Psychopharmacology (2003) 165:118–127DOI 10.1007/s00213-002-1235-7

O R I G I N A L I N V E S T I G A T I O N

Larry W. Hawk Jr · Andrew R. Yartz ·William E. Pelham Jr · Thomas M. Lock

The effects of methylphenidate on prepulse inhibitionduring attended and ignored prestimuli among boyswith attention-deficit hyperactivity disorderReceived: 2 January 2002 / Accepted: 30 July 2002 / Published online: 1 November 2002� Springer-Verlag 2002

Abstract Rationale and objectives: The present studyinvestigated attentional modification of prepulse inhibi-tion of startle among boys with and without attention-deficit hyperactivity disorder (ADHD). Two hypotheseswere tested: (1) whether ADHD is associated withdiminished prepulse inhibition during attended prestimuli,but not ignored prestimuli, and (2) whether methylphe-nidate selectively increases prepulse inhibition to attendedprestimuli among boys with ADHD. Methods: Participantswere 17 boys with ADHD and 14 controls. Participantscompleted a tone discrimination task in each of twosessions separated by 1 week. ADHD boys were admin-istered methylphenidate (0.3 mg/kg) in one session andplacebo in the other session in a randomized, double-blindfashion. During each series of 72 tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to onepitch and ignore the other. Bilateral eyeblink electromy-ogram startle responses were recorded in response toacoustic probes (50-ms, 102-dB white noise) presentedfollowing the onset of two-thirds of tones, and duringone-third of intertrial intervals. Results: Relative tocontrols, boys with ADHD exhibited diminished prepulseinhibition 120 ms after onset of attended but not ignoredprestimuli following placebo administration. Methylphe-nidate selectively increased prepulse inhibition to attend-ed prestimuli at 120 ms among boys with ADHD to alevel comparable to that of controls, who did not receivemethylphenidate. Conclusions: These data are consistentwith the hypothesis that ADHD involves diminishedselective attention and suggest that methylphenidate

ameliorates the symptoms of ADHD, at least in part, byaltering an early attentional mechanism.

Keywords Attention-deficit hyperactivity disorder ·ADHD · Startle reflex · Prepulse inhibition ·Methylphenidate · Stimulants

Introduction

Attention-deficit hyperactivity disorder (ADHD) is diag-nosed on the basis of problems of inattention and/orhyperactivity-impulsivity [Diagnostic and StatisticalManual of Mental Disorders (DSM)-IV, American Psy-chiatric Association 1994]. Similarly, current theoreticalperspectives on ADHD focus on deficits of attention,inhibition, or both. As Douglas (1999) reviews, there isevidence of impairment in a range of cognitive controlprocesses, including sustained attentional allocation.Others have argued against a central attentional deficitin ADHD (Sergeant and van der Meere 1990) and havefocused on behavioral inhibition (Quay 1997; Barkley1999; Sergeant et al. 1999). Despite important differencesamong these models, all acknowledge that ADHD likelyinvolves poor inhibition. However, neither attention norinhibition has a single operational definition, and manytasks likely involve elements of both processes (Halperinet al. 1991). Consequently, it has been suggested thatinvestigators choose measures that most simply anddirectly assess the constructs of interest (Douglas 1999;Sergeant et al. 1999).

Prepulse inhibition of the startle reflex has much tooffer in this respect (see the special issue of Psychophar-macology on prepulse inhibition, edited by Koch andRobbins 2001). Prepulse inhibition refers to a decrementin the magnitude of the startle response that occurs whena weak task-irrelevant prestimulus (or prepulse) ispresented 60–500 ms before the onset of the startle-eliciting stimulus (for reviews, see Filion et al. 1998;Blumenthal 1999). Prepulse inhibition may reflect apartially automatic mechanism for protecting the initial

L.W. Hawk Jr ()) · A.R. Yartz · W.E. Pelham JrDepartment of Psychology, State University of New York,Park Hall Box 604110, Buffalo, NY 14260-4110, USAe-mail: lhawk@buffalo.edu

W.E. Pelham JrDepartment of Psychiatry, State University of New York, Buffalo,New York, USA

T.M. LockDepartment of Pediatrics, State University of New York, Buffalo,New York, USA

processing of sensory stimuli (Graham 1975) or a moregeneral gating mechanism (Braff and Geyer 1990) thatserves a critical inhibitory function in sensory, cognitive,and motor output processing.

Furthering its utility as a model system, the brainstemcircuitry that mediates prepulse inhibition in the rat iswell-known (Fendt et al. 2001). While several neuro-transmitter systems regulate prepulse inhibition, thedopaminergic system is predominant in both rat (Swerd-low et al. 2001) and human (Braff et al. 2001) studies.Importantly, striatal dopamine also figures prominently inboth the pathophysiology and the treatment of ADHD(Solanto et al. 2001).

