Association Between Response Inhibition and Working

Memory in Adult ADHD: A Link to Right Frontal

Cortex Pathology?
Luke Clark, Andrew D. Blackwell, Adam R. Aron, Danielle C. Turner, Jonathan Dowson,
Trevor W. Robbins, and Barbara J. Sahakian
Background: We sought to assess the relationship between response inhibition and working memory in adult patients with attention-
deficit/hyperactivity disorder (ADHD) and neurosurgical patients with frontal lobe damage.

Methods: The stop-signal reaction time (SSRT) test and a spatial working memory (SWM) task were administered to 20 adult patients with
ADHD and a group of matched controls. The same tasks were administered to 21 patients with lesions to right frontal cortex and 19 patients
with left frontal lesions.

Results: The SSRT test, but not choice reaction time, was significantly associated with search errors on the SWM task in both the adult ADHD
and right frontal patients. In the right frontal patients, impaired performance on both variables was correlated with the volume of damage
to the inferior frontal gyrus.

Conclusions: Response inhibition and working memory impairments in ADHD may stem from a common pathologic process rather than
being distinct deficits. Such pathology could relate to right frontal-cortex abnormalities in ADHD, consistent with prior reports, as well as
with the demonstration here of a significant association between SSRT and SWM in right frontal patients.

Key Words: Executive function, hyperactivity, impulsivity, prefron- related brain activation (Schweitzer et al. 2004; Valera et al. 2005)
tal cortex has been confirmed in adults with ADHD. Working memory
impairment also is remediated by methylphenidate treatment
(Kempton et al. 1999; Mehta et al. 2004; Turner et al. 2005),

T
he symptoms of childhood attention-deficit/hyperactivity
disorder (ADHD), in particular the attentional difficulties,
often persist into adulthood, where they may be associ-
ated with significant functional impairment (Faraone et al. 2000;
Gallagher and Blader 2001). Neuropsychological research has
aimed to identify consistent markers of cognitive dysfunction in
ADHD (for review, see Aron and Poldrack 2005; Castellanos et al.
2006; Castellanos and Tannock 2002). Impaired response inhibi-
tion, measured with go–no go and stop-signal tasks, has been
proposed to represent a core deficit in childhood ADHD (Barkley
1997; Nigg 2001; Sonuga-Barke 2002), with a recent meta-
analysis yielding a moderate effect size (Cohen’s d ⫽ .58) for
stop-signal reaction time (SSRT; Lijffijt et al. 2005). Studies in
adults with ADHD largely have confirmed deficient stop-signal
performance (Lijffijt et al. 2005; Murphy 2002; Wodushek and
Neumann 2003) and its remediation by psychostimulant treat-
ment (Aron et al. 2003a).
Working memory processes also have been widely studied by
ADHD researchers, and a recent meta-analysis in childhood
ADHD found a strong effect size (Cohen’s d ⫽ 1.06) on tests
requiring manipulation of spatial working memory (SWM; Mar-
tinussen et al. 2005). Impaired working memory performance
(Dowson et al. 2004; Kovner et al. 1998; Lovejoy et al. 1999;
McLean et al. 2004; Murphy et al. 2001) and abnormal task-
From the Department of Experimental Psychology (LC, TWR), and Depart-
ment of Psychiatry (ADB, DCT, JD, BJS), University of Cambridge School
of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, United King-
dom; and Department of Psychology (ARA), University of California, Los
Angeles, Los Angeles, California.
Address reprint requests to Luke Clark, D. Phil., Department of Experimental
Psychology, University of Cambridge, Downing Street, Cambridge CB2
3EB, United Kingdom; E-mail: lc260@cam.ac.uk.
Received August 11, 2005; revised May 8, 2006; accepted July 6, 2006.
consistent with catecholaminergic models of frontostriatal dys-
function in ADHD (Arnsten and Li 2005). It remains unclear
whether inhibitory control and working memory impairments
represent distinct deficits in ADHD or dual manifestations of a
common pathologic mechanism (Castellanos and Tannock
2002). The primary objective of the present study was to examine
the relationship between these putatively core deficits in adults
with ADHD by correlating SSRT with SWM performance.
A second objective was to examine further a putative neuro-
psychological model of ADHD, according to which right frontal
hypofunction or hypoplasia (Aron and Poldrack 2005; Casey et
al. 1997; Castellanos et al. 1996; Castellanos and Tannock 2002;
Durston et al. 2004; Filipek et al. 1997) may explain cognitive
impairment. If this model holds, then it would be expected that
patients with right frontal damage also would show impairments
in SSRT and SWM. Consequently, we also studied two groups of
neurosurgical patients with lesions to right and left frontal cortex
and compared their profiles with the pattern in adult ADHD.
Because we have shown elsewhere that the extent of impairment
of response inhibition is correlated selectively with the volume of
damage in the right inferior frontal gyrus (IFG; Aron et al. 2003b;
see also Chambers et al. 2006 and Rieger et al. 2003) and that
right IFG is recruited during successful stopping in healthy
volunteers (Aron and Poldrack 2006; Rubia et al. 2003), we also
examined the relation between damage to subsectors of frontal
cortex (such as IFG) and SSRT and SWM.
Methods and Materials
Subjects
Twenty subjects with a DSM-IV diagnosis of ADHD were
recruited from a clinic that specializes in the assessment of
suspected adult ADHD. Data from ADHD subjects were collected
as part of the placebo arm of a pharmacologic challenge study

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doi:10.1016/j.biopsych.2006.07.020 © 2007 Society of Biological Psychiatry
1396 BIOL PSYCHIATRY 2007;61:1395–1401 L. Clark et al.

