Psychopharmacology (2003) 165:118127

DOI 10.1007/s00213-002-1235-7
ORI GI NAL I NVE S T I GAT I ON
Larry W. Hawk Jr Andrew R. Yartz
William E. Pelham Jr Thomas M. Lock
The effects of methylphenidate on prepulse inhibition
during attended and ignored prestimuli among boys
with attention-deficit hyperactivity disorder
Received: 2 January 2002 / Accepted: 30 July 2002 / Published online: 1 November 2002
Springer-Verlag 2002
Abstract Rationale and objectives: The present study
investigated attentional modification of prepulse inhibi-
tion of startle among boys with and without attention-
deficit hyperactivity disorder (ADHD). Two hypotheses
were tested: (1) whether ADHD is associated with
diminished prepulse inhibition during attended prestimuli,
but not ignored prestimuli, and (2) whether methylphe-
nidate selectively increases prepulse inhibition to attended
prestimuli among boys with ADHD. Methods: Participants
were 17 boys with ADHD and 14 controls. Participants
completed a tone discrimination task in each of two
sessions separated by 1 week. ADHD boys were admin-
istered methylphenidate (0.3 mg/kg) in one session and
placebo in the other session in a randomized, double-blind
fashion. During each series of 72 tones (75 dB; half 1200-
Hz, half 400-Hz), participants were paid to attend to one
pitch and ignore the other. Bilateral eyeblink electromy-
ogram startle responses were recorded in response to
acoustic probes (50-ms, 102-dB white noise) presented
following the onset of two-thirds of tones, and during
one-third of intertrial intervals. Results: Relative to
controls, boys with ADHD exhibited diminished prepulse
inhibition 120 ms after onset of attended but not ignored
prestimuli following placebo administration. Methylphe-
nidate selectively increased prepulse inhibition to attend-
ed prestimuli at 120 ms among boys with ADHD to a
level comparable to that of controls, who did not receive
methylphenidate. Conclusions: These data are consistent
with the hypothesis that ADHD involves diminished
selective attention and suggest that methylphenidate
ameliorates the symptoms of ADHD, at least in part, by
altering 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/or
hyperactivity-impulsivity [Diagnostic and Statistical
Manual of Mental Disorders (DSM)-IV, American Psy-
chiatric Association 1994]. Similarly, current theoretical
perspectives on ADHD focus on deficits of attention,
inhibition, or both. As Douglas (1999) reviews, there is
evidence of impairment in a range of cognitive control
processes, including sustained attentional allocation.
Others have argued against a central attentional deficit
in ADHD (Sergeant and van der Meere 1990) and have
focused on behavioral inhibition (Quay 1997; Barkley
1999; Sergeant et al. 1999). Despite important differences
among these models, all acknowledge that ADHD likely
involves poor inhibition. However, neither attention nor
inhibition has a single operational definition, and many
tasks likely involve elements of both processes (Halperin
et al. 1991). Consequently, it has been suggested that
investigators choose measures that most simply and
directly assess the constructs of interest (Douglas 1999;
Sergeant et al. 1999).
Prepulse inhibition of the startle reflex has much to
offer in this respect (see the special issue of Psychophar-
macology on prepulse inhibition, edited by Koch and
Robbins 2001). Prepulse inhibition refers to a decrement
in the magnitude of the startle response that occurs when
a weak task-irrelevant prestimulus (or prepulse) is
presented 60500 ms before the onset of the startle-
eliciting stimulus (for reviews, see Filion et al. 1998;
Blumenthal 1999). Prepulse inhibition may reflect a
partially automatic mechanism for protecting the initial
L.W. Hawk Jr (
)
) A.R. Yartz W.E. Pelham Jr
Department of Psychology, State University of New York,
Park Hall Box 604110, Buffalo, NY 14260-4110, USA
e-mail: lhawk@buffalo.edu
W.E. Pelham Jr
Department of Psychiatry, State University of New York, Buffalo,
New York, USA
T.M. Lock
Department of Pediatrics, State University of New York, Buffalo,
New York, USA
processing of sensory stimuli (Graham 1975) or a more
general gating mechanism (Braff and Geyer 1990) that
serves a critical inhibitory function in sensory, cognitive,
and motor output processing.
Furthering its utility as a model system, the brainstem
circuitry that mediates prepulse inhibition in the rat is
well-known (Fendt et al. 2001). While several neuro-
transmitter systems regulate prepulse inhibition, the
dopaminergic system is predominant in both rat (Swerd-
low et al. 2001) and human (Braff et al. 2001) studies.
Importantly, striatal dopamine also figures prominently in
both the pathophysiology and the treatment of ADHD
(Solanto et al. 2001).
