health - tdah disentangling deficits in adults with attention-deficit hyperactivity disorder

7/30/2019 Health - Tdah Disentangling Deficits in Adults With Attention-Deficit Hyperactivity Disorder

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ORIGINAL ARTICLE

Disentangling Deficits in Adults WithAttention-Deficit/Hyperactivity Disorder

Evelijne M. Bekker, PhD; Carin C.E. Overtoom, PhD; J.J. Sandra Kooij, MD;Jan K. Buitelaar, PhD, MD; Marinus N. Verbaten, PhD; J. Leon Kenemans, PhD

Context: A lack of inhibitory control has been sug-gested to be the core deficit in attention-deficit/hyperactivity disorder (ADHD), especially in adults. Thismeans that a primary deficit in inhibition mediates a cas-cade of secondary deficits in other executive functions,such as attention. Impaired stopping has been claimedto support the inhibition hypothesis. However, execu-tive functions such as inhibition and attention are hardto disentangle.

Objective: To use event-related potentials in adult pa-tients with ADHD to show that impaired stopping is as-sociated with abnormalities of attention.

Design: The stop signal task was presented to 24 adultswith ADHD combined subtype and 24 controls. Stopevent-related potentials are distorted by overlap fromevent-related potentials to other stimuli in close tempo-ral proximity, but we applied a method (Adjar level 2)to effectively remove this overlap.

Results: In line with an inhibitory control deficit, thestop signal reaction time was longer in adults withADHD (F1,46=7.12, P.01) whereas there was no sig-nificant difference for go stimulus reaction time. Over-lap-free stop event-related potentials revealed smallerstop P3s in adults with ADHD (F1,44=4.20, P.05). Inchildren with ADHD, this has been interpreted to re-flect deficient inhibitory control. However, controlswere also found to have larger early responses in the au-

ditory cortex (N1) when stop signals resulted in suc-cessful stops, relative to failed stops, signifying in-creased attention (F1,23=11.88, P.01). This differencewas completely absent in adults with ADHD.

Conclusions: Disturbed attentional processing of thestop signal contributed to impaired stopping in adultswith ADHD. This finding may have implications fortreatment.

Arch Gen Psychiatry. 2005;62:1129-1136

EXECUTIVE FUNCTIONS THAT

govern everyday human be-havior are manifold in na-ture. They range from beingable to maintaina certain fo-

cus of attention, to switching attentionfrom one source of information to an-other, to the ability to suppress inad-equate but prepotent or ongoing re-sponse tendencies (response inhibition).These subfunctions have to be combinedto achieve ones daily goals.1 At an opera-tional level, the relative contributions ofthese subfunctions are hard to distin-guish. Behavioral measures such as speed

and accuracy that are generally used as in-dices of executive functions by definitionreflect the compound contributions of dif-ferent subfunctions. Their distinction be-comes particularly urgent when identify-ing core deficits underlying psychiatricdisorders. A prime example is attention-deficit/hyperactivity disorder (ADHD).

The most prevalent subtype of ADHD(combined type) is characterized by symp-toms of inattention, impulsivity, and hy-

peractivity.2 Since its first clinical descrip-

tions, researchers have focused onidentifying the core deficit underlying allother symptoms in ADHD. Deficits of re-sponse inhibition3,4 or attention5,6 havebeenclaimed to play a critical role. Nigg7 re-viewed the literature on ADHD and con-cluded that in children with the combinedsubtype, impaired performance was mostconsistently found for tasks measuring re-sponse inhibition. However, this does notsettle the controversysurrounding the corenature of a response inhibition deficit.

Results from the stop signal task, whichis generally accepted as the best behav-

ioral approximation of response inhibi-tion,8 seem to support the notionthat poorinhibitory control is central to ADHD inchildren9 and especially in adults.10,11 Inthe stop signal task, subjects are in-structed to withhold their responses in avisual choice reaction time task when astop signal, usually a tone, is presented.The probability of successful stops isthought to depend on the relative speedsof 2 independently operating processes: the

Author Affiliations:Department ofPsychopharmacology(Drs Bekker, Overtoom,Verbaten, and Kenemans),Department of Psychonomics(Dr Kenemans), UtrechtUniversity, Utrecht, theNetherlands; Department ofDevelopmental Psychology,

Experimental PsychologyGraduate School, University ofAmsterdam, Amsterdam, theNetherlands (Dr Overtoom);Parnassia Psycho-MedicalCenter, the Hague, theNetherlands (Dr Kooij); andDepartment of Psychiatry andChild and AdolescentPsychiatry, University MedicalCenter, St Radboud, Nijmegen,the Netherlands (Dr Buitelaar).