Thus, it would seem reasonable to hypothesize thatchildren with ADHD exhibit diminished prepulse inhibi-tion. However, in a large study of boys with and withoutADHD, Ornitz and colleagues (1992) found that ADHDwas not associated with reduced prepulse inhibition.Similarly, Castellanos et al. (1996) observed diminishedprepulse inhibition among boys with Tourette’s Syn-drome and ADHD, but not among boys with ADHD only.These studies suggest that ADHD alone is not associatedwith a deficit in passive prepulse inhibition, which doesnot require any controlled attentional processing of theexperimental stimuli.

However, current perspectives emphasize problems inthe allocation of controlled processes in the disorderrather than deficits in automatic processing (Berman et al.1999; Sergeant et al. 1999). Consistent with this account,Satterfield et al. (1994) reported comparable event-relatedpotentials to ignored stimuli among controls and unmed-icated children with ADHD, but children with ADHDexhibited reduced processing of attended stimuli, asevidenced by P300 (see similar findings by Klorman etal. 1994; Jonkman et al. 2000; c.f. Smithee et al. 1998).

Prepulse inhibition can also be used to study controlledattention – active attention to prestimuli increases thedegree to which startle is inhibited (DelPezzo andHoffman 1980). This effect has been most clearlydemonstrated in the tone discrimination paradigm ofDawson and colleagues (Dawson et al. 1993; Filion et al.1993; Schell et al. 1995; Jennings et al. 1996). High- andlow-pitched tones, which serve as continuous prestimulifor acoustic startle probes, are presented in an intermixedseries. The participant is paid to accurately attend toduration of tones of one pitch but is asked to ignore tonesof the other pitch. In this paradigm, prepulse inhibition isevident at various short prepulse-probe stimulus onsetasynchronies (SOAs; i.e., 60, 120, and 240 ms) and isgreater during attended than ignored tones at 120 ms butnot at 60 ms or 240 ms. This enhanced prepulse inhibitionto attended prestimuli at the 120-ms SOA is believed toreflect a brief controlled attentional process, perhapsrelated to confirming the identity of the attended prepulse(Dawson et al. 1997). While most of this work has beendone with adult participants, attentional modification ofprepulse inhibition at a 120-ms SOA was recentlyreplicated in 9- to 12-year-old boys (Hawk et al. 2002a).

The present study tested the hypothesis that unmedi-cated boys with ADHD, unlike controls, do not exhibitnormal attentional modification of prepulse inhibition at120 ms. It was expected that boys with ADHD wouldexhibit diminished prepulse inhibition during attended,but not ignored, prestimuli, relative to controls.

The second goal of the present work was to examinethe effects of a low dose of methylphenidate on prepulseinhibition among boys with ADHD. Methylphenidate isthe most frequently prescribed medication for ADHD(Goldman et al. 1998), and it improves both behavioraland cognitive aspects of the disorder at doses between0.3 mg/kg and 1.0 mg/kg (Schachar and Ickowicz 1999).Methylphenidate prevents re-uptake of dopamine andnorepinephrine, and both actions are believed to beimportant in the drug’s efficacy (Castellanos 1999;Schachar and Ickowicz 1999; Mehta et al. 2001). Froma clinical perspective, methylphenidate would be expect-ed to increase children’s focus on attended tones duringthe discrimination task, enhancing prepulse inhibitionduring attended, but not ignored, prestimuli. Indeed,methylphenidate would be expected to reduce prepulseinhibition to ignored prestimuli, both because drugs thatincrease mesolimbic dopamine availability decrease pas-sive prepulse inhibition (Mansbach et al. 1988; Hutchisonand Swift 1999) and because methylphenidate mightfacilitate ignoring. We tested these hypotheses by exam-ining children with ADHD twice, once following inges-tion of 0.3 mg/kg methylphenidate and once followingpill placebo, under randomized, double-blind conditions.Comparison of startle modification between medicatedboys with ADHD and unmedicated controls allowed adetermination of the extent to which methylphenidatenormalized prepulse modification. Placebo and methyl-phenidate were not administered to controls both due toethical concerns about administering non-therapeuticstimulants to naive normal participants and becauseprevious work with balanced-placebo designs have con-sistently failed to reveal expectancy effects on methyl-phenidate’s impact on cognitive, behavioral, or socialperformance in children with ADHD (Pelham et al. 1997,2001b, 2002).

Materials and methods

Participants

Participants were 17 boys with a primary diagnosis of ADHD and14 similarly aged controls.1 All ADHD and control participantswere recruited via a mailing sent to parents of children who hadrecently participated in a larger study of the effects of methylphe-

1 The data for the controls are from a more extensive report thatexamined startle modification at multiple SOAs, as well as the test–retest reliability of startle modification (Hawk et al. 2002a). In thepresent study, the primary focus is on ADHD, attentional modi-fication of prepulse inhibition at the 120-ms SOA, and the effects ofmethylphenidate. However, we have included a subset of previ-ously published control data to allow for more informativecomparisons

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nidate among children with ADHD (Pelham et al. 2001a) andcomparisons to non-ADHD controls. For the present study,participants were further screened for parent-reported healthproblems and visual and auditory impairments.