Table 1. Demographic Characteristics of the Subjects with Adult ADHD

(n ⫽ 20) and the Healthy Controls (n ⫽ 22)

Characteristics ADHD Controls

Age (y) 28.0 (8.6) 25.1 (5.4)

Gender (M:F) 13:7 14:2
NART-estimated IQ 108.3 (5.9)a 113.3 (3.5)
Years education 13.7 (1.7) 14.4 (3.2)
Data are mean (SD) unless otherwise marked.
ADHD, attention-deficit/hyperactivity disorder; F, female; IQ, intelli-
gence quotient; M, male; NART, . Figure 1. Lesion overlap in the right (top) and left frontal (bottom) lesion
a
p ⬍ .005. groups.

possibly because of the inhibitory requirement to suppress

(Turner et al. 2004). Demographic characteristics are described in
regular pronunciation on the NART.
Table 1. Informant ratings (usually from a parent) were used to
Forty neurosurgical patients with focal, unilateral lesions to
assess ADHD symptoms during childhood, and ratings by the
the frontal lobes were recruited from the Cambridge Cognitive
patient and an informant were used to assess symptoms experi-
Neuroscience Research Panel at the MRC Cognition and Brain
enced during the previous 6 months. A diagnosis could fall into
Sciences Unit. Twenty-one patients had right-sided lesions, and
several categories. A predominantly inattentive type (n ⫽ 4), a
19 patients had left-sided lesions. Demographic and clinical
predominantly hyperactive–impulsive type (n ⫽ 2), or a com-
characteristics are reported in Table 2. Most subjects were
bined-type diagnosis (n ⫽ 10) required six of nine DSM-IV
prescribed anticonvulsant medication, which was taken as usual
ADHD criteria to be met during both childhood and the previous
on the test day (carbamazepine, right [R] 6, left [L] 3; phenytoin
6 months. A diagnosis of ADHD in partial remission (n ⫽ 2)
R5, L4; valproate R3, L2; lamotrigine R2, L0; warfarin R2, L0; and
required six of nine criteria to be met during childhood, and
no medication R6, L11). Lesion location was confirmed by
three of nine in the previous 6 months, and a diagnosis of ADHD
magnetic resonance imaging (MRI) scan on a 1.5-T scanner, by
not otherwise specified (n ⫽ 2) required three of nine criteria to
using an SPGR (spin gradient echo) T1-weighted coronal se-
be met during both childhood and the previous 6 months.
quence and a T2-weighted axial sequence. Lesions were traced
Patients also were assessed with the Global Severity Index (GSI)
onto each structural scan by using MRIcro (Rorden and Brett
from the Brief Symptom Inventory (Derogatis 1993). The GSI is a
2000) to create a three-dimensional lesion volume (Figure 1
self-report measure of so-called caseness, in which clinically
shows lesion overlaps) and were normalized to the standard
meaningful symptoms are indicated by a value of .6 for male and
template by using SPM96 with cost-function masking to exclude
of .8 for female subjects. The group mean for this study was 1.6
the area of damage from the calculation of the normalization
(SD, .7). Seven patients currently were receiving stimulant med-
parameters (Brett et al. 2001). MRIcro was used to prepare five
ication for ADHD and were asked to omit their medication for 24
anatomic regions of interest in the frontal lobes: inferior frontal
hours before testing.
gyrus (IFG), middle frontal gyrus (MFG), superior frontal gyrus
Sixteen healthy controls were recruited by community adver-
(SFG), the orbital region (ORB), and the medial frontal region
tising and were age- [t (34) ⫽ 1.14, p ⫽ .262] and gender- (␹2 ⫽
(MED; Aron et al. 2003b; Clark et al. 2003). The normalized
2.40, Fisher’s exact p ⫽ .245) matched to the adult ADHD group
lesion volume was superimposed onto each region of interest to
(Table 1). Controls and adult ADHD groups were matched for
calculate the volume of damage within each brain region.
years of formal education [t (34) ⫽ .889, p ⫽ .380] but controls
Exclusion criteria for all subjects were a NART-estimated IQ
scored around five points higher on estimated intelligence
score of ⬍90; significant visual or motor impairment; or a current
quotient (IQ) according to the National Adult Reading Test
mood, psychotic, or substance-related diagnosis. The research
(NART; Nelson and Willison 1991) [t (34) ⫽ 2.98, p ⫽ .005],
was approved by Cambridge Local Research Ethics Committee,
and written informed consent was provided by all participants
Table 2. Demographic Characteristics of the Patients with Unilateral before testing.
Lesions to Right (n ⫽ 21) or Left (n ⫽ 19) Frontal Lobes
Procedure
Characteristic Right Left
All volunteers completed the stop-signal test (Logan 1994)
Age (y) 56.1 (11.9) 54.5 (10.4) and the CANTAB Spatial Working Memory test (Cambridge
Gender (M:F) 7:14 11:8 Cognition, Cambridge, United Kingdom; http://www.camcog.
NART-estimated IQ 114.5 (7.1) 115.1 (10.0) com) as part of a neuropsychological assessment. Tests were
Years educationa 12.7 (2.8) 11.9 (2.8) administered on an Advantech PC (Taipei, Taiwan) with a
Lesion size (cc) 72.8 (60.0)b 35.1 (38.9) 10.5-in. touch-screen monitor and a two-choice response box.
Time after onset (mo) 70.3 (105.9) 46.7 (35.6) The stop-signal test is an established measure of response
Etiology (n) inhibition. On each trial, the subject is required to make a rapid
Hemorrhage 6 7 left- or rightward button press to a left- or right-facing arrow (the
Infarction 4 4 go stimulus). On a minority of trials (25%), an auditory stop signal
Tumor resection 11 7 (a 100-ms, 300-Hz tone) is presented at a variable delay (the
Abscess 0 1 stop-signal delay, SSD) after the go stimulus. The subject must
Data are mean (SD) unless otherwise marked. attempt to suppress their motor response on hearing the stop
a
Missing data from 3 right frontal and 7 left frontal patients. signal. Subjects complete five blocks of 64 trials with 16 stop
b
p ⬍ .05. trials per block (80 stop trials, total). The SSRT can be estimated