Thus, it would seem reasonable to hypothesize that
children with ADHD exhibit diminished prepulse inhibi-
tion. However, in a large study of boys with and without
ADHD, Ornitz and colleagues (1992) found that ADHD
was not associated with reduced prepulse inhibition.
Similarly, Castellanos et al. (1996) observed diminished
prepulse inhibition among boys with Tourettes Syn-
drome and ADHD, but not among boys with ADHD only.
These studies suggest that ADHD alone is not associated
with a deficit in passive prepulse inhibition, which does
not require any controlled attentional processing of the
experimental stimuli.
However, current perspectives emphasize problems in
the allocation of controlled processes in the disorder
rather than deficits in automatic processing (Berman et al.
1999; Sergeant et al. 1999). Consistent with this account,
Satterfield et al. (1994) reported comparable event-related
potentials to ignored stimuli among controls and unmed-
icated children with ADHD, but children with ADHD
exhibited reduced processing of attended stimuli, as
evidenced by P300 (see similar findings by Klorman et
al. 1994; Jonkman et al. 2000; c.f. Smithee et al. 1998).
Prepulse inhibition can also be used to study controlled
attention active attention to prestimuli increases the
degree to which startle is inhibited (DelPezzo and
Hoffman 1980). This effect has been most clearly
demonstrated in the tone discrimination paradigm of
Dawson and colleagues (Dawson et al. 1993; Filion et al.
1993; Schell et al. 1995; Jennings et al. 1996). High- and
low-pitched tones, which serve as continuous prestimuli
for acoustic startle probes, are presented in an intermixed
series. The participant is paid to accurately attend to
duration of tones of one pitch but is asked to ignore tones
of the other pitch. In this paradigm, prepulse inhibition is
evident at various short prepulse-probe stimulus onset
asynchronies (SOAs; i.e., 60, 120, and 240 ms) and is
greater during attended than ignored tones at 120 ms but
not at 60 ms or 240 ms. This enhanced prepulse inhibition
to attended prestimuli at the 120-ms SOA is believed to
reflect a brief controlled attentional process, perhaps
related to confirming the identity of the attended prepulse
(Dawson et al. 1997). While most of this work has been
done with adult participants, attentional modification of
prepulse inhibition at a 120-ms SOA was recently
replicated 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 exhibit
normal attentional modification of prepulse inhibition at
120 ms. It was expected that boys with ADHD would
exhibit diminished prepulse inhibition during attended,
but not ignored, prestimuli, relative to controls.
The second goal of the present work was to examine
the effects of a low dose of methylphenidate on prepulse
inhibition among boys with ADHD. Methylphenidate is
the most frequently prescribed medication for ADHD
(Goldman et al. 1998), and it improves both behavioral
and cognitive aspects of the disorder at doses between
0.3 mg/kg and 1.0 mg/kg (Schachar and Ickowicz 1999).
Methylphenidate prevents re-uptake of dopamine and
norepinephrine, and both actions are believed to be
important in the drugs efficacy (Castellanos 1999;
Schachar and Ickowicz 1999; Mehta et al. 2001). From
a clinical perspective, methylphenidate would be expect-
ed to increase childrens focus on attended tones during
the discrimination task, enhancing prepulse inhibition
during attended, but not ignored, prestimuli. Indeed,
methylphenidate would be expected to reduce prepulse
inhibition to ignored prestimuli, both because drugs that
increase mesolimbic dopamine availability decrease pas-
sive prepulse inhibition (Mansbach et al. 1988; Hutchison
and Swift 1999) and because methylphenidate might
facilitate ignoring. We tested these hypotheses by exam-
ining children with ADHD twice, once following inges-
tion of 0.3 mg/kg methylphenidate and once following
pill placebo, under randomized, double-blind conditions.
Comparison of startle modification between medicated
boys with ADHD and unmedicated controls allowed a
determination of the extent to which methylphenidate
normalized prepulse modification. Placebo and methyl-
phenidate were not administered to controls both due to
ethical concerns about administering non-therapeutic
stimulants to naive normal participants and because
previous work with balanced-placebo designs have con-
sistently failed to reveal expectancy effects on methyl-
phenidates impact on cognitive, behavioral, or social
performance in children with ADHD (Pelham et al. 1997,
2001b, 2002).
Materials and methods
Participants
Participants were 17 boys with a primary diagnosis of ADHD and
14 similarly aged controls.