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, OCT 2005 WWW.ARCHGENPSYCHIATRY.COM1129

2005 American Medical Association. All rights reserved.


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go process and the stop process. The speed of the stopprocess, the stop signal reaction time (SSRT), can be es-timated by weighting the distribution of choice reactiontimes (RTs) associated with the go process with the pro-portion of successful stops (Ps). Relative to controls, chil-dren and adults with ADHD have been found to displayslower SSRTs.9-15

TheincreaseinSSRT foundin patients withADHDmightbe taken as evidence in favor of a core deficit in response

inhibition. However,SSRTsreflect other aspects of stop sig-nal processing as well, among which are attention to theset of task stimuli as a whole and the ability to switch at-tention from go stimuli to the occasional stop signal. In-deed, several authors have argued that the slower SSRTsin children with ADHD can be explained by a more gen-eral deficit of attention that is also manifest in the reactionto go stimuli.5,10 Recently, it hasbecomeclear that in adultswith ADHD, slowing is specifically related to the process-ing of the stop signal.10,11 However, even then, the possi-bility that the primary deficit lies in the ability to switchattention to the stop signal is still open.11

Event-relatedbrain potentials (ERPs)providean onlinemeasure of cortical processing and allow for a separation

of processing related to attention vs inhibition. The inter-pretationof ERPs to stop signals is,however,problematic.Because gostimuli generallyleadstopsignals byonly a fewhundredmilliseconds,ERPstostopsignalsarestronglyover-lappedby ERPs to go stimuli. Hence,confoundingoverlaphasplagued theinterpretation of previously reportedstopsignal ERPs in healthy subjects16-18 and children withADHD.19-22 InchildrenwithADHD,smallerN1stogostimulipreceding stopfailures19 aswellassmallerN2s20,21 andP3s22

to stop signals have been reported. Inconsistencies acrossstudies might reflect differential dealing with overlap dis-tortion. In our opinion, the only method that validly ad-dresses overlap problems is the Adjacent Response filtermethod (Adjar level 2) developed by Woldorff.23 Ina pre-

vious studywith healthy subjects,we demonstrated the ef-ficacyofAdjarinthestopsignaltask.24 Aftercorrection,suc-cessful stops were associated with a larger positivity overfrontocentral areasasfrom140-millisecondspoststop sig-nalthanfailedstops.ThisstopP3hasbeenreportedbeforeandhas beeninterpretedto reflect response inhibition,16,18

but previous studies could not exclude an interpretationin terms of overlap from ERPs to other stimuli (eg, motorpotentials with a negative polarity thatare smaller forsuc-cessful stops than for failed stops).

Even with the overlap problem being resolved for thestop P3, the interpretation in terms of inhibition remainssomewhat arbitrary. A completely new finding after Adjarcorrection was that successful stops were associated with

a larger negative peak at about 100 milliseconds post-stimulus. This N1 almost certainly originates in auditorycortex and is very sensitive to selective attention.25 Moregenerally, it reflects thetrial-to-trial varying impacta stimu-lus has in auditory cortex, which is an essential ingredi-ent oftheamount ofattention that isswitched to the stimu-lus on its presentation. This prompts the intriguingpossibility that impaired stopping at least partly dependson the inability to switch attention to the stop signal.

In the present study, Adjar-corrected stop signal ERPsobtained from adults with ADHD (n=24) were com-

pared with those obtainedfrom matched controls (n= 24).Three hypotheses were tested. First, in the present sampleof controls, successful stops are associated with larger N1sand stop P3s than failed stops. Second, the stop P3 effectis reduced in adults with ADHD, suggesting a deficientinhibitory mechanism. Third, the N1 effect is reducedin the ADHD group, suggesting that deficient atten-tional switching to the stop signal is the precursor of de-ficient inhibitory control.