Table 1 presents demographic information regarding bothgroups, as well as clinical characteristics of the ADHD group.Mean age and full-scale IQ scores on the third edition of theWechsler Intelligence Scale for Children (Wechsler 1991; forcontrols, IQ was estimated from the vocabulary and block-designsubtests) were comparable for the ADHD and control participants(F values <1). As indicated in Table 1, all participants were maleCaucasians.

All members of the ADHD group met DSM-IV (AmericanPsychiatric Association 1994) criteria for ADHD. Specifically,parents were administered the National Institute of Mental HealthDiagnostic Interview Schedule for Children Version IV (DISC;Shaffer et al. 2000), and parents and teachers also completed theDisruptive Behavior Disorders checklist (DBD; Pelham et al. 1992)and the IOWA Conners ratings scales (Goyette et al. 1978; Pelhamet al. 1989). A DSM-IV symptom was considered present if eitherparents (DISC and DBD) or the teacher (DBD) endorsed it, andoverlap between raters was required on at least one symptom.Table 1 presents severity data, in the form of symptom counts, forthe DISC, parent and teacher DBD, and parent and teacher IOWAConners. Also, as can be seen in Table 1, most of the presentsample were of the combined subtype and co-morbid oppositional-defiant disorder was present in just under half of the sample.

All participants were paid US $5 per session and could earn upto US $5 more for task performance during each session (see

Procedure). Participants were given a US $10 bonus uponcompletion of both sessions.

Apparatus

A computer program (VPM; Cook et al. 1987), running on aPentium-class computer (Gateway; North Sioux City, S.D.)controlled the presentation of tone prestimuli and startle probes,and sampled all physiological signals (skin conductance and heartrate were also measured).

Digital acoustic stimuli were created with SoundEdit16(Macromedia; San Francisco, Calif.) on an Apple Macintoshcomputer. Startle probes were 50-ms, 102-dB bursts of white noisewith near-instantaneous rise/fall times. Prestimuli were 75-dB, 400-and 1200-Hz tones, of 5- and 8-s duration, with 25-ms rise/falltimes. All acoustic stimuli were presented by VPM via aSoundblaster (Milpitas, Calif.) AWE64 Gold sound card, externallyamplified with a Denon (Tokyo) AVR-1400 stereo receiver, andplayed through a pair of matched Telephonics (Huntington, NY)TDH-49P headphones.

The bilateral eyeblink startle response was measured elec-tromyographically from orbicularis oculi, using TDE-23 Ag/AgClsurface electrodes (Med Associates, East Fairfield, Vt.) filled withMed Associates electrode gel and centered 0.5 cm below the pupiland outer canthus of each eye. The left and right electromyogram(EMG) signals were amplified by separate Grass Instruments (WestWarwick, Ohio) 7P3 preamplifiers and 7DA driver amplifiers withhalf-power cutoff frequencies set to 10 Hz and 500 Hz. Amplifieroutput was fed to the A/D converter of a Scientific Solutions(Solon, Ohio) Lab Master DMA interface, which sampled theamplified EMG at 1000 Hz from 50 ms before until 300 ms afterthe onset of each startle probe.

Medication

All children with ADHD had taken a stable dose of methylphe-nidate for at least 1 month immediately preceding entry into thelarger study (Pelham et al. 2001a) from which the current samplewas recruited. Because the present study was conducted during thesummer, five participants were on “drug holidays” and had notreceived medication for 2 weeks to 2 months before either of thelab sessions. Of the remaining 12 ADHD children, 11 had beenmedication free for 18–36 h before both lab sessions. One ADHDparticipant had been medication free for 19 h before one session butonly for 13.5 h before the other. Thus, all participants were familiarwith methylphenidate and its effects, and most had recentexperience with the drug. However, no participant reported anymethylphenidate use within the 12 h (approximately four half-lives;Swanson and Volkow 2001) prior to any experimental session. Noparticipant was taking any other psychotropic medication at thetime of the study.

Both participants and experimenters were blind to medicationcondition, as methylphenidate (0.3 mg/kg) and placebo were eachpresented in a single opaque capsule filled with methylcellulose.Although we did not assess whether ADHD participants coulddistinguish methylphenidate from placebo, prior work suggests theycannot accurately make this distinction (Dalby et al. 1978). Drugorder was counterbalanced, with 9 of 17 ADHD participantsreceiving methylphenidate during session 1. To assess startlemodification during methylphenidate’s active window, the tonediscrimination task was begun 1 h after medication ingestion.

Procedure

Institutional Review Boards at the State University of New York atBuffalo and the Children’s Hospital of Buffalo approved allprocedures.

