RESEARCH ARTICLE

Deficits in inhibitory control and conflict resolution on cognitiveand motor tasks in Parkinson’s disease

Ignacio Obeso • Leonora Wilkinson • Enrique Casabona • Maria Luisa Bringas •

Mario Alvarez • Lazaro Alvarez • Nancy Pavon • Maria-Cruz Rodrıguez-Oroz •

Raul Macıas • Jose A. Obeso • Marjan Jahanshahi

Received: 28 January 2011 / Accepted: 16 May 2011 / Published online: 4 June 2011

� Springer-Verlag 2011

Abstract Recent imaging studies in healthy controls with

a conditional stop signal reaction time (RT) task have

implicated the subthalamic nucleus (STN) in response

inhibition and the pre-supplementary motor area (pre-SMA)

in conflict resolution. Parkinson’s disease (PD) is charac-

terized by striatal dopamine deficiency and overactivity of

the STN and underactivation of the pre-SMA during

movement. We used the conditional stop signal RT task to

investigate whether PD produced similar or dissociable

effects on response initiation, response inhibition and

response initiation under conflict. In addition, we also

examined inhibition of prepotent responses on three

cognitive tasks: the Stroop, random number generation and

Hayling sentence completion. PD patients were impaired on

the conditional stop signal reaction time task, with response

initiation both in situations with or without conflict and

response inhibition all being significantly delayed, and had

significantly greater difficulty in suppressing prepotent or

habitual responses on the Stroop, Hayling and random

number generation tasks relative to controls. These results

demonstrate the existence of a generalized inhibitory deficit

in PD, which suggest that PD is a disorder of inhibition as

well as activation and that in situations of conflict, execu-

tive control over responses is compromised.

Keywords Fronto-striatal circuits � Parkinson’s disease �Subthalamic nucleus � Inhibition � Stop signal task

Introduction

The basal ganglia and the frontal cortex are intimately

connected via the fronto-striatal circuits, and direct, indi-

rect and hyperdirect pathways between these structures

have been delineated (Alexander et al. 1986; Middleton

and Strick 2000). The direct and indirect pathways have

been proposed to constitute an ideal system for response

selection and initiation under competition or conflict, with

the indirect pathway via the subthalamic nucleus (STN)

inhibiting inappropriate responses to allow selection and

initiation of the appropriate response through the direct

pathway (e.g. Chevalier and Deniau 1990; Redgrave et al.

1999). In Parkinson’s disease (PD), degeneration of dopa-

minergic neurons in the pars compacta of the substantia

nigra alters the balance of activity in the direct and indirect

pathways, the net effect of which increased inhibitory

outflow from the internal segment of the globus pallidus

I. Obeso � L. Wilkinson � M. Jahanshahi (&)

Cognitive-Motor Neuroscience Group, Sobell Department

of Motor Neuroscience and Movement Disorders, UCL Institute

of Neurology, The National Hospital for Neurology and

Neurosurgery, 33 Queen Square, London WC1N 3BG, UK

e-mail: m.jahanshahi@ion.ucl.ac.uk

E. Casabona � M. L. Bringas � M. Alvarez � L. Alvarez �N. Pavon � R. Macıas

Movement Disorders and Neurophysiology Units, Centro

Internacional de Restauracion Neurologica (CIREN),

La Habana, Cuba

M.-C. Rodrıguez-Oroz � J. A. Obeso

Department of Neurology, Clınica Universitaria and Medical

School of Navarra, Neuroscience Centre, CIMA,

University of Navarra, Pamplona, Spain

M.-C. Rodrıguez-Oroz � J. A. Obeso

Centro de Investigacion Biomedica en Red Sobre Enfermedades

Neurodegenerativas (CIBERNED), Instituto Carlos III,

Ministerio de Investigacion y Ciencias, Barcelona, Spain

Present Address:L. Wilkinson

Brain Stimulation Unit, National Institute of Neurological

Disorders and Stroke, Bethesda, MD 20892-1430, USA

123

Exp Brain Res (2011) 212:371–384

DOI 10.1007/s00221-011-2736-6

(GPi), and a resultant reduced activation of cortical pro-

jection sites via the thalamus (DeLong 1990). Conse-

quently, frontal areas such as the pre-supplementary motor

area (pre-SMA) are underactivated in PD during self-gen-

erated or self-initiated movement (Playford et al. 1992;

Jahanshahi et al. 1995). In the indirect pathway, reduced

external segment of the globus pallidus (GPe) output is

associated with increased and abnormally synchronized

STN neuronal activity (e.g. Vila et al. 1997; Kuhn et al.

2009), and this abnormal activity is considered a key

pathophysiological feature of PD and the rationale for

surgical treatment of the disorder with deep brain stimu-

lation (DBS) of the STN.

The stop signal reaction time (RT) task (Logan and

Cowan 1984) has been widely used for the assessment of

inhibition of overt motor responses. A conditional version of

the stop signal RT task (Aron et al. 2007) has the advantage

that it allows concurrent assessment of response initiation,

response inhibition and response initiation under conflict.

The conditional stop signal RT is a two-choice RT requiring

responses to left or right pointing arrows. For each partici-

pant, one of the arrows is assigned as the ‘critical’ and the

other as the ‘non-critical’ direction, with the instruction to

inhibit responses when a stop signal is presented after a

‘critical’ go stimulus but to respond as usual when a stop

signal follows a go stimulus in the ‘non-critical’ direction.

This conditional task requires response initiation on some

trials (‘critical’ or ‘non-critical’ go trials), suppression of a

prepared response on other trials (‘critical’ stop signal trials)

and response initiation under conflict (‘non-critical’ stop

signal trials) on yet another set of trials. Of interest in rela-

tion to the pathophysiology of PD is the demonstration in an

imaging study with healthy participants that on the condi-

tional stop signal task, relative to the Go trials, both suc-

cessful stopping on ‘critical’ stop trials and conflict induced

slowing on ‘non-critical’ stop trials are associated with

significant activation of the ‘braking’ network of right

inferior frontal cortex (IFC), STN and pre-SMA (Aron et al.

2007). Based on correlations between activation in the IFC

and STN with each other and with the stop signal RT

(SSRT), it was proposed that these two areas formed an

inhibition network for stopping. In contrast, the pre-SMA

activation did not significantly correlate with SSRT but

increased in proportion to the conflict induced slowing of

RTs on non-critical stop signal trials and hence was con-

sidered to play a role in conflict monitoring/resolution.