METHODS

SUBJECTS

Twenty-four outpatient adults with ADHD diagnosed with thecombinedsubtype (mean SD age, 34.311.68 years; range,18-57years; 12 men; 3 left-handed) were matched on age and genderwith 24 controls (mean age, 34.9 years; range, 18-57 years; 12men; 1 left-handed). The vocabulary and block design subtestsof the Wechsler AdultIntelligence Scale III26 were administeredto ensure comparable IQ across groups (meanSD age-scaledscores were 10.33.6 and 10.03.0 for adults with ADHD and11.13.2 and 10.53.9 for controls, respectively; F1,46=0.79,P=.38, and F1,46=0.21, P=.65). All subjectsclaimed to have nor-

mal hearing and normal or corrected-to-normal vision. Prior toparticipation, theuse of psychoactivemedication (atleast 6 timesthehalf-life concerned); drugs (at least 3 weeks); alcohol (atleast24 hours); and nicotine, caffeine, and cacao (at least 12 hours)was prohibited.All subjects signedinformed-consentforms.Theethics committee of the Utrecht University Medical Center(Utrecht, the Netherlands) approved this study.

RECRUITMENT AND SCREENING

Patients were recruited when first seeking clinical help and hadno former experience with psychostimulant medication, whichis commonamongnewlyreferred patients with ADHD intheNeth-erlands. Controls wererecruited withadvertisementsin localnews-papers and received 90.00 each for their participation. All sub-

jects were first screened with a telephone interview addressingpastand current ADHDsymptoms; psychiatric, neurological, andmedical disorders; physical impairments; use of medication;andsubstance abuse. Then, subjects filled out translated versions oftheBrown ADDScale,27 theConnersAdult ADHD Rating Scales,28

and the DSM-IVADHD-rating scale for current and past ADHDsymptoms.29 Finally, we administered 2 structured interviews: atranslated version of the Diagnostic Interview Schedule assess-ing ADHD symptoms (DIS-L)30 and the computerized Compos-ite International Diagnostic Interview,31 assessing comorbidDSM-IVdisorders.In contrastwith controls, patients scored aboveADHD cut-off values on the 3 self-report questionnaires (detailsdescribed elsewhere11) and the DIS-L.

EXCLUSION

Subjectswho reportedclinicallyunstable conditions (ie,suicidalbehaviors, psychosis,mania,or physicalaggression),organicbraindisorder, epilepsy, or past concussions were excluded.

Regarding controls, subjects were additionally excluded ifthey were currently suspected of having ADHD, other psychi-atric disorders, or substance abuse; if they were diagnosed witha developmental disorder in childhood; or if they reported ADHDamong relatives. This decision was based on the telephone in-terview, the self-report questionnaires,27-29 and the DIS-L.30

Regarding the ADHD group, patients were additionally ex-cluded if an experienced physician stated that the severity of a




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comorbid disorder was such that it required treatment first orthat abstinence frompreviously prescribed medication was in-advisable. Comorbid Axis I disorders included currentdepres-sion (n= 2, both dysthymic), lifetime depression (n = 13), cur-rentanxiety disorders (n= 8), bipolar disorder (n= 1, lifetime),tic disorder (n= 1, lifetime), substance abuse (n= 3, ie, alco-hol,cannabis,and amphetamine),and alcohol dependence (n= 1,lifetime). Two subjects ceased the use of a selective serotoninreuptake inhibitor prior to participation.

DIAGNOSTIC PROCEDURE

A psychiatrist whospecializes in adult ADHD supervisedeach di-agnostic evaluation performed by an experienced physician. Ifneeded,theymet the patienttogether (n= 2). Only ifbothagreedwasthepatientallowedto participate.To bediagnosedwithADHD,subjects musthave (1)met 6 of 9 DSM-IVcriteria for inattentionandhyperactivity/impulsivityfor a diagnosis in childhood andatleast5of9criteriainadulthood, 32 (2) described persistent ADHDsymptoms from childhood to adulthood, and (3) experienced amoderateto severe level of impairment attributableto theADHDsymptoms. Currentand childhoodsymptomswere evaluatedwitha semistructured diagnostic interview for ADHD and comorbiddisorders (the SGIK)33 and the DIS-L.30 Other childhooddisrup-tive disorders wereassessedwitha translatedversion of thestruc-

tured diagnostic interview for retrospective diagnosis of ADHDand other disruptive disorders, the sections N (oppositional de-fiant disorder), O (conduct disorder), and P (antisocial person-ality disorder) of the DIS-IV.30 If possible, school reports wereexamined,and 17 parents(70.8%)or 7 siblings(29.2%)were in-terviewed witha semistructured interview on childhood ADHDsymptoms. Twenty-one (87.5%)partners attendedall interviewswith the patients and were asked for their opinions on the pres-ence, severity,and durationof current ADHD symptomsas wellas thelevelof dysfunction causedby thesesymptoms. Finally, thephysician filled out the DSM-IVrating scale29 and based the di-agnosis of childhood-onset and current ADHD on all of thisinformation.