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L. Clark et al.
by titrating the SSD at which subjects successfully stop on 50% of
stop trials. A tracking algorithm is used to adjust the SSD to the
subject’s stopping ability (Osman et al. 1990). Successfully
inhibited responses increased the SSD by 50 ms on the next trial
(making the next trial more difficult), whereas a failure to stop
decreased the SSD by 50 ms on the next trial (making the next
trial easier). To ensure unpredictability of the SSD, four inter-
leaved staircase functions were used, starting at 100, 200, 400,
and 500 ms. The SSRT was computed by subtracting average SSD
after stabilization (stop trials 41– 80) from the median reaction
time on go trials (Band et al. 2003; Logan 1994). The median is
used in this calculation because of the standard positive skewing
of rapid reaction-time data.
Dependent variables on the stop-signal test were the SSRT,
the median go RT, and the number of discrimination errors (e.g.,
a left button-press to a right-facing arrow). Data were screened
for outliers to confirm convergence of the four staircase functions
around a consistent stop-signal delay. One left frontal subject
failed to converge and displayed an SSRT (568 ms) that was more
than three SDs from the mean for the left frontal group. This
subject was excluded from further analysis.
The CANTAB Spatial Working Memory test (Owen et al. 1990,
1996) is a self-ordered search task in which the subject is
presented with a spatial array of colored boxes on the screen and
is required to search boxes for hidden tokens. The participant
must touch each box in turn until one opens with a blue token
inside (a search). When a blue token has been found, the token
must be placed in a store by touching an area on the right-hand
side of the screen. The subject then must begin a new search for
the next blue token. The instructions state that a token will be
hidden only under one box on each search and that once a box
has yielded a token, the box would not yield a token in
subsequent searches. As such, ongoing searches can be limited
to boxes in which a token has yet to appear, placing a demand
on working memory to hold successful locations online. This is
repeated until a token has been found in every box on the
screen. When a blue token has been found in each of the boxes,
a new trial begins (with new boxes in new locations on the
screen). The task includes four unscored practice trials with three
boxes to search, followed by four scored trials with four boxes,
four trials with six boxes, and four trials with eight boxes.
An error is recorded when the participant returns to a box
in which a token previously has been found (BSE) within a
given trial or when the participant returns to a box within the
same search (within-search error). Owen et al. (1990) sug-
gested that an efficient strategy for completing this task is to
follow a predetermined sequence by beginning with a specific
box and then, once a blue token has been found, to return to
that box to start the new search sequence. An estimate of the
use of this strategy (strategy score) is calculated by summing
the number of times that the participant begins a new search
from a different box for the six- and eight-box trials. A high
score represents poor use of this strategy, and a low score
represents efficient use.
Statistical Analysis
Univariate t tests (p ⬍ .05 for significance) were used to
compare the adult ADHD group against the healthy control
group and to compare the right and left frontal lesion groups.
The relationship between stop-signal test variables (SSRT, me-
dian go RT) and SWM variables (total BSE, strategy score) was
assessed with Pearson’s correlations. Correlation coefficients
were compared between groups by using Fisher’s z transforma-
BIOL PSYCHIATRY 2007;61:1395–1401 1397
Table 3. Neuropsychological Performance in Adult Subjects with
Attention-Deficit/Hyperactivity Disorder (ADHD) and Healthy Controls
Parameter ADHD Controls
Stop-Signal Test
Stop-Signal Reaction Time (msec) 171.6 (40.3) 173.1 (48.1)
Median Go Reaction Time (msec) 424.3 (60.8) 420.4 (57.9)
Discrimination Errors (n) 3.0 (2.8) 6.0 (8.9)
Spatial Working Memory
Between-Search Errors (Total) 19.8 (17.5)a 9.2 (13.7)
Within-Search Errors (Total) 1.4 (2.8) .8 (2.0)
Strategy Score 30.1 (6.5) 26.6 (6.6)
Data are mean (SD).
a
p ⬍ .05 (one-tailed).
tion (Howell 1997, p. 261). In the frontal-lesion groups, Pearson’s
correlations were used to examine the relationship between the
volume of damage in the five regions of interest and response
inhibition (SSRT) and working memory (BSE) performance.
Results
Adult ADHD Group Versus Healthy Controls
Neuropsychological performance in the adult ADHD and
healthy control groups is shown in Table 3. On the SWM task, the
adult ADHD group made more BSE than did controls [t (34) ⫽
1.98; p ⫽ .028, one-tailed]. When level of difficulty (four-, six-,
and eight-move problems) was entered as a within-subjects
variable in a mixed-model ANOVA, there was a significant
group-by-difficulty interaction [F (1.5, 49.3) ⫽ 4.71, p ⫽ .022,
Greenhouse-Geisser corrected] and main effect of difficulty level
[F (1.5, 49.3) ⫽ 28.1, p ⬍ .0001, Greenhouse-Geisser corrected].
The ADHD subjects performed similarly to controls on the easier
(four- and six-move) problems but made more errors at the
eight-move stage [t (34) ⫽2.32, p ⫽ .026] (Figure 2). The ADHD
and control groups did not differ on total within-search errors
[t (34) ⫽.649, p ⫽ .520] or on strategy score [t (34) ⫽ 1.59, p ⫽
.121].
On the stop-signal test, ADHD and control groups did not
differ significantly on SSRT [t (34) ⫽ .101, p ⫽ .920], median go
reaction time [t (34) ⫽ .194, p ⫽ .847], or discrimination errors
[t (34) ⫽ 1.45, p ⫽ .157]. However, in the subjects with adult
ADHD, SSRT was correlated significantly with total between-
search errors on SWM [r(20) ⫽.538, p ⫽ .014] (Figure 3). In
control subjects, SSRT and SWM BSE were not associated
[r(16) ⫽ ⫺.133, p ⫽ .623]. This correlation coefficient was
significantly greater in the ADHD group compared with in the
control group (test of independent correlations, z ⫽ 2.01; p ⫽
.023, one-tailed). In the ADHD group, SSRT was not associated
significantly with SWM strategy score [r(20) ⫽.234, p ⫽ .321], and
median go RT was not associated with total BSE [r(20) ⫽.234, p ⫽
.321] or strategy score [r(20) ⫽.008, p ⫽ .972]. These supplementary
correlations also were nonsignificant in the control subjects (all r ⬍
.251, p ⬎ .20).
In view of previous data describing differences in executive
function between subtypes of adult ADHD (Dinn et al. 2001;
Gansler et al. 1998), we can report that the two subjects with the
hyperactive–impulsive subtype displayed longer SSRTs (mean ⫽
187, SD ⫽ 55) and more total BSE (mean ⫽ 31.0, SD ⫽ 9.9) than
did the 10 subjects with the combined subtype (SSRT mean ⫽
164, SD ⫽ 42; BSE mean ⫽ 25.1, SD ⫽ 19.8) and the 4 subjects
with the inattentive subtype (SSRT mean ⫽ 162, SD ⫽ 42;
between-search errors (BSE) mean ⫽ 9.0, SD ⫽ 14.9).
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1398 BIOL PSYCHIATRY 2007;61:1395–1401 L. Clark et al.