In light of evidence for the overactivity of the STN and

underactivity of the pre-SMA as pathophysiological fea-

tures of PD and that PD patients exhibit deficits in inhibitory

control (Cooper et al. 1994; Gauggel et al. 2004; Bokura

et al. 2005; Baglio et al. 2009; Beste et al. 2009) and in

conflict resolution (Praamstra and Plat 2001; Seiss and

Praamstra 2004, 2006; Wylie et al. 2005, 2009a), the aim of

this study is to investigate both inhibition of a prepared

response and response initiation under conflict in the same

PD cohort of patients. We used the conditional stop signal

RT task to determine whether movement-related underac-

tivation of the pre-SMA and overactivity of the STN in PD

produce consistent or dissociable effects on response initi-

ation (Go RTs), response inhibition (SSRT) and response

initiation under conflict (conflict induced slowing, CIS).

Furthermore, to test the generality of inhibitory deficits in

PD across motor and cognitive domains, we also included

three cognitive tasks requiring executive control: the

Stroop, random number generation and the Hayling Sen-

tence Completion test in which selection of the correct

response necessitates inhibition of alternative competing,

prepotent or habitual responses. We predicted that (1)

inhibition of a prepared response as well as response initi-

ation under conflict would both be impaired on the condi-

tional stop signal RT in PD relative to age-matched healthy

controls and (2) relative to controls, patients with PD would

show concurrent deficits in volitional suppression of pre-

potent responses across both motor and cognitive tasks.

Methods

Participants

Eighteen right-handed individuals with a clinical diagnosis

of idiopathic PD (12 men, mean age = 55.72, SD = 6.7)

were recruited from the outpatients clinic at the Centro In-

ternacional de Restauracion Neurologica (CIREN), Havana,

Cuba. The patients were consecutive referrals for functional

neurosurgery and were assessed prior to surgery. The Uni-

fied Parkinson’s Disease Rating Scale (UPDRS) was used to

obtain a measure of disease severity when patients were off

their usual medication. All patients met the UK Brain Bank

diagnostic criteria for PD (Hughes et al. 1992), had a good

dopaminergic response, and absence of atypical symptoms.

The sample had advanced illness (UPDRS III M = 42.00,

SD = 12.4). All patients were non-demented as demon-

strated by scores[26 on the mini–mental state examination

(MMSE; Folstein et al. 1975). The patients were also

screened for clinical depression (scores [18) on the Beck

Depression Inventory (BDI; Beck et al. 1961). While three

patients had a score above the cut-off, these high scores were

related to the negative impact of living with PD, and there

was no evidence of clinical depression as established during

neurological examination and the NeuroPsychiatric Inven-

tory (NPI) interview. The patients were treated with levo-

dopa and dopamine agonists and were assessed on their

usual medication. For each patient, the levodopa equivalent

dose (LEDD) was calculated following the procedures of

Williams-Gray et al. (2007).

372 Exp Brain Res (2011) 212:371–384

123

Twenty-nine volunteers (16 men, 23 right-handed) aged

between 45 and 68 (M = 57.13, SD = 6.8) took part in the

study. The control group was recruited via advertisement

and was assessed at the UCL Institute of Neurology, UK,

by the same investigator (IO) who completed the patient

assessments in Havana. None of the controls had any

neurological disorder or history of psychiatric illness or

drug or alcohol abuse, and none were taking any medica-

tion. Information about the patients with PD and the con-

trols is presented in Table 1.

The study was approved by The National Hospital for

Neurology and Neurosurgery and Institute of Neurology

Joint Research Ethics Committee as well as the Cuban

National Ethical Committee. Informed consent was

obtained prior to participation in the study.

Conditional stop signal task

The conditional stop signal task employed here was—with

the exception of the use of a visual rather than auditory stop

signal—otherwise identical to that used by Aron et al.

(2007). It allowed measurement of both (a) how well a

participant can inhibit an already initiated response and

(b) the time it takes to initiate a response under conditions

of conflict or ‘conflict induced slowing’. The stop signal

task consisted of a combination of Go and Stop trials. On

Go trials, a left (or right) pointing green arrow was pre-

sented 500 ms after presentation of a black circular fixation

point in the centre of a computer screen, and participants

had to respond as fast as possible using their index and

middle fingers of their dominant hand to press a left or right

key. On Stop trials (25% of all trials), a stop signal (red

cross) was presented after a variable stop signal delay

(SSD) following the green arrow. For each participant,

either the left or right pointing arrows were designated as

the ‘critical’ direction. When a stop signal was presented

following an arrow/go signal in the ‘critical’ direction, the

participants had to stop their response. In contrast, when a

stop signal was presented following an arrow/go signal in

the ‘non-critical’ direction, participants were instructed to

ignore the stop signal and respond to the ‘non-critical’ go

signal. For 10/18 PD patients and 14/29 controls, the

‘critical’ direction was left, and for 8/18 PD patients and

15/29 of the controls, it was right. There were three blocks

of trials consisting of 32 Stop and 96 Go trials per block

(128 total trials per block) presented in a randomized order.

In each block, the number of left and right pointing arrows

was equal. Durations from 0.5 to 4 s were inserted as null

events between the Stop or Go trials.

A trial began with the presentation of a black circular

fixation point in the centre of the screen. This was replaced

after 500 ms by the presentation of a green arrow in the

centre of the screen. The green arrow remained on the

screen a maximum of two seconds (limited hold), followed

by the background screen during the null period. If a par-

ticipant responded within the limited hold length, the arrow

disappeared, leaving the background screen and the null

period.

On Stop trials, the green arrows were replaced by a red

cross at some stop signal delay (SSD) after the green arrow.

The SSD value for the Stop trials was sampled from one of

four staircases, changing dynamically throughout the task

based on the participant’s behaviour. Initially, the four

staircases started with SSD values of 100, 150, 200 and

250 ms, respectively. For each SSD, successful inhibition

of a response on a Stop trial made inhibition more difficult

on the next Stop trial by increasing the SSD by 50 ms. In

contrast, if the response was not successfully inhibited,

then inhibition became easier by decreasing the SSD by

50 ms. Staircases of four step-up and step-down algorithms

were used in this way to ensure convergence to P(inhibit)

of 50% by the end of the three blocks. This allowed us to

obtain measures of each individual’s mean SSD when the

probability of them successfully inhibiting their behaviour

is at 50%. This is required to estimate participants’ SSRT.