TASKS AND PROCEDURES

The use of drugs (amphetamine, barbiturates,benzodiazepines,cocaine, morphine, and tetrahydrocannabinol) was tested witha urinal drug-detection device (Instant-View Drug Screen;RapidDetect, Poteau,Okla),andtheuse ofalcoholwastestedwitha breathdevice(Alcotest; DrgerMedical,Lbeck,Germany). Electroen-cephalographic data wererecorded while subjectsperformedthestopsignal task, thestop change task, andthe continuousperfor-mance task. Only the stop signal task is discussed here.

Stimuli were presented on a computer screen in a sound-attenuating cabinat a distance of 100cm. Oneach trial, a square-wave, black-on-white grating (750 milliseconds) immediatelysucceeded a white plus symbol (500 milliseconds). Intertrialintervals varied from 1000 to 1250 milliseconds. Subjects wereinstructed to press a button with the right index finger when a

grating with a high (4.8 cycles per degree) spatial frequencyappeared and to press another button with the left index fin-ger when a grating with a low (0.6-cpd) spatial frequency ap-peared. The mapping of the response hand reversed after halfof the blocks. Unpredictably, on 40% of the trials, a tone (1000Hz, 80 dB, 400 milliseconds) waspresented binaurally throughearplugs (higher than usual [25%] presentation rates19,22 werenotexpectedto affectSSRT34 but might yield stop P3swith rela-tively small amplitudes and short latencies35). The tone indi-cated that the planned response to the grating should be with-held. The delay between go stimuli and stop signals (stimulusonset asynchrony, or SOA) was jittered in a range of 240 milli-

seconds (with steps of 10 milliseconds) surrounding its meanvalue.23 In the first block, the mean SOA was always set on 250milliseconds. After each block, the meanSOA was adjusted witha tracking algorithm36 to yield a performance of 50% successfulinhibitions, corrected for the estimated number of omissions.37

The sequence of task presentation and the mapping of theresponse hand (ie, right-hand response to high spatial frequen-cies or to low spatial frequencies first) were balanced acrosssubjects. Subjects received a practice block without tones anda practice block consisting of the stop signal task. Before we

reversed theresponse hand, we presented a practice block with-out tones. We presented 6 experimental blocks that contained126 trials: 76 trials without a tone and 50 trials with a tone.

Within each block, the sequence of trials was pseudorandom-izedwith therestriction of a maximum of 3 successive stop trials.

We stressed the speed of responding so that the subjects wouldnot develop waiting strategies. If reaction times increasedmorethan 10% compared with thepractice block without tones,sub-

jects were urged to speed up their responses.

ELECTROPHYSIOLOGICAL RECORDINGS

Electroencephalographic data were recorded using an elasticcap with 62 tin electrodes arranged according to the Interna-tional 10-10 system.38 Tin electrodes were also used for bipo-

lar recording of the vertical electro-oculogram fromabove andbelow the left eye and the horizontal electro-oculogram fromthe outer canthi of each eye. Electroencephalographic signalswere referenced to the left mastoid. The AFz electrode func-tioned as ground. Impedances were kept below 5 k. Data ac-quisition was continuous with a sampling rate of 1000 Hz. Sig-nals were cut off below 0.05 Hz and above 50 Hz. Offline, signalswere down-sampled to 250 Hz and cut off above 30 Hz.

DATA ANALYSIS

Performance measures were calculated separately for each sub-ject and each block. Mean RTs were computed out of a re-sponsewindow of 150 to 1250 millisecondspoststimulus. Fur-thermore, we calculated the SSRT,8 the corrected percentage

of successful inhibitions,37

andthe mean SOA. All measures wereaveraged across blocks (individual data) and subjects (grand-average data).