Sessions were conducted in an IAC (Bronx, N.Y.) 2.7�2.5-melectrically and acoustically isolated chamber. After parental

Table 1 Demographic and clinical characteristics. Except forpercentages, values are means (standard deviations). ADHDattention-deficit hyperactivity disorder, DBD disruptive behaviordisorders checklist, DISC diagnostic interview schedule forchildren

ADHD Controls

Demographics

Mean age in years 11.4 (0.9) 11.4 (1.1)Mean WISC-III IQ 110 (13) 112 (16)Sex, % male 100% 100%Ethnicity, % Caucasian 100% 100%

Severity

DISC hyperactive/impulsive symptoms 7.4 (1.5)DISC inattention symptoms 8.4 (1.2)Parent DBD symptomsInattention 7.5 (1.3)Hyperactivity/impulsivity 6.1 (2.6)Parent IOWA Conners ratingsInattention/overactivity 10.6 (3.8)Oppositional/defiant 6.9 (4.2)Teacher DBD symptomsInattention 5.1 (3.4)Hyperactivity/impulsivity 3.0 (2.5)Teacher IOWA Conners ratingsInattention/overactivity 8.8 (3.3)Oppositional/defiant 4.2 (3.8)

ADHD subtype

Combined 76%Hyperactive-impulsive 12%Inattentive 12%Co-morbidityOppositional-defiant disorder 41%Conduct disorder 29%Nocturnal enuresis 12%Anxiety disorder 12%Chronic motor tic disorder 6%

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consent and participant assent were obtained, medication wasadministered to ADHD participants. All other procedures wereidentical between participants with ADHD and controls, and datafor the two groups were collected concurrently.

To reduce the strangeness of the environment and to increaseinterest in the experimental task, each participant was asked topretend that he was an astronaut on a mission to decode a messagefrom outer space. Electrodes were attached and the child was leftalone in the subject chamber. Participants were monitoredthroughout the session via a hands-free intercom and a videocamera. As part of their “astronaut training”, participants listened toseries of tones to ensure that both tone pitch and duration werediscriminated. Participants were then presented with two test startleprobes.

The experimenter returned to the subject room to provideinstructions for the task, as adapted from Jennings et al. (1996).Participants were instructed to attend to either low or high tonesand to press a hand-held button at the offset of a longer-than-usualpresentation of the attended pitch. They were informed thatdetection of longer-than-usual tones of the attended pitch woulddetermine the amount of bonus money they were paid. Perfectperformance earned US $5.00, with each error of omission orcommission resulting in a loss of US $0.50.

Each of the 72 trials of the tone discrimination task consisted ofa 5-s or 8-s tone and a 15-s to 29-s intertrial interval (ITI). Withineach block of 24 trials, there were 12 high tones (1200 Hz) and 12low tones (400 Hz). Within each pitch, there were eight 5-s tonesand four 8-s tones. Startle probes were presented during two-thirdsof tones (two probes each at 120-, 240-, 2000-, and 4500-ms SOAsin each trial block) as well as during one-third of the ITIs, with anaverage of 26 s between startle probes. Six pseudorandom orders ofstimuli were used to counterbalance across participants thesequence of SOAs and tone pitches. Attended pitch was counter-balanced across sessions and the order in which pitches wereattended (low during session 1 and high during session 2 vs highduring session 1 and low during session 2) was counterbalancedbetween subjects.

Upon completion of the tone discrimination task, the sensorswere removed and the participant was provided with a short break,after which he completed an 11-min continuous performance task(further details are available from the authors). The participant wasthen informed about his performance and paid for the session.

Session 2, completed 1 week later, followed the aboveprocedures, except that the medication condition was switchedfor ADHD children, and all children attended to the opposite tonepitch.

Data reduction and analysis

Prepulse inhibition

Startle eyeblink magnitude was the primary dependent variable.Eyeblink EMG responses were digitally integrated offline (rectifiedand low-pass filtered with an 80-ms time constant) and scored withthe algorithm of Balaban et al. (1986), as in prior work (Hawk andCook 2000; Hawk et al. 2002a).

Eyeblink EMG magnitude subject averages were computed foreach session � SOA (120, 240, 2000, 4500) � pitch (attended,ignored) cell, as well as for the ITI for each session. Percentprepulse modification for each SOA was computed as [(MITI–Mprepulse)/(MITI)]�100. To reduce subject loss due to missing data inone or more cells of the design, modification scores were averagedacross the right and left eyes and across trial blocks.

Three separate analyses of variance (ANOVAs) addressed themajor questions in this study, which focused on short-lead prepulseinhibition. 2In all analyses, pitch (attended vs ignored) and SOA(120 ms vs 240 ms) were included as within-subjects factors, andattend order (attend low first vs attend high first) was a between-subjects covariate. The first ANOVA contrasted the controls(session 1) with ADHD boys during the placebo session; thus,group was a between-subjects factor. The second ANOVA testedwhether methylphenidate increased prepulse inhibition among boyswith ADHD; medication was included as a within-subjects factor.The third ANOVA contrasted startle modification between ADHDboys during the methylphenidate session and controls (session 1).All interactions were followed up with simple main-effectsanalyses. To determine under which conditions the prestimulireliably inhibited startle, intercept tests were also examined in thecontrols versus ADHD-placebo and ADHD-placebo versus ADHD-methylphenidate analyses.

One potential problem in the comparisons between ADHD andcontrols is that attentional modification may decrease over time(Schell et al. 2000; Hawk et al. 2002a). Because the primarycomparisons of ADHD and controls did not control for possiblesession effects, a supplemental set of analyses were completed. Thecontrol data were again from session 1. The first ANOVAcontrasted the controls with ADHD boys during the placebosession but was restricted to ADHD boys who received placeboduring session 1 (n=8). Similarly, the second ANOVA examinedprepulse modification among controls and ADHD boys during themethylphenidate session, but only those ADHD boys who receivedmethylphenidate during session 1 (n=9).