As each block had 32 Stop trials, 16 of these Stop trials

were for the ‘critical’ direction. Therefore, each staircase

moved four times within each block for the Stop trials of

the ‘critical’ direction. SSDs for the Stop trials of the ‘non-

critical’ direction were yoked to the ‘critical’ direction

values. The staircases were independent but were randomly

mixed in a block of trials.

Participants were instructed that the most important

aspect of the task was to respond to the green arrows by

pressing the correct response key as fast and as accurately

as possible; while at the same time, they should also look

Table 1 Demographic and clinical characteristics of the patients with Parkinson’s disease (PD) and healthy controls

Group Age MMSE BDI UPDRS III (off med) Disease duration (years)

Parkinson’s disease (n = 18) 55.72 (6.7) 28.11 (1.3) 14.00 (8.2) 42.00 (12.4) 9.39 (2.9)

Controls (n = 29) 57.03 (6.9) 29.59 (.6) 6.07 (5.1)

P .41 .001 .001

Mean values are shown; the numbers in parentheses are standard deviations. MMSE mini–mental state examination, BDI Beck Depression

Inventory, UPDRS III Unified Parkinson’s Disease Rating Scale part III

Exp Brain Res (2011) 212:371–384 373

123

out for the appearance of the red cross and try to withhold

their response to the green arrow on the occasions when the

red cross followed a green arrow pointing in the ‘critical’

direction. In addition, participants were informed that due

to the variable nature of the SSD, it would not always be

possible to stop their response on ‘critical’ stop trials.

Finally, participants were specifically instructed not to let

their performance on the stopping task interfere with their

performance on the Go task, and in particular, they were

asked not to delay their performance on the Go task in

order to improve their chances of stopping after green

arrows pointing in the ‘critical’ direction. Following these

instructions, 20 practice trials were completed. Each block

was preceded by an instruction screen and ended with

presentation of the mean correct reaction time (RT) and the

number of discrimination errors on the Go trials.

Several RT measures were computed to the nearest ms:

mean Go RT for both ‘critical’ and ‘non-critical’ trials,

percentage of Stop trials with successful inhibition (Stop-

Inhibit) for the ‘critical’ direction, number of Stop trials

resulting in inhibition for the ‘non-critical’ direction and

mean RT on Stop trials without successful inhibition

(StopRespond) for both ‘critical’ and ‘non-critical’ direc-

tions. Similar to Aron et al. (2007), one of the main

comparisons of interest was ‘non-critical’ Stop trials minus

‘non-critical’ Go trials, which is the measure of ‘conflict-

induced slowing’. Additionally, we also looked at suc-

cessful inhibition using the standard Race Model (Logan

and Cowan 1984) to compute the stop signal reaction time

(SSRT). We estimated SSRT by subtracting the average

SSD from the mean correct ‘critical’ Go RT. Due to the

dynamic adjusting of the SSD, we computed the average

SSD for each participant, using the values of the four

staircases after the participant had converged on 50%

P (inhibit) which similar to Aron et al. (2007) was aver-

aged from the mean values for the last six moves in each

staircase. Discrimination errors (using the incorrect finger

to press the wrong key for the right or left stimulus pre-

sented) and omission errors (failure to respond to a go

signal in the ‘critical’ or ‘non-critical’ direction) and

commission errors (responding to a stop signal presented

after a ‘critical’ go trial which resulted in the ‘critical’

StopRespond RTs) were recorded.

Other tests of inhibition

Hayling sentence completion test (Burgess and Shallice

1997)

In the Hayling sentence completion test, participants

complete a series of sentences from which the last word is

missing. For the assessment of the patients in Cuba, we

produced a Spanish version of the Hayling test using the

same sentences where possible or constructing closely

related sentences with a high-frequency missing word in

Spanish, which were pre-tested, on 50 Cuban healthy

participants. The test has two sections: (1) Section A:

response initiation: participants were instructed to provide

an appropriate word to complete a sentence from which the

last word is missing. For example, ‘the captain wanted to

stay with the sinking…’ for which the word ‘ship’ would

be an appropriate response and (2) Section B: response

suppression: For each sentence read out, participants were

required to provide a word that made no sense at all in the

context of the sentence. For example, ‘Most cats see very

well at …’ for which ‘night’ is the high-frequency word

that has to be suppressed and ‘banana’ would be an

appropriate and unrelated response. The response time (i.e.

mean response latency across all items measured with a

stopwatch) was measured separately for sections A and B.

In addition, in section B, for each item, an error score was

obtained by classifying responses as belonging to category

A (connected to the meaning of the sentence) or category B

(somewhat related to the meaning of the sentence). Using

the scoring guidelines and normative data provided in the

Hayling manual, RTs for sections A and B were converted

using the normative Hayling table, and scaled scores for

the combined Type A and B errors in section B were

obtained. The higher the converted scores are, the better

performance in the test.

Stroop interference test (Stroop 1935)

The Stroop test assesses the ability to inhibit the prepotent

response of reading words in order to produce the alter-

native response of naming the colour of ink the words are

printed in. Based on the Delis–Kaplan battery (2001), we

used the colour naming as the control condition along with

the Stroop interference condition. In the control condition,

the participant had to name aloud the colour of 100 col-

oured rectangles printed in blue, red or green. In the Stroop

interference condition, the participant had to name the

colour of ink of the colour words blue, red or green printed

in an incongruent colour. A Spanish version of the task was

used for the interference condition where colour words

were written in Spanish. For each condition, the total

completion time, the number of self-corrected and uncor-

rected errors was recorded.