Figure 2. Error rates (between-search errors) on the spatial working memory task increase as a function of difficulty in the adult attention-deficit/hyperactivity
disorder (ADHD) group relative to healthy controls (A) and in the right frontal lesion group compared with left frontal patients (B).

Right- Versus Left-Frontal Lesion Groups
Performance in the neurosurgical cases with unilateral frontal-
lobe lesions is displayed in Table 4. SSRT was significantly slower
in right frontal patients than in left frontal patients [t (37) ⫽2.37,
p ⫽ .027], but the groups did not differ in terms of median go RT
[t (37) ⫽.697, p ⫽ .490] or discrimination errors [t (37) ⫽1.06, p ⫽
.297]. SWM performance was more impaired in the right frontal
group, with a significant difference on total BSE [t (37) ⫽ 2.59,
p ⫽ .014]. In a mixed-model ANOVA including the level of
difficulty, the group-by-difficulty interaction term approached
significance [F (1.7,62.1) ⫽ 2.82, p ⫽ .076, Greenhouse-Geisser
corrected], and the right frontal patients committed more errors at
the six- and eight-move stages [six move, t (37) ⫽ 2.43, p ⫽ .020;
eight move, t (37) ⫽ 2.06, p ⫽ .048]. There was a marginally
significant difference on total within-search errors [t (37) ⫽ 1.77, p ⫽
.085] but no effect on the strategy score [t (37) ⫽ 1.59, p ⫽ .120].
Lesion volume was significantly larger in the right-frontal
patients than in the left frontal patients [t (37) ⫽ 2.62, p ⫽ .013].
To control for lesion size, we performed a supplementary
analysis on subgroups of 10 right frontal and 10 left-frontal
patients who were matched for lesion volume (right mean ⫽ 61.1
cc, SD ⫽ 25.3; left mean ⫽ 48.2 cc, SD ⫽ 38.8; U ⫽ 33.0, p ⫽
.218). The right frontal subgroup demonstrated a slower SSRT
than did the left frontals (mean ⫽ 266.5 ms vs. 206.5 ms,
respectively, U ⫽ 21.0, p ⫽ .028), made more SWM BSE (mean ⫽
46.2 vs. 21.1; U ⫽ 23.0, p ⫽ .041), and made poorer use of
strategy (mean strategy score ⫽ 38.1 vs. 32.2, U ⫽ 17.5, p ⫽ .014).
The groups did not differ on median go RT (mean ⫽ 559.2 ms vs.
541.6 ms; U ⫽ 49.0, p ⫽ .940).
In the right frontal group, SSRT was correlated significantly
with total BSE on SWM [r(21) ⫽.484, p ⫽ .026] (Figure 3). In the
left frontal group, SSRT was not significantly associated with BSE
[r(18) ⫽ ⫺.058, p ⫽ .818], and the correlation coefficient was
significantly greater in the right frontal group compared with the
left (test of independent correlations, z ⫽ 1.68, p ⫽ .047
one-tailed). In the right frontal group, the association between
median go RT and total BSE approached statistical significance
[r(21) ⫽ .389, p ⫽ .081]. Consequently, we ran a partial correla-
tion of SSRT against SWM BSE, controlling for median go RT,
which remained statistically significant [r(18) ⫽ .445, p ⫽ .049].
SWM strategy score was not significantly associated with SSRT
[r(21) ⫽ .130, p ⫽ .573] or with median go RT [r(21) ⫽ .022, p ⫽
.924]. In the left frontal group, SWM strategy score was not
associated with SSRT [r(18) ⫽ .228, p ⫽ .364] or median go RT
[r(18) ⫽ .387, p ⫽ .112], but median go RT was significantly
correlated with BSE [r(18) ⫽ .509, p ⫽ .031].
We have reported elsewhere that the SSRT was selectively
related to the volume of damage in the IFG in a subgroup (n ⫽
Table 4. Neuropsychological Performance in Neurosurgical Patients with
Right-and Left-sided Lesions to Prefrontal Cortex

Parameter Right Frontals Left Frontals

Stop-Signal Test
Stop-Signal Reaction Time (msec) 252.8 (70.9)a 200.9 (69.4)
Median Go Reaction Time (msec) 583.0 (131.0) 555.1 (116.4)
Discrimination Errors 2.9 (3.3) 1.9 (2.2)
Spatial Working Memory
Between-Search Errors (Total) 45.6 (16.2)a 29.7 (22.2)
Figure 3. Stop-signal reaction time is significantly correlated with total BSE Within-Search Errors (Total) 3.2 (3.8) 1.4 (2.1)
on the spatial working memory (SWM) test, in cases with adult attention- Strategy Score 36.7 (6.6) 33.4 (6.1)
deficit/hyperactivity disorder (ADHD; open circles) and cases with right
frontal lobe lesions (filled circles) [correlation coefficient for combined Data are mean (SD).
group, r(41) ⫽ .667, p ⬍ .0001]. a
p ⬍ .05.