We computed ERPs separately for successful stops and failedstops from 100 to 1552 milliseconds relative to the onset of theS1 (go stimulus) and S2 (stop stimulus). The 100 millisecondspreceding S1 served as a baseline. Trials withartifacts or analogue-to-digitalconverter saturation were rejected from further analy-sis (discarded stop trials, 6.28% for controls and 7.35% for adultswith ADHD). Ocular artifacts were estimated and subtracted bytime domainregression.39 Data were mergedacross6 experimen-tal blocks. Stop ERPs were filtered with Adjar level 2 in the in-terval from 100 to 700 milliseconds. Subsequently, a 100-millisecond pre-S2 baseline was applied.

TOPOGRAPHICAL MAPPINGAND SOURCE ANALYSIS

We used BESA 2.240 (MEGIS Software GmbH, Grafelfing, Ger-many) to derivemaps andsource modelsfor the grand-average,average-referenced ERPs elicited by successful and failed stops.Models were derived for each group and each trial type (suc-cessful and failed stops) separately. The N1 was analyzed at thefirst negative peak after80 milliseconds at FCz. Thestop P3 wasanalyzed at the first positive peak after 150 milliseconds at Cz.The default 3-shell head model was used to model intracranialgenerators as a single bilateral dipole source. Digitized elec-




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trode locations were projected on a least-square-fitted sphere,which was rotated with respect to mastoid and nasion loca-tions. The resulting coordinates were averaged across subjectswithin each group. These averaged coordinates were used as arepresentation of recording sites. Each dipole was character-ized by 7 parameters: 3 for location, 3 for orientation, and 1 forstrength or dipole moment. To limit the number of parametersto be estimated, we applied symmetry constraints with respectto location and orientationto each bilateral dipole pair. The pos-sibility of interacting dipoles was reduced by preferring solu-tions with relatively low dipole moments with theaid of an en-ergy constraint (weighted 20% in the compoundcost function,as opposed to 80% for the residual variance). We found the op-timal setof parameters in an iterative manner by searching for a

minimum in the compound cost function. Reported dipole so-lutions were stable across randomly varying starting positions.

STATISTICAL ANALYSIS

All dependent measures were subjected to repeated measures ofvariances (Wilks) containingthe between-factor group(ADHDvs control) and the within-factor trial type (successful vs failedstops) with a critical level of .05. Sample wise testing (4 mil-liseconds) of ERP amplitudes was restricted to leads and timewindowsfor whichthe effects were expectedto be largest, a choicebased on a previous study.24 The N1 was analyzed from 80 to124milliseconds at FCz, andthe stop P3 wasanalyzed from 136to 352 milliseconds at Cz. Because this analysis involved manytests, the probability of making type I errors was minimized byconsidering effects significant only if theyextendedover at least5 time points.41

RESULTS

PERFORMANCE

Performance data have been described in detail else-where.11 Briefly, SSRT was longer in patients with ADHD(meanSD, 185.238.9 milliseconds for controls and

237.3 87.2 millisecondsfor adultswith ADHD: F1,46=7.12,P.01) whereas there was no significant difference re-garding RT (mean SD, 463.368.8 milliseconds for con-trols and 467.987.6 milliseconds for adults with ADHD:F1,46=0.04, P=.84). We adjusted the SOA individually(meanSD, 267.658.4 milliseconds for controls and230.378.1 millisecondsfor adultswith ADHD: F1,46=3.51,P=.07) to yield a probability of successful stops of around50% in both groups36 (46.46.5% for controls and42.810.6% for adults with ADHD: F1,46=2.08, P=.16).

EVENT-RELATED POTENTIALS

Figure 1 displays ERPs elicited by stop signals associ-ated with successful and failed stops at FCz and Cz. Asfor the N1, stop signals elicited a pronounced negativepeak around 100 milliseconds latency. At FCz, the N1was larger for successful than for failed stops, but onlyfor the control group (interactionwith group,92-124 mil-liseconds: F1,46=4.77, P.05; effect of trial type in the con-trol group, 80-124 milliseconds: F1,23=11.88, P.01). Thisis particularly visible in Figure 2, which displays dif-ferencewaves obtained by subtractingERPs for failedstopsfromthose for successful stops. Mean amplitudes andstan-dard deviations are summarized in the Table.