Random number generation (Jahanshahi et al. 1998, 2000)

Participants were asked to generate numbers from 1 to 9 in

a random fashion for 100 trials in synchrony with a pacing

visual stimulus presented at 1 Hz. The concept of ran-

domness was explained with the analogy of picking out

numbers out of a hat with replacement. The 100 numbers

374 Exp Brain Res (2011) 212:371–384

123

generated by the participant were recorded as well as the

total time taken to generate them. Participants generated

numbers in their mother tongue. To measure randomness,

we obtained count scores that are measures of seriation

during random number generation (RNG), based on the

method of Spatt and Goldenberg (Spatt and Goldenberg

1993). Count Score 1 (CS1) and Count Score 2 (CS2)

measure the number of times the participant counts in

ascending or descending series, respectively, in steps of

one or steps of two. In calculating the count scores, the

sequence length is squared to give higher weights to runs of

longer sequences. High count scores indicate an inability to

suppress habitual counting tendencies during RNG.

Results

Patient and control groups did not differ significantly in

terms of age [t(45) = -.82, P = .41], sex distribution

[v(1) = 1.65, P = .19] or handedness [t(21.3) = -1.47,

P = .15]. Although none of the PD patients were demented

or clinically depressed, nevertheless as a group they scored

significantly lower than controls on the MMSE and signifi-

cantly higher on the BDI (see Table 1). One patient and one

control were excluded as they failed to reach the criterion of

successful inhibition on approximately 50% of trials.

Conditional stop signal task

Critical trials

The data relating to the conditional stop signal task are

presented in Table 2. The dynamic adjustment of SSD

converged on probabilities of inhibition that were close to

50% and these percentages did not differ significantly

between groups (Table 2), which is a prerequisite for cor-

rect interpretation of the results. For the patients, the mean

SSD (M = 183.69, SD = 98.2) was shorter than the mean

SSD for the controls (M = 209.15, SD = 95.2), but the

difference was not significant [t(45) = -.88, P = .38].

Using the Race Model, SSRT was estimated at

289.86 ms (SD = 48.1) for controls and 382.41 ms

(SD = 94.1) for PD patients, with the patients having

significantly longer SSRTs than the controls [t(22.5) = 3.87,

Table 2 Mean reaction time (RT, in milliseconds) and error data for the conditional stop signal reaction time task for the patients with

Parkinson’s disease (PD) and the healthy controls

Trial description Measure PD patients Controls P

‘Critical’ direction

Goa RT 566.10 (124.0) 495.69 (89.7) .02*

StopInhibit % Correct inhibition 53.56 (10.9)% 52.59 (10.1)% .76§

StopRespond RT 568.96 (118.3) 465.85 (79.6) .003**

Go errors Number of omissions 5.06 (6.8) .62 (1.0) .001§**

‘Non-critical’ direction

Go RT 513.32 (96.8) 433.14 (44.3) .003**

StopInhibit % Incorrect inhibition 7.32 (5.7)% 3.10 (4.4)% .01*

StopRespondb RT 678.61 (164.7) 552.30 (78.9) .006*

Go errors Number of omissions 3.44 (4.4) .45 (.7) .001§*

Other variables

Go discrimination errors Number of errors 1.83 (3.4) .45 (.6) .11§

Mean SSD Time 183.69 (98.2) 209.15 (95.2) .38

SSRT RT 382.41 (94.1) 289.86 (48.1) .001**

Conflict induced slowing (CIS) Time 165.29 (93.3) ms 119.15 (67.6) ms .05*

Standard deviations are given in brackets

SSD the average stop signal delay, computed from four staircases (see ‘Methods’) at the point at which P(inhibit) = *50%

SSRT is computed for each participant by subtracting the mean SSD from the mean critical Go RT

Go omission errors failure to respond on a go trial

Go discrimination errors pressing the response key in the opposite direction indicated by the stimulus

CIS the cognitive induced slowing measured by subtracting mean non-critical Go RTs from mean non-critical StopRespond RTs

** Ps \ .005; * Ps \ .05; § Mann–Whitney test used. The rest were independent samples t testsa Mean ‘critical’ Go RTs are significantly slower than mean ‘non-critical’ Go RTs (P \ .01) between groups comparisonb Mean ‘critical’ StopRespond RTs were significantly slower than mean ‘non-critical’ StopRespond RTs in controls (P \ .01) but not in the PD

group

Exp Brain Res (2011) 212:371–384 375

123

P = .001] (Fig. 1). In addition, as expected the StopRe-

spond RTs (M = 465.85, SD = 79.6) of the controls were

faster than their Go RTs (M = 495.69, SD = 89.7), a

difference that approached significance (t(28) = 1.9,

P = .06) by an average of 29 ms; whereas for the PD

patients, StopRespond RTs (M = 568.96, SD = 118.3) did

not differ from Go RTs (M = 566.10, SD = 124.0,

t(17) = -.11, P = .90).

On ‘critical’ Go trials, controls responded quickly and

accurately (Table 2; Fig. 1). In contrast, PD patients

responded significantly slower on ‘critical’ Go trials than

controls, and they made significantly more omission errors

(Table 2). Furthermore, PD patients made more discrimina-

tion errors than controls, albeit non-significantly so (Table 2).

‘Non-critical’ trials

For ‘non-critical’ trials, one of the main measures of

interest is the difference between mean ‘non-critical’ Go

RTs and mean ‘non-critical’ StopRespond RTs as this

provides a measure of ‘conflict induced slowing’ (CIS). To

establish whether RTs differed significantly in the two

groups across trial types, an ANOVA was performed on

mean ‘non-critical’ RT with Trial Type (Go vs. StopRe-

spond) as a within-subject variable and Group as a

between-groups variable. This analysis revealed a signifi-

cant main effect of Trial Type [F(1,45) = 146.26, P \ .001]

because, overall, ‘non-critical’ StopRespond RTs were

slower than the non-critical Go RTs, which is indicative of

the CIS effect due to the conditional nature of stopping.

There was also a significant main effect of Group

[F(1,45) = 14.96, P \ .001], showing that, overall, the

Control group had faster ‘non-critical’ RTs relative to the

PD group. Most importantly, there was a significant

Group 9 Trial Type interaction [F(1,45) = 3.84, P = .05],

indicating that the magnitude of the CIS effect was sig-

nificantly larger in the PD than in the Control group.