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L. Clark et al.
Figure 4. The volume of damage (in cubic centimeters) to the right inferior frontal gyrus (IFG) in the neurosurgical patients with right frontal lobe lesions was
significantly associated with the stop-signal reaction time (SSRT; msec; A) [r(21) ⫽ .588, p ⫽ .005] and with the total between-search errors (BSE) on the Spatial
Working Memory (SWM; B) task [r(21) ⫽ .537, p ⫽ .012].
15) of these right frontal patients (Aron et al. 2003b). This
correlation remained significant in the larger data set (n ⫽ 21) in
the present study [IFG: r(21) ⫽ .588, p ⫽ .005; MFG: r(21) ⫽ .290,
p ⫽ .202; SFG: r(21) ⫽ .119, p ⫽ .607; ORB: r(21) ⫽ .297, p ⫽
.191; MED: r(21) ⫽ .464, p ⫽ .034]. A stepwise multiple regres-
sion analysis (probability of F to enter p ⬍ .05; probability of F to
remove p ⬎ .10), including the five regions of interest as
potential predictors of SSRT, confirmed that IFG volume was the
only significant predictor [adjusted r2 ⫽ .346, F (1,19) ⫽ 10.1, p ⫽
.005] (Figure 4A). ROI analysis for SWM BSE in the right frontal
group revealed a similar relationship with IFG damage [IFG:
r(21) ⫽ .537, p ⫽ .012, MFG: r(21) ⫽ .165, p ⫽ .246; SFG: r(21) ⫽
.115, p ⫽ .618; ORB: r(21) ⫽ .335, p ⫽ .137; MED: r(21) ⫽ .354,
p ⫽ .115], confirmed with stepwise multiple regression [adjusted
r2 ⫽ .289, F (1,19) ⫽ 7.72, p ⫽ .012] (Figure 4B). In the left frontal
patients, volume of IFG damage was not significantly correlated
with SSRT [r(18) ⫽ ⫺.325, p ⫽ .188] or SWM BSE [r(18) ⫽ .038,
p ⫽ .882].
Discussion
In adult subjects with ADHD, response inhibition, as indexed
by SSRT, was correlated significantly with BSE on a self-ordered
SWM task. These two constructs, which are independently
reliable deficits in ADHD groups (Lijffijt et al. 2005; Martinussen
et al. 2005), appear to be associated in the adult variant of the
disorder. Intriguingly, the same association between response
inhibition and working memory search errors also was identified
in a group of neurosurgical patients with unilateral lesions to the
right frontal lobe. In a subset of these patients (n ⫽ 15), our work
elsewhere demonstrated that SSRT was highly correlated with the
volume of damage in the right IFG but not other sectors of the
right frontal cortex (Aron et al. 2003b). In the present data, this
correlation between damage to the right IFG and SSRT remained
significant in a larger group of patients, and moreover, damage to
right IFG also predicted SWM performance. Together with prior
reports of right frontal hypoplasia or hypofunction in ADHD
(reviewed in Aron and Poldrack 2005; Castellanos and Tannock
2002), these results suggest that the right IFG region performs a
function common to both SWM and SSRT, and this could explain
the significant association between these two variables in ADHD
patients.
BIOL PSYCHIATRY 2007;61:1395–1401 1399
The association between SSRT and SWM performance was not
apparent in healthy volunteers or in a second group of neurosurgi-
cal patients with left frontal lobe lesions. This demonstrates some
specificity of the SSRT–SWM link in adult ADHD and right frontal
lobe damage. Compared with healthy volunteers, the adult ADHD
group committed more SWM BSE, particularly at the most
difficult eight-move stage of the task (see also Dowson et al.
2004; McLean et al. 2004). However, surprisingly, SSRT was
comparable in the adult ADHD group and the healthy controls,
consistent with a previous report by Epstein et al. (2001), though
not with a number of other studies (Bekker et al. 2005; Murphy
2002; Ossmann and Mulligan 2003; Wodushek and Neumann
2003). We note that 10 of 20 ADHD subjects had completed the
stop-signal test on a previous occasion (as testing was completed
as part of a cross-over study), and it is possible that their SSRTs
had benefited from this prior practice. Those subjects tested on
their first session displayed slower SSRTs (mean ⫽ 184, SD ⫽ 41)
than did controls (mean ⫽ 173, SD ⫽ 48), and this difference may
reach statistical significance in a larger sample. SSRT also was
slower in those subjects with the hyperactive–impulsive subtype
than in the subjects with the inattentive or combined subtypes
(Dinn et al. 2001; Gansler et al. 1998). Even in this apparently
intact SSRT range (⬍200 ms), we have shown elsewhere that
response inhibition still is amenable to pharmacologic enhance-
ment (Aron et al. 2003a; Turner et al. 2004). It is possible that
these ADHD subjects lie at the upper end of an impaired normal
distribution in adult ADHD.
Tasks of self-ordered working memory incorporate both
mnemonic and strategic components (Owen et al. 1990, 1996;
Robbins 1998). In the present study, the SWM strategy score was
not associated with SSRT in adult ADHD subjects or patients with
right frontal lobe damage. We infer that the inhibitory processes
measured by the SSRT are associated selectively with the short-
term memory maintenance component of SWM, assessed by the
number of BSE. Although causal inferences cannot be drawn
from a correlational analysis, it is pertinent that this version of the
stop-signal task (requiring left- and rightward responses to left-
and rightward pointing arrows) does not load heavily on work-
ing memory. The only task requirement is to suppress a response
after presentation of the auditory stop signal, and ADHD children
appear fully able to keep this instruction in mind (Logan et al.
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1400 BIOL PSYCHIATRY 2007;61:1395–1401
2000). We consider it to be unlikely that working memory
demands impinge upon SSRT. In contrast, failures of inhibitory
