NIMH multimodal

treatment study of AD/HD. J Abn Child Psychol. 2001;29:215-228.

17. Sonuga-Barke EJ, De Houwer J, De Ruiter K, Ajzenstzen M, Holland S.

AD/HD and the capture of attention by briefly exposed delay-related cues:

evidence from a conditioning paradigm. J Chid Psychol Psychiatry.

2003;44:1-11.

18. Thorell LB. Do delay aversion and executive function deficits make distinct

contributions to the functional impact of ADHD symptoms: A study of early

academic skill deficits. J Child Psychol Psychiatry. 2007;14:1061-1070.

19. Campbell SB, von Stauffenberg C. Delay and inhibition as early predictors of

ADHD symptoms in third grade. J Abn Child Psycho. 2009;37:1-15.

20. Van den Bergh FS, Bloemarts E, Groenink L, Olivier B, Oosting RS.Delay

aversion: effects of 7-OH-DPAT, 5-HT1A/B-receptor stimulation and D-

cycloserine. Pharmacolocy, Biochemistry, and Behavior. 2006;85:736-743.

21. Wåhlstedt C, Thorell LB, Bohlin. Heterogeneity in ADHD: neuropsycholgical

pathways, comorbidity and symptom domain. J Abn Child Psychol.

2009;37:551-564.

22. Koch G, Brusal L, Carrillo F, Lo Gerfo E, Torriero S, Oliveri M, Mir P,

Caltagrone C, Stanzione P. Cerebellar magnetic stimulation decreases-inducd

dyskinesias in Parkinson disease. Neurology. 2009;73:113-119.

23. Shih LY, Kuo WJ, Yeh TC, Tzeng OJ, Hsieh JC. Common neural mechanisms

for explicit timing in the sub-second range. Neuroreport. 2009;20:897-901.

18
24. Neufang S, Fink GR, Herpetz-Dahlmann B, Willmes K, Konrad K.

Developmental changes in neural activation and psychphysiological

interaction patterns of brain regions associated with interference control and

time perception. Neuroimage. 2008; 43:399-409.

25. Toplak ME, Rucklidge JJ, Hetherington R, John SCF, Tannock R. Time

perception deficits in attention-deficit/hyperactivity disorder and comorbid

reading difficulties in child and adolescent samples. J Child Psychol

Psychiatry. 2003;44:888-903.

26. Barkley RA, Koplowitz S, Anderson T, McMurray MB. Sense of time in

children with ADHD: effects of duration, distraction, and stimulant

medication. J Internat Neuropsychol Soc. 1997;3:359-369.

27. Barkley RA, Murphy KR, Bush T. Time perception and reproduction in young

adults with attention deficit hyperactivity disorder. Neuropsychol.

2001;15:351-360.

28. Rommelse NNJ, Oosterlaan J, Buitelaar J, Faraone SV, Sergeant JA. Time

reproduction in children with ADHD and their nonaffected siblings. J Am

Child Adolesc Psychiatry. 2007;46:582-590.

29. Rubia K, Noorloos J, Smith A, Gunning B, Sergeant J. Motor timing deficits

in community and clinical boys with hyperactivity behavior: the effect of

methylphenidate on motor timing. J Abn Child Psychol. 2003;31:301-313.

30. Smith A, Taylor E, Rogers JW, Newman S, Rubia K. Evidence for a pure time

perception deficit in children with ADHD. J Child Psychol Psychiatry.

2002;43:529-542.

31. Yang B, Chan RCK, Zou X, Jing J, Mai J, Li J. Time perception deficit in

children with ADHD. Brain Res. 2009;1170:90-96.

19
32. Ben-Pazi H, Gross-Tsur V, Bergman H, Shalev RS. Abnormal rhythmic motor

response in children with attention-deficit-hyperactivity disorder. Dev

Medicine Child Neurol. 2003;45:743-745.

33. Rommelse NNJ, Altink ME, Oosterlaan J, Beem L, Buschgens CJM, Buitelaar

J, Sergeant JA. Speed, variability, and timing on motor output in ADHD:

which measures are useful for endophenotypic research? Behav Gen.

2008;38:121-132.

34. Rubia K, Taylor A, Taylor E, Sergeant J. Synchronization, anticipation, and

consistency in motor timing of children with dimensionally defined attention

deficit hyperactivity behavior. Percept Mot Skills. 1999;89:1237-1258.