In light of the significant Group 9 Trial Type interac-

tion, post hoc analysis of the group differences on the

‘non-critical’ direction was undertaken. Similar to critical

Go trials, PD patients responded significantly slower on

‘non-critical’ Go trials than controls (Table 2). In addition,

the ‘non-critical’ StopRespond RT, [recall in this instance

is the RT for correct responses following a ‘non-critical’

stop signal, (i.e. a ‘to be ignored’ stop signal)], was also

significantly longer in PD patients relative to controls

(Table 2). A difference score measure of CIS was calcu-

lated for each participant by subtracting mean ‘non-critical’

Go RTs from the mean ‘non-critical’ StopRespond RT.

Therefore, a positive CIS difference score is indicative of

higher CIS or greater slowing under conflict. The mean CIS

in the PD group (M = 165.29, SD = 93.3) was signifi-

cantly greater for the controls (M = 119.15, SD = 67.6,

t(45) = 1.96, P = .05) (Fig. 2).

Patients made significantly more errors of omission on

‘non-critical’ Go trials than controls (Table 2). Further-

more, PD patients incorrectly inhibited their responses and

failed to respond on ‘non-critical’ Stop trials significantly

more often than controls (Table 2).

In both groups, Go RTs in the ‘critical’ direction were

slower than Go RTs in the ‘non-critical’ direction, with the

differences being significant for the controls (t(28) = 5.69,

P \ .001) and the PD patients (t(17) = 2.52, P = .02).

Controlling for group differences in Go RTs, depression

and global cognitive ability

To control for group differences in Go RTs, ANCOVAs were

performed to compare group differences in SSRT and CIS

after co-varying out the critical Go RTs. Group differences in

the SSRT, [F(1,44) = 13.22, P \ .01] and the CIS, [F(1,44) =

3.83, P = .05] remained significant even after co-varying out

group differences in ‘critical’ Go RTs. These results suggest

that the delayed inhibition (SSRT) and delayed response

initiation under conflict (CIS) of the PD patients were not

solely attributable to their slowed Go RTs.

The two groups also differed significantly in MMSE and

BDI scores. Therefore, to control for the contribution of

Fig. 1 a Mean RTs in

milliseconds in the ‘critical’

direction for the Go and

StopRespond (trials with a stop

signal on which participants

failed to stop and responded)

trials for PD patients and

healthy controls. b The mean

stop signal reaction times

(SSRT) for the patients (whitebars) and the healthy controls

(black bars). An asteriskindicates a significant difference

between groups. Error barsdepict standard errors

376 Exp Brain Res (2011) 212:371–384

123

cognitive impairment and self-reported depression to SSRT

and CIS, the group differences were re-examined using

these scores as covariates. SSRT differences between

groups remained significant after co-varying out the effect

of MMSE [F(1,44) = 10.49, P \ .01] and BDI [F(1,44) =

17.21, P \ .001]. The group differences in CIS did not

remain significant after co-varying out MMSE [F(1,44) =

4.48, P = .47] and approached significance after co-vary-

ing out BDI [F(1,44) = 3.59, P = .06].

Other tests of inhibition

Hayling sentence completion test

To compare the mean converted response times for Hay-

ling sections A (initiation) and B (inhibition) for the PD

(Section A converted response times: M = 5.24,

SD = 1.1, Section B converted response times: M = 5.24,

SD = 1.0) and controls (Section A converted response

times: M = 6.07, SD = .9, Section B converted response

times: M = 5.48, SD = .8), an ANOVA was performed on

Hayling Section (A vs. B) as a within-subject variable and

Group as a between-groups variable. This analysis revealed

a significant Group 9 Hayling Section interaction

[F(1,45) = 4.59, P = .03], indicating that the degree of

difference between performance on sections A and B (or

the ‘Hayling effect’) differed significantly between the

groups. Similarly, the main effects of Hayling Section

[F(1,45) = 4.59, P = .03] and Group were significant

[F(1,45) = 4.80, P = .03]. In light of the significant inter-

action, we compared the difference score in response times

between sections A and B of the Hayling (Hayling effect)

for the patients and controls. This difference score was

significantly higher/better for the controls than the PD

patients (t(45) = 2.96, P = .03), due to the fact that the

patients failed to modulate their response times as a func-

tion of Hayling section whereas the controls did so.

PD patients made significantly more Type A errors rela-

tive to controls (PD M = 14.69, SD = 14.7, Control

M = 5.18, SD = 6.5, Mann–Whitney U = -2.89,

P \ .01). The Type B errors were again significantly

greater in PD patients (M = 9.75, SD = 9.5) compared to

Controls (M = 1.39, SD = 1.4, Mann–Whitney U =

-4.01, P \ .001). These clearly indicate that PD patients

found it difficult to withhold the prepotent response in sec-

tion B of the Hayling test (Fig. 3).

The mean global scaled score on the Hayling test was

significantly better for the controls (Control M = 5.90,

SD = 1.1) than the PD patients (PD M = 4.06, SD = 1.6,

t(45) = -4.29, P \ .001), indicating impairment of

suppression of prepotent response for the PD patients rel-

ative to the controls. Using the MMSE and BDI as

covariates, the differences in Hayling global score between

the groups were still significant after co-varying out MMSE

[F(1,45) = 5.00, P = .03] and BDI [F(1,45) = 13.57,

P = .001].

Stroop interference task

Figure 4 shows the mean total completion time for the

control and inhibition conditions of the Stroop test, plotted

separately for the two groups. An ANOVA was performed

on mean total completion time with Condition (control vs.

interference) as a within-subject variable and Group as a

between-groups variable. This analysis revealed significant

main effects of Group [F(1,45) = 40.43, P \ .001]—

showing that PD patients were significantly slower than

controls across both Stroop conditions and Condition

[F(1,45) = 200.69, P \ .001]. The Group 9 Condition

interaction [F(1,45) = 6.15, P \ .01] was also significant,

Fig. 2 a Mean RTs in milliseconds in the ‘non-critical’ direction for

the Go and StopRespond trials (trials on which a stop signal was

presented which participants were instructed to ignore and respond)

for PD patients and the healthy controls. b Mean conflict induced

slowness (CIS) in milliseconds plotted for PD patients (white bars)

and healthy controls (black bars). An asterisk indicates a significant

difference between groups. Error bars depict standard errors

Exp Brain Res (2011) 212:371–384 377

123

indicating that the magnitude of the PD versus control

differences was differentially greater for the Stroop inter-

ference than the control task. In light of the significant

Group 9 Condition interaction, we examined group dif-

ferences in the difference score (interference - control),

which was significantly larger for the PD patients (M =

33.16, SD = 16.5) than controls (M = 20.66, SD = 13.0,

t(44) = 2.85, P \ .01), confirming a significantly greater

‘Stroop effect’ and conflict induced slowing for the patients

(Fig. 4). Furthermore, the Group 9 Condition interaction

remained significant after co-varying out MMSE [F(1,45) =

3.9, P = .05] and BDI [F(1,45) = 6.29, P = .01], showing

that the differences in the magnitude of the Stroop effect

between groups was significant above and beyond any

effects of cognitive impairment or depression.