control may contribute directly to inflated BSE on the self-
ordered SWM task. This may occur via an impaired ability to
inhibit stimulus-driven motor responses or via a perseverative
mechanism whereby previously acquired stimulus–response
mappings compound failures of motoric inhibition and exacer-
bate erroneous responding to previously reinforced locations
(Collins et al. 1998). It is, however, possible that the association
between SSRT and SWM may be mediated by a third cognitive
process, such as sustained attention, or shifting, which accounts
for variance in both tasks.
The present findings relate specifically to adult subjects with
ADHD and may not necessarily generalize to the childhood variant
of the disorder. Several other caveats and limitations should be
noted. First, the relatively small size of the ADHD patient group
prohibited a rigorous analysis of the effects of ADHD subtype.
Second, large demographic differences between the adult ADHD
and frontal lesion patients (particularly in age and estimated IQ) did
not justify direct between-group comparisons. From the descriptive
data in Tables 3 and 4, the lesion patients appear more impaired,
consistent with a large and rapid-onset brain lesion, contrasting with
subtle neurodevelopmental pathology in ADHD. Third, many of the
frontal lesion patients were receiving anticonvulsant treatment,
which could impact deleteriously upon cognitive function (Daban
et al. 2006; Mecarelli et al. 2004; although see Read et al. 1998).
Given the comparable levels of medication in the right- and
left-sided groups, this appears unlikely to contribute to the SSRT–
SWM association in the right frontal group. Fourth, half of the
ADHD subjects had completed the stop-signal test on a previous
occasion, and it is possible that their SSRTs benefited from this prior
practice. This appears very unlikely to contribute to the SSRT-SWM
correlation in the ADHD group, but it could account for the similar
mean SSRT value for ADHD subjects compared with controls. A
recent study examining SSRT estimates across multiple testing
blocks in healthy volunteers found an initial estimate of SSRT (over
5 blocks of 64 trials) that was more than 40 ms slower than
subsequent estimates, which then remained stable over time (Co-
hen, Aron, and Poldrack, unpublished data, 2006). Future research
should control carefully for this training effect by establishing a
prestudy baseline for SSRT.
Manipulation of working memory and response inhibition are
key aspects of executive function associated with the integrity of
the prefrontal cortex. The extent to which varieties of executive
function may be dissociated at the cognitive or neuroanatomic
level remains controversial, with some evidence for a unitary
central executive that enables a range of higher-level functions
(Kimberg and Farah 1993; Roberts et al. 1994), contrasting with
other data that suggest distinct underlying mechanisms for
inhibitory control and working memory (Miyake et al. 2000;
Mostofsky et al. 2003). The primacy of response inhibition
deficits to the ADHD impairment has been questioned in some
recent work (Bekker et al. 2005; Rhodes et al. 2005), and there is
accumulating interest in affective (so-called hot) aspects of
executive function in ADHD, such as risky decision making or
reversal learning (Castellanos et al. 2006; Roiser et al. 2003). Our
results show how damage to a specific sector of frontal cortex (the
IFG) affects two classic measures of executive function—SSRT and
SWM—and how these measures are correlated in both right frontal
patients and adults with ADHD. Future research is required to
establish whether an underlying function (such as inhibition of
prepotent responses) could explain this association, or whether
another process, such as sustained attention is important. It is
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L. Clark et al.
striking that the right IFG is the critical focus in frontal patients for
performance on these tasks. Hypofunction or hypoplasia of this
brain region has been implicated frequently in neuroimaging stud-
ies of (mainly childhood) ADHD (reviewed in Aron and Poldrack
2005; Castellanos and Tannock 2002). The existence of a candidate
neural substrate is a distinct advantage for further studies of the
relation between SSRT and SWM, as well as for clinical research
investigating the neuroanatomic, neurochemical, and genetic basis
of ADHD and its amelioration.
LC and ADB contributed equally to this manuscript.
This work was supported by a Wellcome Trust Programme
Grant (to TWR, BJS, B.J. Everitt, and A.C. Roberts) and was
completed within the University of Cambridge Behavioural and
Clinical Neuroscience Institute, supported by a consortium
award from the Medical Research Council (United Kingdom)
and the Wellcome Trust. Many thanks to the Cambridge Cogni-
tive Neuroscience Research Panel, Dr. N. Antoun, Dr. F. Manes,
and Dr. P.C. Fletcher for radiologic tracing and assistance with
structural magnetic resonance imaging analyses.
Conflict of interest: TWR and BJS are consultants for Cam-
bridge Cognition. In addition to a university appointment, ADB
now is employed by Cambridge Cognition.
Arnsten AF, Li BM (2005): Neurobiology of executive functions: Catecholamine
influences on prefrontal cortical functions. Biol Psychiatry 57:1377–1384.
Aron AR, Dowson JH, Sahakian BJ, Robbins TW (2003a): Methylphenidate
improves response inhibition in adults with attention-deficit/hyperac-
tivity disorder. Biol Psychiatry 54:1465–1468.
Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW (2003b): Stop-
signal inhibition disrupted by damage to right inferior frontal gyrus in