ITI startle magnitude

Paralleling the prepulse inhibition analyses, three ANOVAs wereconducted on ITI startle magnitude to determine whether anydifferences in prepulse inhibition might be due to differences in thedegree of baseline (i.e., ITI) startle responding.

Task performance

As for prepulse modification, task performance was examinedusing ANOVA, with separate ANOVAs examining controls versusADHD-placebo, ADHD-placebo versus ADHD-methylphenidate,and controls versus ADHD-methylphenidate. Percent misses (errorsof omission; there were 12 attended target tones) and percent falsealarms (errors of commission) were examined separately. Theanalysis of percent false alarms included attend (attended vsignored tone pitch; there were 24 attended non-targets and 36ignored non-targets) as a within-subjects variable.

2 A parallel series of analyses were conducted on percent prepulsefacilitation at the long-lead SOAs (2000 ms and 4500 ms). Becauseprepulse inhibition is of primary interest, these results aresummarized here. As expected (Filion et al. 1993; Jennings et al.1996; Hawk et al. 2002a), long-lead prepulse facilitation was robustin all analyses (P values <0.001). However, there were no groupdifferences in long-lead prepulse facilitation (all P values >0.20).While there was a reliable medication � drug order � attendinteraction among the ADHD group (P<0.04), further examinationof the data suggested that the interaction reflected a session effectrather than an interesting effect of methylphenidate. That is, whenthe data were re-coded according to session (mathematicallyequivalent to medication � drug order), follow-up tests indicatedmarginally greater facilitation during attended than ignored duringsession 1 (means = 70% and 50% facilitation, respectively;P<0.09), but the pattern reversed during session 2 (means = 41%and 62%, respectively; P=0.18). We have observed a comparableeffect among the controls (Hawk et al. 2002a). Further details areavailable from the authors

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Results

Percent prepulse inhibition

Figure 1 presents mean percent prepulse inhibition forignored and attended prestimuli at the 120-ms and 240-msSOAs, separately for ADHD–placebo, ADHD–methyl-phenidate, and controls. In the analysis comparingADHD–placebo to controls, group differences variedacross SOAs and attention conditions (group � SOA andgroup � SOA � attend F1,28 values=10.7 and 6.3; P values<0.005 and 0.02, respectively). Simple main-effectsanalyses revealed the hypothesized pattern. At 120 ms,ADHD–placebo exhibited less prepulse inhibition thandid controls during attended prestimuli, but not duringignored prestimuli (F1,28 values=6.5 and 0.2; P values<0.02 and 0.67, respectively). At 240 ms, ADHD–placeboand controls exhibited comparable prepulse inhibition –or lack thereof – during both attended and ignoredprestimuli (F1,28 values <1.8; P values >0.19). Intercepttests conducted separately for ADHD–placebo and con-trol participants demonstrated that percent prepulseinhibition was reliably different from 0% only duringattended prestimuli at 120 ms among controls (F=25.2,P<0.001). The pattern of findings was fully replicated inthe supplemental ANOVA that compared controls to onlythose ADHD participants who received placebo duringsession 1 (group � SOA and group � SOA � attend F1,19values=9.2 and 7.0; P values <0.01 and 0.02, respective-ly).

Relative to placebo, methylphenidate exerted a specif-ic effect on prepulse inhibition among boys with ADHD(medication � SOA � attend F1,14=8.0, P<0.02; Fig. 1).As predicted, follow-up tests indicated that methylpheni-date significantly enhanced prepulse inhibition duringattended prestimuli but not during ignored prestimuli at120 ms (F1,14 values=7.2 and 0.0; P values <0.02 and0.95, respectively). At 240 ms, methylphenidate did not

reliably affect prepulse inhibition during attended orignored prestimuli (both F values <1). These findings didnot vary with the order of drug administration (F1,14=1.6,P=0.23). Percent prepulse inhibition was statisticallydifferent from 0% only at the 120-SOA during attendedprestimuli during the medication session (F=14.2,P<0.005; F values for all other medication � SOA �attend conditions <3.3, P values >0.08).

The analysis comparing medicated ADHD boys tocontrols revealed a statistically reliable attend effect(F1,28=8.2, P<0.01), indicating robust enhancement ofprepulse inhibition during attended relative to ignoredprestimuli. While this effect did not vary with SOA, SOA� attend F<1, post-hoc tests revealed that attentionalmodification was robust at 120 ms and was not evident at240 ms (attend F1,28 values=8.3 and 0.0; P values <0.01and 0.84, respectively). Most importantly, there was noevidence of differential prepulse inhibition betweencontrols and ADHD boys tested following methylpheni-date administration (group � attend and group � SOA �attend F values <1). The supplemental analysis compar-ing controls to only those ADHD boys who receivedmethylphenidate during session 1 revealed an identicalpattern of findings (attend F1,20=5.7, P<0.03; group �attend and group � SOA � attend F values <1).