Regarding the stop P3, Figure 1 shows a larger posi-

tivity for successful than for failed stops, particularly atCz (140-352 milliseconds: F1,46=4.21, P.05). Espe-cially the difference waves in Figure 2 suggest that thestop P3 was smaller for the ADHD group. However, wedid not find the expected interaction with group. Closerinspection revealed that the distribution across individu-als of trial-type differences in amplitude deviated fromnormality in the ADHD group. Removal of 1 outlier (andthe matched counterpart) yielded an interaction withgroup (172-200 milliseconds: F1,44=4.20, P.05), indi-cating smaller stop P3s in adults with ADHD (see also

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Figure 1. Stop signal event-related potentials associated with successful (solid lines) and failed stops (dotted lines) at leads FCz and Cz, separately for the controlgroup and the attention-deficit/hyperactivity disorder group. The white and black arrows indicate the N1 and stop P3 effect, respectively. The 2 vertical lines referto the window of statistical analysis. ADHD_F indicates the ADHD group failed stop; ADHD_S, the ADHD group successful stop; CNTRL_F, the control group failedstop; CNTRL_S, the control group successful stop.




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Table). However, Figure 1 suggests that the interaction

with group reflects longer latencies rather than smalleramplitudes of the stop P3 in the ADHD group, whichwould be consistent with the increase in SSRT. This al-ternative interpretationwas only partlyconfirmed:sample-wise testing for each group separately yielded an effectof trial type in the interval of 140 to 300 milliseconds forthe control group (F1,22=11.29, P.01) and in the inter-val of 152 to 352 milliseconds for the ADHD group(F1,22=15.83, P.01).

To confirm the contribution of auditory cortex to theN1, we conducted coarse source localization using BESA2.2.40 Figure 3 shows that the resulting source modelsand associated scalp topographiesare consistent withgen-erators in auditory cortex.42 Analogous source modeling

for thestop P3 suggested bilateral dipole pairs in more me-dial frontocentral regions (Figure 3). Importantly, statis-tical analysis using the latency-of-best-fit method to esti-mate individual source models43 confirmed that thelocations of stop P3 sources were more medial than thoseof N1 sources (F1,46=52.55, P.01; after removal of theoutlier mentioned earlier in thearticle, F1,44=48.47, P.01).

Post hoc correlations between the difference in N1 aswell as P3 amplitude (successful minus failed) and SSRTwere assessed. No significant correlations were found.This might be due to uncontrolled sources of variance,

such as interindividual variability in N1 and P3 effects

reflecting global neurophysiological differences, or to anindirect relation between SSRT and successful vs failedstopping. Furthermore, the amplitude measures were notfound to correlate with self-report scales reflecting at-tention and impulsivity, respectively. This might addi-tionally be due to conceptualization differences be-tween experimental and clinical measures or to lowvalidity of self-report scales.

COMMENT

The present study revealed that successfully stopping anongoing response process is associated with a sequence

of cortical activations elicited by the stop signal. Success-ful stops were associated with enhanced short-latency (100milliseconds) activation in sensory cortex, followed by alonger-latency (as from 140 milliseconds) enhancementof activity in more medial frontocentral areas. These N1and stop P3 effectsweresmaller in adults with ADHD, whoalso manifested impaired stopping as reflected in the be-havioral index of stopping speed, the SSRT.

Our first hypothesis, that successful stops are associ-ated with larger N1s and stop P3s than failed stops in thecontrol group, was confirmed. Around 100 milliseconds,

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Figure 2. Difference waves obtained by subtracting event-related potentials (ERPs) for failed stops from ERPs for successful stops at leads FCz and Cz, separatelyfor the control group (dark lines) and the attention-deficit/hyperactivity disorder (ADHD) group (gray lines). See legend of Figure 1. CNTRL indicates the controlgroup; ADHD, the ADHD group.

Table. Mean Event-Related Potential Amplitudes for ADHD and Control Groups*

ERP

ADHD Controls

Successful Failed Successful Failed

N1 (92-124 ms at FCz) 9.25 5.14 9.06 4.43 10.67 3.62 8.67 3.16

Stop P3 (n = 24; 172-200 ms at Cz) 5.45 3.74 2.87 3.86 4.24 5.33 0.22 7.04

Stop P3 (n = 23; 172-200 ms at Cz) 5.28 3.73 3.22 3.52 4.56 5.21 0.02 7.10

Abbreviation: ADHD, attention-deficit/hyperactivity disorder.*All values are means and standard deviations in V, calculated in the interval for which significant differences between the ADHD and control groups were found.