35. Rubia K, Halari R, Christakou A, Taylor E. impulsiveness as a timing

disturbance: neurocognitive abnormalities in attention-deficit hyperactivity

disorder during temporal processes and normaliztion iwht methylphenidate.

Philosophical transactions of the Royal Society of London. Series B, Biol Sci.

2009;364(1525): 1919-1931.

36. Coghill D, Nigg J, Rothenberger A, Sonuga-Barke EJ, Tannock R. Whither

causal models in the neuroscience of ADHD? Dev Sci. 2005;8(2):105-114.

37. Swanson JM, Kinsbourne M, Nigg J, Lamphear B, Stefanatos GA, Volkow N,

Taylor E, Casey BJ, Castellanos FX, Wadhwa PD. Etiologic subtypes of

attention-deficit/hyperactivity disorder: Brain imaging, molecular genetic and

environmental factors and the dopamine hypothesis. Neuropsychol Rev.

2007;17:39-59.

38. Gottesman II, Gould TD. The endophenotype concept in psychiatry:

Etymology and strategic intentions. Am J Psychiatry. 2003;160:636-645.

20
39. Waldman ID. Statistical approaches to complex phenotypes: evaluating

neuropsychological endophenotypes for attention-deficit/hyperactivity

disorder. Biol Psychiatry. 2005;57:1347-1356.

40. Schachar RJ, Crosbie J, Barr CL, Ornstein TJ, Kennedy J, Malone M, Roberts

W, Ickowicz A, Tannock R, Chen S, Pathare T. Inhibition of motor responses

in siblings concordant and discordant for attention deficit hyperactivity

disorder. Am J Psychiatry. 2005;162:1076-1082.

41. Rommelse NNJ, Altink ME, Oosterlaan J, Buschgens CJM, Buitelaar J,

Sergeant JA. Support for an independent familial segregation of executive and

intelligence endophenotypes in ADHD families. Psychol Med. 2008;38:1595-

1606.

42. Himpel S, Banaschewski T, Gruttner A, Becker A, Heise A, Uebel H,

Albrecht B, Rothenberger A, Rammsayer T. Duration discrimination in the

range of milliseconds and seconds in children with ADHD and their

unaffected siblings. Psychol Med. 2009;6:1-7.

43. Slaats-Willemse D, de Sonneville L, Swaab-Barneveld H, Buitelaar J. Motor

flexibility problems as a marker for genetic susceptibility to ADHD. Biol

Psychiatry. 2005;58:233-238.

44. Bitsakou P, Psychogiou L, Thompson M, Sonuga-Barke E. Delay aversion in

Attention Deficit/Hyperactivity Disorder (ADHD): An empirical investigation

of the broader phenotype. Neuropsychologia. 2009,47:446-456.

45. Toplak ME, Tannock R. Tapping and anticipation performance in attention

deficit hyperactivity disorder. Percept Mot Skills. 2005;100:659-675.

46. Carelli MG, Forman H, Mantyla T. Sense of time and executive functioning in

children and adults. Child Neuropsychol. 2008;14: 372-386.

21
47. Barkley RA. Behavioural inhibition, sustained attention, and executive

functions: Constructing a unifying theory of ADHD. Psychol Bull.

1997;121:65-94.

48. Engelhardt PE, Nigg JT, Carr LA, Ferreira F. Cognitive inhibition and

working memory in attention-deficit hyperactivity disorder. J Abn Psychol.

2008;117:591-605.

49. Kassalimis DS, Margarity M, Vlachos F. Cerebellar function, dyslexia and

articulation speed. Child Neuropsych. 2008;14:303-313.

50. Ramus F, Pidgeon E, Frith U. the relationship between motor control and

phonology in dyslexic children. J Child Psychol Psychiatry. 2003;44:712-722.

51. Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Anney R, et al. The

analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity

disorder: association signals in DRD4, DAT1 and 16 other genes. Mol

Psychiatry. 2006;11:934-953.

52. Taylor E, Sandberg G, Thorley G, Giles S. The epidemiology of childhood

hyperactivity. Maudsley Monograph No. 33. Oxford: Oxford University

Press;1991.