ITI startle magnitude

The analysis of ITI startle magnitude failed to revealreliable differences between controls (mean€SEM=14.7€4.8 �V) and ADHD participants during the meth-ylphenidate session (12.1€2.4 �V) or the placebo session(13.8€2.5 �V) – both F values <1. Similarly, for the boyswith ADHD, methylphenidate did not significantly alterITI startle magnitude relative to placebo (F<1). Thus, thefindings for percent prepulse inhibition were not due todifferences in baseline ITI startle magnitude.

Task performance

Table 2 presents the task performance data separately forADHD–placebo, ADHD–methylphenidate, and controls.As can be seen, performance was generally good and didnot differ across groups. In the analysis of ADHD–placebo versus controls, false alarms were more likelyfollowing short attended tones than following ignored

Fig. 1 Mean percent startle eyeblink electromyogram (EMG)magnitude modification, relative to inter-trial interval (ITI), forboys with attention-deficit hyperactivity disorder (ADHD) follow-ing both placebo and methylphenidate (MPH) administration, andfor controls. Error bars are within group and condition standarderror

Table 2 Mean (standard error) percent of false alarms and missesfor boys with attention-deficit hyperactivity disorder (ADHD)following placebo and methylphenidate (MPH) administration, andfor controls

ADHD–placebo ADHD–MPH Controls

False alarmsIgnored tones 1.1 (0.7) 1.3 (1.1) 2.6 (2.2)Attended tones 8.1 (3.8) 6.6 (4.3) 12.8 (5.9)Misses 11.8 (4.2) 12.3 (4.9) 8.3 (2.6)

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tones (attend F1,28=11.4, P<0.005), as would be expected.However, the percentage of false alarms did not reliablydiffer between controls and ADHD–placebo, group andgroup � attend (F values <1). An identical pattern ofstatistically significant effects emerged in the analyses ofADHD–methylphenidate versus ADHD–placebo andADHD–methylphenidate versus controls [attend F values(1,14 and 1,28, respectively) =8.4 and 10.2, P values<0.02 and 0.005, respectively; group and group � attend Fvalues <1]. Methylphenidate did not reliably influencefalse alarm rates, medication and medication � attend (Fvalues <1).

Overall, misses were relatively infrequent. The numberof misses did not differ between controls and the ADHDgroup following placebo or methylphenidate (F values<1), and misses were not influenced by methylphenidate,relative to placebo, among the children with ADHD(F<1).

Discussion

The first major aim of the present work was to compareattentional modification of short-lead prepulse inhibitionof startle among children with ADHD to that of a controlgroup of boys without behavior problems. The pattern offindings both replicated and extended prior work onADHD. Two previous studies reported comparable pas-sive prepulse inhibition among boys with and withoutADHD (Ornitz et al. 1992; Castellanos et al. 1996).Similarly, we found that responses to ignored prestimuliwere equivalent for our participants with and withoutADHD. Thus, it appears that basic sensorimotor gating isintact among boys with ADHD. More generally, thefindings for ignored prestimuli are consistent with theproposition that ADHD is not associated with a deficit inautomatic information processing (Douglas 1999; Ser-geant et al. 1999).

However, there was evidence of reduced controlledattentional processing among the boys with ADHD.Specifically, during the placebo session, the ADHDgroup showed less prepulse inhibition than the controlgroup during attended prestimuli at the 120-ms SOA.Prepulse inhibition at this SOA is believed to reflect theoperation of early controlled attentional resources, as thedistinction between attended and ignored stimuli is made(Dawson et al. 1997). Thus, the present data suggestimpairment in this early discrimination process amongboys with ADHD. One possibility is that there is simply adelay in the discrimination. Some support for thishypothesis emerges from a re-examination of Fig. 1 andan alternative decomposition of the reliable group � SOA� attend interaction. When changes across SOAs areexamined for each group � attend cell, an interestingpattern emerges (Fig. 1). Controls exhibit the expectedreduction in prepulse inhibition during attended prestim-uli from 120 ms to 240 ms (F1,28=9.7, P<0.005).Conversely, ADHD–placebo participants demonstrate areliable increase in prepulse inhibition (F1,28=4.5,

P<0.05). It would be quite informative to examineintermediate SOAs, such as 180 ms, to determine whetherADHD boys exhibit the same degree of attentionalmodification as controls, but with a delayed time course.Alternatively, the observed pattern may reflect “inconsis-tent or erratic allocation of attention,” a pattern which hasbeen observed in reaction time studies of ADHD (Dou-glas 1999, p 125).

Whether due to an absolute deficit, change in timecourse, or more variability, the data suggest ADHD isassociated with a problem with early selective, controlledprocessing. This finding is consistent with other psy-chophysiological (Satterfield et al. 1994) and behavioral(Berman et al. 1999; Douglas 1999) studies of ADHD.The prepulse inhibition data are also consistent withtheoretical models of deficient inhibition in ADHD (Quay1997), though further work is necessary to relate prepulseinhibition to other laboratory-based indices of behavioralinhibition (Quay 1997), self-regulation (Douglas 1999),and/or executive function (Barkley 1999). Such workremains in the early stages, even in the adult literature(Filion et al. 1999). It will be of further interest todetermine whether prepulse modification is related toecologically valid indices of attentional disturbance(Evans et al. 2001; Pelham et al. 2001a, 2001b) andwhether the results of the present study of Caucasian boysgeneralize across sex and ethnicity.