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stop signals elicited a negative deflection over frontocen-tral scalp sites. In the control group, successful stops wereassociated with a larger N1 than failed stops. Similar re-sults were found in a previous study with healthy sub-jects24 after overlap removal with Adjar level 2.23 Becausethe N1 has been shown to be very sensitive to manipula-tions of selective attention to auditory stimuli,25 these find-ings imply that whether an auditory stop signal results ina successful or a failed stop at least partly depends on the

amount of attention that is paid or switched to thestop sig-nal. Further analysis of overlap-free stop ERPs revealedlarger positiveamplitudes for successful thanfor failed stopsover central scalp sites as from 140 milliseconds. This stopP3 has previously been claimed to reflect response inhibi-tion.16,18 Replication afteroverlap removal excludesthe pos-sibility that this effect merely reflects differences in motor-related potentials24 (see the introduction).

Coarse source localization of the N1 yielded modelsconsistent with generators in auditory cortex. The stopP3 was modeled in more medial regions. This is in line

with source models reported for the no-go P3 elicited ingo/no-go tasks44,45 and might reflect a generator in ante-rior cingulate cortex, which is thought to be involved inresponse inhibition, either directly or by the detectionof conflict that signals other brain areas to exert inhibi-tory control.46 Previous source localization of the stopP3 revealed generators in more posterior regions.18 Theseprobably reflect overlapping activity related to the pro-cessing of the go stimulus, underlining the importance

of applying Adjar level 2 to validly isolate cortical pro-cessing of the stop signal. It should be noted that di-poles reflect an oversimplification of actually activatedbrain areas. Previous studies using functional magneticresonance imaging have suggested right lateralized fron-tostriatal involvement in response inhibition.47,48

Consistent with earlier findings in children,22 the stopP3 effect was smaller in adults with ADHD. Previous re-sults indicating smaller N2s to stop signals20,21 or smallerN1s to go stimuli19 (not reported) could not be repli-cated. The reduced stop P3 can be interpreted by assum-

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Figure 3. Source models and isocontour maps derived for the grand-average, average-reference data at the peak latency of the N1 (top panel) and the stop P3(bottom panel) for each group and each trial type separately. For the control group, filled, black dipole pairs (1) correspond to successful stops and open, whitedipole pairs (3) correspond to failed stops. For the ADHD group, filled, gray dipole pairs (5) correspond to successful stops and open, gray dipole pairs(7) correspond to failed stops. Dots indicate the location of the dipole source; the direction of the line represents its axis of orientation. Isocontour maps showthe potential distribution of the average-referenced data. The dark shaded areas reflect negative activity; the nonshaded areas reflect positive activity. Spacing is0.8 V. Regarding the N1, in the control group, source models were derived at 99 milliseconds for successful stops (percentage variance not explained by themodel (RV, 1.52%) and 116 milliseconds for failed stops (RV, 1.52%). In the ADHD group, source models were derived at 99 milliseconds for successful stops(RV, 2.06%) and 99 milliseconds for failed stops (RV, 1.26%). Regarding the stop P3, in the control group, source models were derived at 266 milliseconds forsuccessful stops (RV, 3.62%) and 316 milliseconds for failed stops (RV, 3.78%). In the ADHD group, source models were derived at 283 milliseconds forsuccessful stops (RV, 2.59%) and 316 milliseconds for failed stops (RV, 4.39%). ADHD_F indicates the ADHD group failed stop; ADHD_S, the ADHD groupsuccessful stop; CNTRL_F, the control group failed stop; CNTRL_S, the control group successful stop.




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ing that, although individuals with ADHD can generatean inhibitory response to stop signals with a probabilitysimilar to that found for controls (around 50%, if stimu-lus conditions are appropriately adjusted), stopping wasless efficient or the activation of the inhibition systemwas weaker in individuals with ADHD, as was also indi-cated by the increase in SSRT. Because the difference inonset of the stop P3 effect (140 milliseconds for con-trols, 152 milliseconds for ADHD) was smaller than the

difference in SSRT (185 milliseconds for controls, 237milliseconds for ADHD), which is thought to reflect thefinishing time of the internal stop response,8 this com-ponent might not be directly related to inhibition of on-going responses. Furthermore, it should be noted thatbecause of the transmission delay, inhibitory processesreflected in the stop P3 are not likely to exert an effecton behavioral measures until around 100 millisecondsafter its onset.16 Therefore, at least on some part of thetrials, processes other than those reflected in the stop P3are associated with (impaired) response inhibition.