53. Goodman R. The Strengths and Difficulties Questionnaire: A research note. J

Child Psychol Psychiatry. 1997;38:581-586.

54. Logan GD, Schachar RJ, Tannock R. Impulsivity and inhibitory control.

Psychol Sci. 1997;8:60-64.

55. Hogan AM, Vergha-Khadem F, Kirkham FJ, Baldeweg T. Maturation of

action monitoring from adolescents to adulthood: an ERP study. Dev Sci.

2005;8:525-534.

22
56. Kuntsi J, Oosterlaan J, Stevenson J. Psychological mechanisms in

hyperactivity: I. Response inhibition deficit, working memory impairment,

delay aversion, or something else? J Child Psychol Psychiatry All Discip.

2001;42:199-210.

57. Bitsakou P, Antrop I, Wiersema JR, Sonuga-Barke EJS. Probing the limits of

Delay Intolerance: Preliminary young adult data from the Delay Frustration

Task (DeFT). J Neurosci Meth. 2006;151:38-44.

58. Sonuga-Barke EJ, Taylor E. The effect of delay on hyperactive and non-

hyperactive children’s response times: a research note. J Child Psychol

Psychiatry. 1992;33:1091-1096.

59. Wetherill GB, Levitt H. Sequential estimation of points on a psychological

function. Br J Math Stat Psychol. 1965;18:1-10.

60. Wechsler D. Wechsler Intelligence Scale for Children (3rd ed.). San Antonia,

TX: Psychological Corporation; 1991.

61. Torgesen JK, Wagner RK, Rashotte CA. Test of word reading efficacy

(TOWRE). Austin, TX: Pro-ed; 1999.

62. Sattler JM. Assessment of children: WISC-III and WPPSI-R Supplement. San

Diego, CA: Sattler, J. M.; 1992.

63. Bidwell LC, Willcutt EG, DeFries JC, Pennington BF. Testing for

neuropsychological endophenotypes in siblings discordant for Attention-

Deficit/Hyperactivity Disorder. Biol Psychiatry.2007;62:991-998.

64. Nigg JT, Blaskey L, Stawicki J, Sachek J. Evaluating the endophenotype

model of ADHD neuropsychological deficit: results for parents and siblings of

children with DSM-IV ADHD combined and inattentive subtypes. J Abn

Psychol. 2004;113:614-625.

23
65. Slaats-Willemse D, Swaab-Barneveld H, de Sonneville L, van der Meulen E,

Buitelaar J. Deficient response inhibition as a cognitive endophenotype of

ADHD. J Am Acad Child Adolesc Psychiatry. 2003;42:1242-1248.

66. Waldman ID, Nigg JT, Gizer IR, Park L, Rappley MD, Friderici K. The

adrenergic receptor α-2A gene (ADRA2A) and neuropsychological executive

functions as putative endophenotypes for childhood ADHD. Cogn Aff Behav

Neurosci. 2006;6:18-30.

67. Doyle AE, Biederman J, Seidman LJ,Reske-Nielsen JJ, Faraone S.

Neuropsychological functioning in relatives of girls with and without ADHD.

Psychol Med. 2005;35:1121-1132.

68. Andreou P, Neale BM, Chen W, Christiansen H, Gabriels I, Heise A, et al.

Reaction time performance in ADHD: improvement under fast-incentive

condition and familial effects. Psychol Med. 2007;31:1-13.

69. Kuntsi J, Rogers H, Swinard G, Rörger N, van der Meere J, Rijsdijk F

Asherson P. Reaction time, inhibition, working memory and ‘delay aversion’

performance: genetic influences and their interpretation. Psychol Med.

2006;36:613-1624.

70. Sonuga-Barke EJS, Wiersema JR, van der Meere JJ, Roeyers H. Context

dependent dynamic models of attention deficit/hyperactivity disorder:

differentiating common and unique elements of the state regulation deficit and

delay aversion models. Neuropsychol Rev.2009;online first.

71. Markomichali P, Donnelly N, Sonuga-Barke E. Cognitive training for

attention, inhibition and working memory deficits: A potential treatment for

ADHD? Advances in ADHD. 2009;3:89-96.

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Table 1: Sample and clinical characteristics of ADHD probands, their unaffected siblings and typical control cases by age.