For the interference condition, PD patients (M = 2.31,

SD = 4.1) made significantly more uncorrected errors than

controls (M = .18, SD = .6, Mann–Whitney U = -3.03,

P \ .01). For the control condition, there was a significant

difference between the number of uncorrected errors made

by PD patients (M = 1.28, SD = 1.2) and controls (M =

.03, SD = .18, Mann–Whitney U = -4.75, P \ .001). For

the interference condition, PD patients (M = 1.88,

SD = 1.5) made significantly more self-corrected errors

than controls (M = .50, SD = .9, Mann–Whitney U =

-3.28, P = .001). For the control condition, there was a

significant difference between the number of self-corrected

errors made by PD patients (M = 1.31, SD = 1.3) and

controls (M = .03, SD = .1, Mann–Whitney U = -4.42,

P \ .001).

Random number generation

Figure 5 shows mean CS1 and CS2 scores on the RNG test,

plotted for the two groups. An ANOVA was performed on

mean count scores with Measure (CS1 vs. CS2) as a

within-subject variable and Group as a between-groups

variable. This analysis revealed significant main effects of

Measure [F(1,41) = 25.94, P \ .001] and Group [F(1,41) =

14.1, P \ .001] and a significant Group 9 Measure

[F(1,41) = 4.22, P = .04] interaction. In light of the sig-

nificant Group 9 Measure interaction, post hoc analyses

were performed to compare group differences in CS1 and

CS2 scores. The patients (M = 92.13, SD = 40.7) had

significantly higher CS1 scores than controls (M = 58.93,

Fig. 3 Mean converted Type A and Type B errors (see text for

description) on the Hayling test, for PD patients and healthy controls.

An asterisk indicates a significant difference between groups. Errorbars depict standard errors

Fig. 4 Mean total completion time in milliseconds on the colour

naming control condition and the main inhibition condition of the

Stroop for PD patients and healthy controls. An asterisk indicates a

significant difference between groups. Error bars depict standard

errors

Fig. 5 Mean total count score 1 (CS1) and count score 2 (CS2) for

the random number generation task for PD patients and healthy

controls. An asterisk indicates a significant difference between

groups. Error bars depict standard errors

378 Exp Brain Res (2011) 212:371–384

123

SD = 26.3 t(41) = 3.2, P \ .01), but the two groups did

not differ in terms of CS2 scores (PD: M = 47.06,

SD = 25.0; Controls M = 39.78, SD = 12.9, t(41) = 1.2,

P = .21). The Group 9 Measure interaction was no

longer significant when group differences in MMSE

[F(1,41) = 1.5, P = .22] and BDI scores were covaried out

[F(1,41) = 1.5, P = .26].

Correlational and regression analysis

For the PD group, we examined the association between

the two key variables from the stop signal task that is

SSRT and CIS and other variables of interest on this task

(omission errors on ‘critical’ and ‘non-critical’ direction,

discrimination errors) and demographic and clinical vari-

ables (age, UPDRS, LEDD, duration of illness, MMSE

and BDI) and cognitive measures of inhibition (Hayling

Type A, Type B errors and global score; Stroop control

and interference response times; and RNG CS1 scores).

Table 3 shows both significant and non-significant corre-

lations between either SSRT or CIS and the demographic,

clinical and cognitive inhibition measures. None of the

remaining correlations were of a sizeable magnitude

(above 0.47) or significant.

To identify the variables that contributed to the variance

of SSRT and CIS, two multiple regression analyses were

performed in the PD group. In the first regression analysis,

the dependent variable was SSRT. The independent vari-

ables entered as potential predictors were demographic or

clinical variables including age, MMSE, mean LEDD and

the Hayling section B Type A error score. This regression

analysis was significant [F(6,15) = 5.74, P = .05,

R2 = .74]. The Hayling Type A errors [b = .511, t(12) =

2.23, P = 0.043] predicted 26% of the variance of SSRT

(adjusted R2) in PD. In the second regression analysis, CIS

was the dependent variable and in addition to age, and

LEDD, MMSE and Stroop interference condition com-

pletion times, the two variables which had significant

correlations with CIS were the independent variables.

MMSE emerged as the only significant predictor [F(6,15) =

7.16, P = .018, R2 = .338, b = -.582, t(12) = 2.68,

P = .018], which accounted for 29% of the variance of

CIS (adjusted R2) in PD.

Discussion

We found impaired inhibition on the conditional stop

signal task in PD patients relative to age-matched controls.

This impaired motor inhibition in PD was also accompa-

nied by deficits in volitional suppression of habitual or

prepotent responses on three cognitive tests the Hayling

sentence completion test, the Stroop, and fast-paced Ta

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Exp Brain Res (2011) 212:371–384 379

123

random number generation relative to controls. The second

main finding is that PD patients had worse conflict reso-

lution than controls on the conditional stop signal task.

Finally, the prolonged SSRT in PD is not simply due to

motor slowness, reduced cognitive efficiency or depres-

sion, as the group differences from healthy controls

remained significant even after controlling for motor

slowness (Go RTs), MMSE or BDI scores.

We have shown, for the first time, deficits in both

response inhibition and conflict resolution in the same

sample of PD patients, supporting previous evidence on the

role of basal ganglia in executive control of action. Motor

inhibition and conflict resolution are two distinct but inter-

related executive processes, since response initiation under

conflict often requires inhibition of alternative competing

responses. In fact, as noted above, imaging has shown that

on the conditional stop signal RT task used here, both

successful inhibition of responses on ‘critical’ stop trials

and conflict induced slowing on ‘non-critical’ stop trials

are associated with activation of the ‘braking’ network of

right IFC, STN and pre-SMA (Aron et al. 2007). Our

results showing that PD patients have deficits on both

motor inhibition and conflict resolution are consistent with

this and also provide further evidence for a generalized

inhibitory deficit in PD patients and that in situations of

conflict, executive control over responses is compromised

in PD. Below, we will first discuss our findings in relation

to delayed motor inhibition and then conflict induced

slowing in PD.