The increase in N1 amplitude for successful stops rela-tive to failedstopswas absentin adultswith ADHD. Giventhat the difference in N1 for successful vs failed stops re-

flects attentional modulation of auditory-cortex activa-tion elicited by the stop signal, it can be concluded thatsuch attentional modulation is absent in adult ADHD. Anumber of reports on children with ADHD have re-vealed significantly reduced enhancement of auditory-cortex activation by stimuli that are deemed relevant bytask.49-51 The present lack of N1 modulation, however,must reflect a more subtle mechanism. Internally gen-erated trial-to-trial variationin N1 amplitudereflects fluc-tuations in the impact that stop signals have in auditorycortex, or, in other words, the amount of attention thatis switched to thestimulus on its presentation. In healthycontrols, these varying amounts of attention are directlyrelated to the probability that subsequent stopping is suc-

cessful. In adults with ADHD, this link between atten-tion and stopping is lacking. Stated differently, no mat-ter what the impact of the stopsignal is in auditory cortex,it does not determine the probability of subsequent stop-ping: only a weakly activated inhibitory mechanism (re-flected in a smaller stop P3 effect) was used for stop-ping. Because attention to go stimuli was unimpaired(there was no group effect on RT), the attentional defi-cit in adults with ADHD seems specifically related to theinability to switch attention to the stop signal. Accord-ingly, task-set switching deficits have been demon-strated in children with ADHD.52 The present study re-veals that in adults with ADHD, at least on part of thetrials, deficits in attentional switching might be the pre-

cursor of deficient inhibitory control, which is reflectedin a disproportional elongation in SSRT (relative to RT).One could argue that in controls, failed stopping was

related to failed attention as well as failed inhibitionwhereas in adults with ADHD, failed stopping was re-lated to failed inhibition only. However, the mean am-plitudes provided in the Table suggest that the N1 asso-ciated with failed stops in the control group wascomparable with the N1 associated with both successfulandfailed stops in theADHD group (difference, 0.58 and0.39 V, respectively), whereas the N1 associated with

successful stops in the control group was enlarged (dif-ference, 1.42 and 1.61 V, respectively). Following thisline of reasoning, enhanced attention contributes to bet-ter stopping in controls, but not in ADHD.

A possible limitation of this study is the inclusion ofpatients with comorbid disorders. Because at least 75%of adults with ADHD suffer from additional DSM-IVdis-orders,53 isolating ADHD is difficult and might not yielda representative sample. The nonsystematic presence of

comorbidity is expected to increase error variance, whichwould reduce the likelihood of finding significant groupeffects. Furthermore, comorbidity mainly consisted of de-pression and anxiety. As for depression, symptoms weremild or currently absent. As for anxiety, in children,SSRTs have been found to be comparable with those mea-sured in controls.9

In sum, the increase in SSRT found in patients withADHD has often been interpreted to support a core defi-cit in inhibitory control rather than in attention. How-ever, behavioral measures used as indices of executivefunctions merely reflect the compound contribution ofdifferent underlying subfunctions, which are hard to dis-tinguish. Event-related potentials enable the disentan-

gling of the relative contribution of inhibitory and at-tentional deficits eventuating in an increased SSRT. Thepresent ERP study revealed that although general atten-tion to task stimuli seemed undisturbed in adults withADHD (no effect on RT), impaired stopping may still berelated to deficiencies in other aspects of attention, in par-ticular the ability to switch attention to the stop signal.This throws doubt on response inhibition as the pri-mary deficit in ADHD and may have important implica-tions for treatment.

Submitted for Publication: December 8, 2004; final re-vision received March 14, 2005; accepted March 25, 2005.Correspondence: Evelijne M. Bekker, PhD, Center for

Mind and Brain, University of California, Davis, Room107, 267 Cousteau Pl, Davis, CA 95616 ([email protected]).Funding/Support: This study was funded by grant 425-20-205 from the Netherlands Organization for Scien-tific Research, the Hague. Carin C.E. Overtoom, PhD, wassupported by a Grotius grant from the University of Am-sterdam, Amsterdam, the Netherlands.Acknowledgment:We thank Ineke de Noord and CarlaOostenbach for assisting in patient recruitment andscreening.

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