It is important to note that the pattern of startlemodulation observed for boys with ADHD is not specificto ADHD. Very similar findings have been observedamong adults with schizophrenia. Using the tone dis-crimination paradigm, schizophrenia is associated withnormal prepulse inhibition during ignored prestimuli butimpaired modification during attended prestimuli (Daw-son et al. 1993, 2000; Braff et al. 2001). While otherdisorders of childhood are associated with reducedpassive prepulse inhibition (i.e., Tourette’s and enuresis;Ornitz et al. 1992, 2000; Castellanos et al. 1996), itremains to be seen whether only ADHD will be associatedwith diminished prepulse inhibition during controlledattentional processing.

Conversely, it will also be of interest to determinewhether the absence of controlled prepulse modulation isrelated to ADHD subtype. It is plausible that deficits insustained attentional processing may be most stronglyassociated with the inattentive subtype of ADHD. Unfor-tunately, the small sample size of the present study,together with the fact that the majority of the ADHDparticipants were of the combined subtype (involvingsymptoms of both inattention and hyperactivity/impulsiv-ity), precluded a test of this hypothesis.

Effects of methylphenidate

The second major aim of the present study was toexamine the impact of methylphenidate, the most fre-quently prescribed medication for ADHD, upon startlemodification in children with ADHD. To accomplish this

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aim, we tested the effect of a commonly employedtherapeutic dose of methylphenidate (0.3 mg/kg) versusplacebo in a repeated-measures, double-blind design.Methylphenidate did not influence prepulse inhibitionduring ignored prestimuli. Instead, the drug specificallyenhanced prepulse inhibition during attended prestimuli atthe 120-ms SOA. As a result, methylphenidate completelyeliminated the difference that we had observed betweenthe ADHD group following placebo and the control group(Fig. 1).

The finding that methylphenidate influenced prepulseinhibition during attended, but not ignored, prestimuli isconsistent with Douglas’ (1999) conclusion that methyl-phenidate affects the allocation of controlled resources,including selective attention. Even more specifically, thepresent data appear consistent with reaction time andevent-related potential data that suggest methylphenidatecan speed the discrimination of target and non-targetstimuli (Klorman et al. 1994). Again, further work withSOAs between 120 ms and 240 ms would be useful fordetermining whether methylphenidate alters the amount,speed, and/or consistency with which early attentionalprocesses are engaged.

The robust effect of methylphenidate in the presentstudy supports the hypothesis that improvement in ADHDoften occurs with relatively low doses of methylphenidateand that higher doses yield diminishing returns (Smith etal. 1998; Evans et al. 2001; c.f., Rapport and Kelly 1991;Schachar and Ickowicz 1999). However, it is important topoint out that all ADHD participants in the present studyhad prior experience with methylphenidate. Indeed, theseparticipants had previously shown a good response tomethylphenidate at a dose similar to that used in thecurrent work (Pelham et al. 2001a), limiting the gener-alizability of the findings. Future work should examinethe dose–response relationship and include children whoare not necessarily methylphenidate “responders.”

It may also be informative to examine the effects ofmethylphenidate on attentional modification of startleamong normal controls. This is important for two reasons.First, it would address a methodological limitation of thecurrent work, namely that controls and ADHD partici-pants were not tested under identical conditions. That is,controls never took pills, and ADHD participants alwaystook either placebo or methylphenidate. Ethical concernsregarding giving non-therapeutic stimulants to childrenand prior data regarding the absence of expectancy effectswith methylphenidate (Pelham et al. 1997, 2001b, 2002)provided the primary rationale for these procedures.Nonetheless, the comparison of controls who took no pillin either session to children with ADHD who took a pillin both sessions is not ideal. Second, of greater theoreticalinterest, there are limited data to support the hypothesisthat the cognitive effects of stimulants are not specific toADHD (Rapoport et al. 1980; see Mehta et al. 2001, for areview). Both issues may be best addressed by examiningthe effects of methylphenidate on prepulse modificationamong adult controls, rather than children, both becauseof the larger literature on the effects of dopaminergic and

noradrenergic drugs in non-ADHD adults (Mehta et al.2001) and diminished ethics concerns.

As is true for many effects of psychotropic drugs, thespecific neurobiological mechanism responsible for theeffect of methylphenidate on prepulse modification is notclear. Methylphenidate blocks the re-uptake of bothdopamine and norepinephrine, and both neurotransmittersappear important in the therapeutic effect of the drug(Castellanos 1999; Schachar and Ickowicz 1999; Mehta etal. 2001; Pliszka 2001). For example, recent imagingwork in adults without ADHD indicated that 0.25 mg/kgoral methylphenidate blocks more that 50% of dopaminetransporter in the striatum (Volkow et al. 1998), signif-icantly increasing striatal dopamine (Volkow et al. 2001).