Delayed inhibition in PD

The PD patients had significantly longer SSRTs than the

age-matched healthy controls, and group differences

remained significant even after co-varying out group dif-

ferences in Go RTs and MMSE, and BDI thus indicating

that the prolonged SSRTs in PD patients were not simply

due to motor slowness, reduced cognitive efficiency or

depression. Our findings on the conditional stop signal RT

task are consistent with the results of Gauggel et al. (2004)

who found significantly longer SSRTs in PD on the standard

stop signal RT task. Similar prolongation of the stop signal

RT relative to orthopaedic controls has been reported in 8

patients with focal lesions of the basal ganglia (Rieger et al.

2003). Evidence from other tasks requiring inhibition of

prepotent responses such as go no go RT (Cooper et al.

1994; Bokura et al. 2005; Baglio et al. 2009; Beste et al.

2009), anti-saccade (Chan et al. 2005; Rivaud-Pechoux

et al. 2007) and flanker (Praamstra and Plat 2001; Seiss and

Praamstra 2004, 2006; Wylie et al. 2005, 2009a) tasks also

supports impairment of inhibitory processes in PD.

The ‘critical’ StopRespond trials are of interest since

these are trials on which the participants failed to inhibit

the response when a stop signal was presented and thus

represent a failure of inhibition. The StopRespond RTs

were significantly slower for the PD patients than the

controls. Furthermore, for the healthy controls, the ‘criti-

cal’ StopRespond RTs were faster than their ‘critical’ Go

RTs by an average of 29 ms, suggesting that the failure to

inhibit the response on these stop signal trials was due to

their faster speed of responding to the Go signal on these

trials. In contrast, such a speed advantage for ‘critical’

StopRespond RTs over ‘critical’ Go RTs was not observed

for the PD patients. This implies that for the PD patients,

failure of inhibition is not simply due to faster RTs on

StopRespond trials, but that other processes such as a

failure to trigger the inhibitory process or lapses of atten-

tion may also be at play. This possibility requires further

investigation in future studies.

Different types of inhibition have been proposed, the

most common distinction being between ‘volitional’ and

‘reactive’ inhibition (e.g. Harnishfeger 1995; Nigg 2000).

Volitional inhibition is intentional and often effortful. It is

necessary for self-control of behaviour, such as stopping

oneself from having another glass of wine or eating another

sweet. Volitional inhibition is also often required for

executive control in conditions involving conflict or inter-

ference from competing responses (e.g. Harnishfeger 1995;

Nigg 2000). Our results provide evidence for impairment

of volitional inhibition in tasks involving interference from

competing responses and hence requiring executive control

in patients with PD. Relative to controls, PD patients were

significantly impaired on the Hayling and Stroop tasks,

similar to previous findings (Brown and Marsden 1988;

Brown and Marsden 1991; Bouquet et al. 2003). A parallel

inability to suppress prepotent and habitual responses and

to engage in strategic response selection is observed during

RNG, during which PD patients produce higher count

scores than matched controls (Brown et al. 1998; Jahan-

shahi et al. 2000; Dirnberger et al. 2005). Our aim in

including the Hayling, Stroop and RNG tasks in the present

study was to demonstrate the cross-task generality of def-

icits in suppression of prepotent responses across tasks

involving both motor (stop signal) and cognitive (Hayling,

Stroop, RNG) volitional inhibition in PD patients. Fur-

thermore, Type A errors on the Hayling task correlated

positively and significantly with SSRT, and the completion

time on the Stroop interference task correlated negatively

and significantly with CIS suggesting an association

between the impairments in motor and cognitive volitional

inhibition in PD.

Response initiation under conflict in PD

The magnitude of the conflict induced slowing/interference

was significantly greater in PD than controls, consistent

380 Exp Brain Res (2011) 212:371–384

123

with previous evidence of deficits in executive control in

PD on tasks involving conflict and requiring volitional

suppression of prepotent responses. While the error rate was

generally low, PD patients made significantly more errors of

omission and discrimination errors on the stop signal RT

task than the controls. Furthermore, instead of ignoring the

stop signal and responding on all ‘non-critical’ trials, PD

patients incorrectly inhibited their responses and failed to

respond on a significantly larger proportion of the ‘non-

critical’ StopRespond trials than the controls. These higher

error rates in PD also suggest the increased susceptibility of

their responses to situations of conflict. These higher error

rates in PD than in controls are also consistent with the

proposal that the basal ganglia together with the anterior

cingulate contribute to error monitoring and the error-rela-

ted negativity which is reduced in PD, thus indicating def-

icits in error detection (Falkenstein et al. 2001).

Inherent in the ‘non-critical’ StopRespond trials is a

conflict between stopping and responding. Thus, on these

trials, the conflict revolves around whether to stop or not,

that is whether to ignore the stop signal (as per experi-

mental instructions) and initiate the prepared response or to

inhibit it. The fact that the StopRespond RTs were the

slowest RTs in both the patient and control groups suggests

that this conflict was operational for all participants.

However, the impact of this conflict was significantly

greater for the PD patients than controls. In addition, as

noted above, the PD patients incorrectly failed to respond

on a significantly larger proportion of the ‘non-critical’

StopRespond trials than the controls.

Similarly, on the Eriksen flanker task, at least in some

studies PD patients were found to show greater interference

effects from the incongruent flanking stimuli (e.g. Praam-

stra and Plat 2001; Wylie et al. 2005, 2009a), particularly

under speed instructions (Wylie et al. 2009b) or when

patients had to inhibit distracters over extended delays

(Cagigas et al. 2007), although others have not found this

(Lee et al. 1999; Falkenstein et al. 2006). This exaggerated

flanker interference effect in PD has been interpreted to

reflect the patients’ reduced ability to suppress the auto-

matic activation of the conflicting response that then

interferes with selection of the correct response indicated

by the target stimulus (Praamstra et al. 1998; Praamstra and

Plat 2001; Wylie et al. 2009a).