ADHD probands Unaffected Siblings Controls

6-12 years 13-17 years 6-12 years 13-17 years 6-12 years 13-17 years Status F p

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

Parent Conners N = 48 N = 23 N = 39 N = 24 N/Aa N/Aa

Hyperactivity 83.31 (9.21) 83.39 (10.33) 55.59 (14.82) 54.29 (12.57) 191.45 <.001
Inattention 73.48 (8.47) 75.13 (9.14) 53.08 (12.80) 51.13 (8.20) 158.19 <.001
Total 80.50 (7.95) 82.35 (8.89) 54.59 (14.41) 52.58 (10.64) 213.85 <.001

Teacher Conners N = 40 N = 19 N = 35 N = 18 N/Aa N/Aa

Hyperactivity 63.53 (14.82) 68.32 (17.47) 49.80 (6.46) 60.17 (14.22) 20.67 <.001
Inattention 61.20 (13.55) 70.32 (13.35) 52.29 (8.90) 59 (8.52) 17.67 <.001
Total 63.33 (14.58) 71.95 (13.55) 51.46 (7.42) 60.61 (10.83) 23.44 <.001
Note: SDQ = Strengths and Difficulties Questionnaire; TOWRE = Test Of Word Reading Efficiency; WISC = Wechsler Intelligence Scales for Children.
a = Typical controls did not complete parent and teacher Conners’ questionnaire.

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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.

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 Table 3: Component Structure of Inhibitory Control, Delay Aversion, and Temporal Processing
measures
Construct Measures Component
Inhibition Timing Delay-Negative Delay-Positive

Inhibitory SSRT -.56 .21 -.20 -.10

Control GNGI .81 -.03 -.22 -.08
MStroop .77 -.05 -.18 .18

Temporal Tapping -.16 .68 -.16 .06

Processing Discrimination -.11 .66 .20 -.05
Anticipation .05 .51 .52 -.06

MIDA .16 .003 .09 .76

Delay Aversion DRT .02 -.06 .56 -.58
DeFT -.25 -.01 .70 .17

Working Memory Digit Span .000 -.48 .08 .49

Eigenvalue 1.72 1.46 1.29 1.26

% Variance 17.25 14.68 12.95 12.68

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.

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 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.

Siblings of Probands Siblings of Probands

without Inhibition with Inhibition
Problems Problems
Factor Score Mean S.D. Mean S.D. df t-value p
Inhibition 0.21 0.84 -0.54 0.86 63 2.71 .009
Timing 0.03 1.00 0.02 0.80 63 0.04 .96
Delay Negative -0.04 0.92 0.39 1.67 63 -1.21 .23
Delay Positive -0.13 0.98 -0.25 1.17 63 0.36 .71

Siblings of Probands Siblings of Probands

without Timing with Timing
Problems Problems
Factor Score Mean S.D. Mean S.D. df t-value p
Inhibition 0.10 0.95 0.06 0.82 63 0.14 .88
Timing -0.20 0.85 0.29 1.02 63 -2.17 .03
Delay Negative -0.02 1.35 0.09 0.68 63 -0.46 .64
Delay Positive -0.18 1.02 -0.11 1.01 63 -0.25 .80

Siblings of Probands Siblings of Probands

without DN with DN
Problems Problems
Factor Score Mean S.D. Mean S.D. df t-value p
Inhibition -0.07 0.87 0.35 0.87 63 -1.88 .06
Timing 0.06 1.01 -0.01 0.89 63 0.33 .73
Delay Negative -0.003 1.21 0.09 0.82 63 -0.34 .73
Delay Positive -0.21 1.02 -0.03 1.01 63 -0.68 .49

Siblings of Probands Siblings of Probands

without DP Problems with DP Problems
Factor Score Mean S.D. Mean S.D. df t-value p
Inhibition 0.02 0.86 0.49 1.05 63 -1.38 .17
Timing 0.05 1.00 -0.08 0.70 63 0.36 .71
Delay Negative 0.06 1.09 -0.17 1.02 63 0.58 .56
Delay Positive -0.09 1.02 -0.54 0.85 63 1.16 .24
Note: DP = Delay Positive; DN = Delay Negative; S.D.=Standard Deviation;

30
Figure 1: The proportion of ADHD cases (N=77) with Inhibiton, Timing and delay-
related problems and their degree of co-occurrence.

31