humans. Nat Neurosci 6:115–116.
Aron AR, Poldrack RA (2005): The cognitive neuroscience of response inhi-
bition: Relevance for genetic research in attention-deficit/hyperactivity
disorder. Biol Psychiatry 57:1285–1292.
Aron AR, Poldrack RA (2006): Cortical and subcortical contributions to stop
signal response inhibition: Role of the subthalamic nucleus. J Neurosci
26:2424 –2433.
Band GP, van der Molen MW, Logan GD (2003): Horse-race model simula-
tions of the stop-signal procedure. Acta Psychol (Amst) 112:105–142.
Barkley RA (1997): Behavioral inhibition, sustained attention, and executive
functions: Constructing a unifying theory of ADHD. Psychol Bull 121:65–94.
Bekker EM, Overtoom CC, Kooij JJ, Buitelaar JK, Verbaten MN, Kenemans JL
(2005): Disentangling deficits in adults with attention-deficit/hyperac-
tivity disorder. Arch Gen Psychiatry 62:1129 –1136.
Brett M, Leff AP, Rorden C, Ashburner J (2001): Spatial normalization of brain
images with focal lesions using cost function masking. Neuroimage 14:
486 –500.
Casey BJ, Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Schubert AB,
et al. (1997): Implication of right frontostriatal circuitry in response inhi-
bition and attention-deficit/hyperactivity disorder. J Am Acad Child Ado-
lesc Psychiatry 36:374 –383.
Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Vaituzis AC, Dickstein
DP, et al. (1996): Quantitative brain magnetic resonance imaging in
attention-deficit hyperactivity disorder. Arch Gen Psychiatry 53:607– 616.
Castellanos FX, Sonuga-Barke EJ, Milham MP, Tannock R (2006): Character-
izing cognition in ADHD: Beyond executive dysfunction. Trends Cogn Sci
10:117–123.
Castellanos FX, Tannock R (2002): Neuroscience of attention-deficit/hyper-
activity disorder: The search for endophenotypes. Nat Rev Neurosci
3:617– 628.
Chambers CD, Bellgrove MA, Stokes MG, Henderson TR, Garavan H, Robert-
son IH, et al. (2006): Executive “brake failure” following deactivation of
human frontal lobe. J Cogn Neurosci 18:444 – 455.
Clark L, Manes F, Antoun N, Sahakian BJ, Robbins TW (2003): The contribu-
tions of lesion laterality and lesion volume to decision-making impair-
ment following frontal lobe damage. Neuropsychologia 41:1474 –1483.
Collins P, Roberts AC, Dias R, Everitt BJ, Robbins TW (1998): Perseveration
and strategy in a novel spatial self-ordered sequencing task for nonhu-
L. Clark et al.
man primates: Effects of excitotoxic lesions and dopamine depletions of
the prefrontal cortex. J Cogn Neurosci 10:332–354.
Daban C, Martinez-Aran A, Torrent C, Sanchez-Moreno J, Goikolea JM, Bena-
barre A, et al. (2006): Cognitive functioning in bipolar patients receiving
lamotrigine: Preliminary results. J Clin Psychopharmacol 26:178 –181.
Derogatis LR (1993): Brief Symptom Inventory (BSI): Administrative, Scoring
and Procedural Manual, 3rd ed. Minneapolis, MN: National Computer
Systems.
Dinn WM, Robbins NC, Harris CL (2001): Adult attention-deficit/hyperactiv-
ity disorder: Neuropsychological correlates and clinical presentation.
Brain Cogn 46:114 –121.
Dowson JH, McLean A, Bazanis E, Toone B, Young S, Robbins TW, et al. (2004):
Impaired spatial working memory in adults with attention-deficit/hyper-
activity disorder: Comparisons with performance in adults with border-
line personality disorder and in control subjects. Acta Psychiatr Scand
110:45–54.
Durston S, Hulshoff Pol HE, Schnack HG, Buitelaar JK, Steenhuis MP, Mind-
eraa RB, et al. (2004): Magnetic resonance imaging of boys with atten-
tion-deficit/hyperactivity disorder and their unaffected siblings. J Am
Acad Child Adolesc Psychiatry 43:332–340.
Epstein JN, Johnson DE, Varia IM, Conners CK (2001): Neuropsychological
assessment of response inhibition in adults with ADHD. J Clin Exp Neuro-
psychol 23:362–371.
Faraone SV, Biederman J, Spencer T, Wilens T, Seidman LJ, Mick E, et al.
(2000): Attention-deficit/hyperactivity disorder in adults: An overview.
Biol Psychiatry 48:9 –20.
Filipek PA, Semrud-Clikeman M, Steingard RJ, Renshaw PF, Kennedy DN,
Biederman J (1997): Volumetric MRI analysis comparing subjects having
attention-deficit hyperactivity disorder with normal controls. Neurology
48:589 – 601.
Gallagher R, Blader J (2001): The diagnosis and neuropsychological assess-
ment of adult attention deficit/hyperactivity disorder. Scientific study
and practical guidelines. Ann N Y Acad Sci 931:148 –171.
Gansler DA, Fucetola R, Krengel M, Stetson S, Zimering R, Makary C (1998):
Are there cognitive subtypes in adult attention deficit/hyperactivity dis-
order? J Nerv Ment Dis 186:776 –781.
Howell DC (1997): Statistical Methods for Psychology. Belmont, CA: Wads-
worth.
Kempton S, Vance A, Maruff P, Luk E, Costin J, Pantelis C (1999): Executive
function and attention deficit hyperactivity disorder: Stimulant medica-
tion and better executive function performance in children. Psychol Med
29:527–538.
Kimberg DY, Farah MJ (1993): A unified account of cognitive impairments
following frontal lobe damage: The role of working memory in complex,
organized behavior. J Exp Psychol Gen 122:411– 428.
Kovner R, Budman C, Frank Y, Sison C, Lesser M, Halperin J (1998): Neuropsy-
chological testing in adult attention deficit hyperactivity disorder: A
pilot study. Int J Neurosci 96:225–235.
Lijffijt M, Kenemans JL, Verbaten MN, van Engeland H (2005): A meta-analytic
review of stopping performance in attention-deficit/hyperactivity disorder:
Deficient inhibitory motor control? J Abnorm Psychol 114:216 –222.
Logan G, Schachar R, Tannock R (2000): Executive control problems in child-
hood psychopathology: Stop signal studies of attention deficit hyperac-