Importantly, alterations in striatal dopamine alsoinfluence passive prepulse inhibition (Mansbach et al.1988; Hutchison and Swift 1999). However, drugs thatincrease mesolimbic dopamine generally disrupt, notenhance, prepulse inhibition in rats and humans (forreviews, see Braff et al. 2001; Geyer et al. 2001). Thisdiscrepancy between the effects of methylphenidate in thepresent study and the effects of many dopamine agonistsin rats could occur for several reasons. For example, theobserved effects of methylphenidate may be specific toADHD; studies of the effect of methylphenidate in adultswithout ADHD would address this question. In addition,there are many differences in the methods used in the twotypes of work, including whether prestimuli are activelyor passively attended and the relative doses of drugadministered. While future studies may resolve thediscrepancy, at present the results of the current workare not consistent with animal studies showing thatincreases in mesolimbic dopamine decrease prepulseinhibition.

Alternatively, it may be more plausible to considerinfluences beyond the striatum. Dopamine activation ofD1 receptors in the prefrontal cortex is important inworking memory (Arnsten 2001), which may be offundamental importance in ADHD (Barkley 1997, 1999).In fact, there is evidence of prefrontal dopaminergicabnormalities in ADHD (Ernst et al. 1998, 1999).Relatedly, prefrontal dopamine regulates subcortical do-paminergic activity in the nucleus accumbens and else-where (Lipska and Weinberger 1993; Taylor and Jentsch2001), and such corticostriatal projections are hypothe-sized to be important in the pathophysiology of ADHDand the beneficial effects of methylphenidate (Grace2001). In addition to dopamine, norepinephrine enhancesfunctioning of the prefrontal cortex (Arnsten 2001), andprefrontal norepinephrine may be important in thepathophysiology of ADHD (Russell et al. 2000). More-over, increases in norepinephrine can facilitate neural andbehavioral responses to target stimuli, relative to irrele-vant or ignored stimuli (Berridge 2001), precisely the typeof mechanism that could explain the selective effect ofmethylphenidate on attended prestimuli that was observedin the present study. Thus, dopaminergic and noradren-ergic aspects of prefrontal cortical function may mediateeffects of methylphenidate on attentional processing in

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ADHD, such as the effects on prepulse modification inthe present study.

Consistent with this hypothesis, data from bothhumans and rats suggest that the prefrontal cortex isimportant in the modulation of prepulse inhibition. Inhumans, positron emission tomography (PET) dataacquired during a tone discrimination paradigm similarto that used in the present study suggest the prefrontalcortex is important in performing the task. Specifically,Hazlett and her colleagues (1998) found that the degree ofattentional modification of prepulse inhibition was asso-ciated with increased activation of several prefrontalregions, including the medial prefrontal cortex. Lesionstudies, as well as dopaminergic stimulation and blockadestudies, suggest that the medial prefrontal cortex is alsopart of the neural circuitry that regulates passive prepulseinhibition in rats (see Swerdlow et al. 2001, for a review).Thus, at present, the prefrontal cortex may be thestrongest candidate for further study in human and animalwork on prepulse inhibition in ADHD.

Methylphenidate is of great interest and will clearly beimportant in future research in this area. However, moreselective agents should also be examined in order tocharacterize the relative contributions of dopamine andnorepinephrine to alteration of prepulse modification inADHD. Drugs that have demonstrated at least someefficacy in treatment of ADHD, such as the alpha-2A-adrenoceptor agonist guanfacine (Scahill et al. 2001), maybe of particular interest.

Uncertainty about the neurobiological mechanismnotwithstanding, the present data provide preliminaryevidence that prepulse modification may be useful forexamining the attentional mechanisms by which treat-ments for ADHD work. This may not be limited topharmacological treatments. Behavioral treatments play astrong role in the management of ADHD (Pelham et al.1998), and the results of an initial study in young adultssuggests that attentional modification of prepulse inhibi-tion is sensitive to the effects of incentives. In that study,prepulse inhibition was enhanced during attended relativeto ignored tone prestimuli among participants provided amonetary incentive for task performance, but not amongparticipants who were simply asked to try to do their best(Hawk et al. 2002b). Given the putative role of alteredresponsivity to reward and punishment in ADHD (Haen-lein and Caul 1987; Iaboni et al. 1997), the tonediscrimination prepulse paradigm may provide a usefulcontext for exploring both behavioral/motivational andpharmacological influences on attentional processing inADHD.

Acknowledgements This research was supported by a ResearchDevelopment Award from the University at Buffalo to L.W.H.Portions of this research were presented at the Thirty-Ninth AnnualMeeting of the Society for Psychophysiological Research, Granada,Spain, 1999. We thank Barbara A. Church for generating theacoustic stimuli, Alyssa M. Johnson and Joshua S. Redford forassistance with data collection, and Elizabeth M. Gnagy, Lisa D.Burrows-MacLean, and Adia N. Onyango for assistance with datacollection and data management.

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