In both the PD and control groups, Go RTs in the

‘critical’ direction were significantly slower than Go RTs

in the ‘non-critical’ direction. This indicates that in this

conditional stop signal RT task, the ‘context’ within which

the go signals were presented, whether on the ‘critical’ or

‘non-critical’ trials, influenced the participants’ strategy

and their speed of reaction to the stimuli. When presented

with an arrow in the ‘non-critical’ direction, participants

knew that they had to respond anyway even if a stop signal

was subsequently presented and, therefore, fast RTs were

appropriate. In contrast, on trials with an arrow presented

in the ‘critical’ direction, there was a possibility that it may

be followed by a stop signal, in which case the response

would need to be inhibited. Thus, on ‘critical’ trials when

participants were aware that they might have to stop a

response on a proportion of trials, their Go RTs were

slower. This ‘anticipatory’ or ‘strategic’ slowing of Go RTs

in the context of trials where a proportion of the responses

would have to be subsequently stopped, a sort of

responding with restraint, was present for both patients and

controls and is consistent with previous evidence of pro-

active adjustment of response strategies on the stop signal

RT task (Rieger and Gauggel 1999; Aron et al. 2007;

Verbruggen and Logan 2009a). Such proactive response

strategy adjustments become evident when stop signals are

expected, as a result of which response thresholds are

increased to slow down Go RTs and increase accuracy and

likelihood of stopping (Verbruggen and Logan 2009b).

Theoretical and clinical implications

In a series of elegant experiments in monkeys, Isoda and

Hikosaka (Isoda and Hikosaka 2007, 2008) have provided

evidence that the STN and pre-SMA play a role in

switching from automatic to controlled eye movements.

They proposed that the pre-SMA acts to suppress the

automatic saccade, resolve response conflict and facilitate

selection of the controlled response. The control signal for

switching originating from the pre-SMA is proposed to be

implemented by the STN through its connections with

other basal ganglia nuclei. Such a switch from automatic to

controlled processing captures the essence of executive

control, and the data from Isoda and Hikosaka (2007, 2008)

confirm the engagement of the fronto-striatal system in

higher-order control processes. The evidence from the

current study also suggests that the basal ganglia may be

involved in volitional inhibition necessary for suppression

of the prepotent response in the stop signal RT, Stroop,

Hayling or RNG tasks. There is also some evidence in

support of this proposal from DBS of the STN in PD which

has shown that acute manipulation of the output from the

STN affects performance on tasks involving executive

control such as the Stroop (Jahanshahi et al. 2000; Sch-

roeder et al. 2002; Witt et al. 2004), a go no go RT task

with high target frequency (Hershey et al. 2004), the stop

signal RT (van den Wildenberg et al. 2006; Ray et al.

2009), suppression of habitual counting during fast-paced

RNG (Thobois et al. 2007) and probabilistic decision-

making under conflict (Frank et al. 2007).

When required to engage in conflictual decision-mak-

ing, patients with PD were more impulsive with DBS of the

STN on than off (Frank et al. 2007). With DBS of the STN,

Exp Brain Res (2011) 212:371–384 381

123

PD patients had problems switching from automatic

habitual counting to strategic response selection during

fast-paced RNG, a deficit associated with increased acti-

vation of the GPi and reduced activation of the prefrontal

cortex and anterior cingulate and reduced pallidal-pre-

frontal/cingulate coupling relative to when the stimulators

were off. This hypothesis that in concert with the prefrontal

cortex, the basal ganglia, particularly the STN, are

involved in inhibitory control to enable either switching

from automatic to controlled processing or response

selection under conflict requires direct examination in

future studies.

The two major clinical manifestations related to abnor-

mal dopaminergic activation in PD are levodopa-induced

dyskinesias and impulse control disorders such as patho-

logical gambling, shopping, binge eating and hypersexual-

ity, as well as punding and compulsive medication use

(Voon et al. 2009), which represent failures of inhibition. In

the cognitive domain, impaired set-shifting (Owen et al.

1991; Hayes et al. 1998; Cools et al. 2001, 2003) and

reversal learning (Cools et al. 2002) have been well docu-

mented in PD, both of which require suppressing responses

from one set of criteria guiding behaviour to respond to

another set of criteria. Therefore, some of the motor,

behavioural and cognitive deficits in PD may reflect the

impairment of inhibitory processes revealed in this study.

The study was undertaken with patients in the ‘on’

medication state because the baseline severity of PD pre-

vented adequate performance of the tests in the ‘off’

medication state. Neuropharmacological studies in experi-

mental animals, in healthy participants or in patients with

ADHD suggest that noradrenaline (NA) is a key neuro-

transmitter with an impact on inhibitory control on the stop

signal task (Chamberlain et al. 2006, 2007, 2009). In

contrast, the effect of dopamine on SSRT remains unclear

(for review see Eagle and Baunez 2010). Definitive

assessment of any dissociable effects of levodopa medi-

cation on Go RTs and SSRT in PD awaits assessment in

future on/off medication studies following overnight

withdrawal of medication or through comparison of

untreated (‘de novo’) and chronically medicated PD

patients. Our preliminary results from a study comparing

performance of PD patients on versus off medication on the

conditional stop signal RT task suggest that levodopa

medication does not significantly influence inhibition or

conflict induced slowing as, respectively, measured by the

SSRT and the CIS (Obeso et al., submitted).

Conclusions

We show here, for the first time, that PD patients are

impaired on a conditional version of the stop signal RT

task, with the initiation of motor responses both in situa-

tions with (‘non-critical’ StopRespond RTs and CIS) or

without conflict (‘critical’ Go RTs) and inhibition of a

prepared motor response (SSRT) all being significantly

delayed relative to age-matched controls. PD patients also

had significantly greater difficulty in suppressing prepotent

or habitual responses on the Stroop, Hayling sentence

completion and RNG tasks relative to controls. These

results demonstrate the existence of a generalized inhibi-

tory deficit in PD patients assessed on medication, which

suggests that PD is a disorder of inhibition as well as

activation and that in situations of conflict, executive

control over responses is compromised in PD.

Acknowledgments We are grateful to all the participants. This

work was supported by a PhD studentship from Fundacion Caja

Madrid (IO), a Career Development Fellowship from the Parkinson’s

disease Society (LW) and a Royal Society Travelling Fellowship.

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