tivity disorder. In: Monsell S, Driver J, eds. Control of Cognitive Processes:
Attention and Performance XVIII. Cambridge, MA: MIT Press, 653-677.
Logan GD (1994): On the ability to inhibit thought and action: A users’ guide
to the stop signal paradigm. In: Dagenbach D, Carr TH, eds. Inhibitory
Processes in Attention, Memory and Language. New York: Academic Press,
189-239.
Lovejoy DW, Ball JD, Keats M, Stutts ML, Spain EH, Janda L, et al. (1999): Neuro-
psychological performance of adults with attention deficit hyperactivity
disorder (ADHD): Diagnostic classification estimates for measures of frontal
lobe/executive functioning. J Int Neuropsychol Soc 5:222–233.
Martinussen R, Hayden J, Hogg-Johnson S, Tannock R (2005): A meta-analy-
sis of working memory impairments in children with attention-deficit/
hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 44:377–384.
McLean A, Dowson J, Toone B, Young S, Bazanis E, Robbins TW, et al. (2004):
Characteristic neurocognitive profile associated with adult attention-
deficit/hyperactivity disorder. Psychol Med 34:681– 692.
Mecarelli O, Vicenzini E, Pulitano P, Vanacore N, Romolo FS, Di Piero V, et al.
(2004): Clinical, cognitive, and neurophysiologic correlates of short-term
BIOL PSYCHIATRY 2007;61:1395–1401 1401
treatment with carbamazepine, oxcarbazepine, and levetiracetam in
healthy volunteers. Ann Pharmacother 38:1816 –1822.
Mehta MA, Goodyer IM, Sahakian BJ (2004): Methylphenidate improves
working memory and set-shifting in AD/HD: Relationships to baseline
memory capacity. J Child Psychol Psychiatry 45:293–305.
Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD
(2000): The unity and diversity of executive functions and their contribu-
tions to complex “frontal lobe” tasks: A latent variable analysis. Cognit
Psychol 41:49 –100.
Mostofsky SH, Schafer JG, Abrams MT, Goldberg MC, Flower AA, Boyce A, et
al. (2003): fMRI evidence that the neural basis of response inhibition is
task-dependent. Brain Res Cogn Brain Res 17:419 – 430.
Murphy KR, Barkley RA, Bush T (2001): Executive functioning and olfactory
identification in young adults with attention deficit-hyperactivity disor-
der. Neuropsychology 15:211–220.
Murphy P (2002): Inhibitory control in adults with attention-deficit/hyperac-
tivity disorder. J Atten Disord 6:1– 4.
Nelson HE, Willison J (1991): National Adult Reading Test (NART) Test Manual.
Windsor, United Kingdom: NFER-Nelson.
Nigg JT (2001): Is ADHD a disinhibitory disorder? Psychol Bull 127:571–598.
Osman A, Kornblum S, Meyer DE (1990): Does motor programming necessi-
tate response execution? J Exp Psychol Hum Percept Perform 16:183–198.
Ossmann JM, Mulligan NW (2003): Inhibition and attention deficit hyperac-
tivity disorder in adults. Am J Psychol 116:35–50.
Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990): Planning
and spatial working memory following frontal lobe lesions in man. Neu-
ropsychologia 28:1021–1034.
Owen AM, Morris RG, Sahakian BJ, Polkey CE, Robbins TW (1996): Double
dissociations of memory and executive functions in working memory
tasks following frontal lobe excisions, temporal lobe excisions or amyg-
dalo-hippocampectomy in man. Brain 119:1597–1615.
Read CL, Stephen LJ, Stolarek IH, Paul A, Sills GJ, Brodie MJ (1998): Cognitive
effects of anticonvulsant monotherapy in elderly patients: A placebo-
controlled study. Seizure 7:159 –162.
Rhodes SM, Coghill DR, Matthews K (2005): Neuropsychological functioning
in stimulant-naive boys with hyperkinetic disorder. Psychol Med
35:1109 –1120.
Rieger M, Gauggel S, Burmeister K (2003): Inhibition of ongoing responses
following frontal, nonfrontal, and basal ganglia lesions. Neuropsychology
17:272–282.
Robbins TW (1998): Dissociating executive functions of the prefrontal cor-
tex. In: Roberts AC, Robbins TW, Weiskrantz L, eds. The Prefrontal Cortex:
Executive and Cognitive Functions. Oxford, United Kingdom: Oxford Uni-
versity Press, 117-130.
Roberts RJ, Hager LD, Heron C (1994): Prefrontal cognitive processing: Work-
ing memory and inhibition in the antisaccade task. J Exp Psychol Gen
123:374 –393.
Roiser JP, Rubinsztein JS, Sahakian BJ (2003): Cognition in depression. Psy-
chiatry 2:43– 47.
Rorden C, Brett M (2000): Stereotaxic display of brain lesions. Behav Neurol
12:191–200.
Rubia K, Smith AB, Brammer MJ, Taylor E (2003): Right inferior prefrontal
cortex mediates response inhibition while mesial prefrontal cortex is
responsible for error detection. Neuroimage 20:351–358.
Schweitzer JB, Lee DO, Hanford RB, Zink CF, Ely TD, Tagamets MA, et al.
(2004): Effect of methylphenidate on executive functioning in adults
with attention-deficit/hyperactivity disorder: Normalization of behavior
but not related brain activity. Biol Psychiatry 56:597– 606.
Sonuga-Barke EJ (2002): Psychological heterogeneity in AD/HD—A dual
pathway model of behaviour and cognition. Behav Brain Res 130:29 –36.
Turner DC, Blackwell AD, Dowson JH, McLean A, Sahakian BJ (2005): Neuro-
cognitive effects of methylphenidate in adult attention-deficit/hyperac-
tivity disorder. Psychopharmacology (Berl) 178:286 –295.
Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ (2004): Modafinil
improves cognition and response inhibition in adult attention-deficit/
hyperactivity disorder. Biol Psychiatry 55:1031–1040.
Valera EM, Faraone SV, Biederman J, Poldrack RA, Seidman LJ (2005): Func-
tional neuroanatomy of working memory in adults with attention-defi-
cit/hyperactivity disorder. Biol Psychiatry 57:439 – 447.
Wodushek TR, Neumann CS (2003): Inhibitory capacity in adults with symp-
toms of attention deficit/hyperactivity disorder (ADHD). Arch Clin Neuro-
psychol 18:317–330.
www.sobp.org/journal