1
All ADHD and control participants
were recruited via a mailing sent to parents of children who had
recently participated in a larger study of the effects of methylphe-
1
The data for the controls are from a more extensive report that
examined startle modification at multiple SOAs, as well as the test
retest reliability of startle modification (Hawk et al. 2002a). In the
present study, the primary focus is on ADHD, attentional modi-
fication of prepulse inhibition at the 120-ms SOA, and the effects of
methylphenidate. However, we have included a subset of previ-
ously published control data to allow for more informative
comparisons
119
nidate among children with ADHD (Pelham et al. 2001a) and
comparisons to non-ADHD controls. For the present study,
participants were further screened for parent-reported health
problems and visual and auditory impairments.
Table 1 presents demographic information regarding both
groups, as well as clinical characteristics of the ADHD group.
Mean age and full-scale IQ scores on the third edition of the
Wechsler Intelligence Scale for Children (Wechsler 1991; for
controls, IQ was estimated from the vocabulary and block-design
subtests) were comparable for the ADHD and control participants
(F values <1). As indicated in Table 1, all participants were male
Caucasians.
All members of the ADHD group met DSM-IV (American
Psychiatric Association 1994) criteria for ADHD. Specifically,
parents were administered the National Institute of Mental Health
Diagnostic Interview Schedule for Children Version IV (DISC;
Shaffer et al. 2000), and parents and teachers also completed the
Disruptive Behavior Disorders checklist (DBD; Pelham et al. 1992)
and the IOWA Conners ratings scales (Goyette et al. 1978; Pelham
et al. 1989). A DSM-IV symptom was considered present if either
parents (DISC and DBD) or the teacher (DBD) endorsed it, and
overlap between raters was required on at least one symptom.
Table 1 presents severity data, in the form of symptom counts, for
the DISC, parent and teacher DBD, and parent and teacher IOWA
Conners. Also, as can be seen in Table 1, most of the present
sample 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 up
to US $5 more for task performance during each session (see
Procedure). Participants were given a US $10 bonus upon
completion of both sessions.
Apparatus
A computer program (VPM; Cook et al. 1987), running on a
Pentium-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 heart
rate were also measured).
Digital acoustic stimuli were created with SoundEdit16
(Macromedia; San Francisco, Calif.) on an Apple Macintosh
computer. Startle probes were 50-ms, 102-dB bursts of white noise
with near-instantaneous rise/fall times. Prestimuli were 75-dB, 400-
and 1200-Hz tones, of 5- and 8-s duration, with 25-ms rise/fall
times. All acoustic stimuli were presented by VPM via a
Soundblaster (Milpitas, Calif.) AWE64 Gold sound card, externally
amplified with a Denon (Tokyo) AVR-1400 stereo receiver, and
played 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/AgCl
surface electrodes (Med Associates, East Fairfield, Vt.) filled with
Med Associates electrode gel and centered 0.5 cm below the pupil
and outer canthus of each eye. The left and right electromyogram
(EMG) signals were amplified by separate Grass Instruments (West
Warwick, Ohio) 7P3 preamplifiers and 7DA driver amplifiers with
half-power cutoff frequencies set to 10 Hz and 500 Hz. Amplifier
output was fed to the A/D converter of a Scientific Solutions
(Solon, Ohio) Lab Master DMA interface, which sampled the
amplified EMG at 1000 Hz from 50 ms before until 300 ms after
the 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 the
larger study (Pelham et al. 2001a) from which the current sample
was recruited. Because the present study was conducted during the
summer, five participants were on drug holidays and had not
received medication for 2 weeks to 2 months before either of the
lab sessions. Of the remaining 12 ADHD children, 11 had been
medication free for 1836 h before both lab sessions. One ADHD
participant had been medication free for 19 h before one session but
only for 13.5 h before the other. Thus, all participants were familiar
with methylphenidate and its effects, and most had recent
experience with the drug. However, no participant reported any
methylphenidate use within the 12 h (approximately four half-lives;
Swanson and Volkow 2001) prior to any experimental session. No
participant was taking any other psychotropic medication at the
time of the study.
Both participants and experimenters were blind to medication
condition, as methylphenidate (0.3 mg/kg) and placebo were each
presented in a single opaque capsule filled with methylcellulose.
Although we did not assess whether ADHD participants could
distinguish methylphenidate from placebo, prior work suggests they
cannot accurately make this distinction (Dalby et al. 1978). Drug
order was counterbalanced, with 9 of 17 ADHD participants
receiving methylphenidate during session 1. To assess startle
modification during methylphenidates active window, the tone
discrimination task was begun 1 h after medication ingestion.
Procedure
Institutional Review Boards at the State University of New York at
Buffalo and the Childrens Hospital of Buffalo approved all
procedures.
Sessions were conducted in an IAC (Bronx, N.Y.) 2.72.5-m
electrically and acoustically isolated chamber. After parental
Table 1 Demographic and clinical characteristics. Except for
percentages, values are means (standard deviations). ADHD
attention-deficit hyperactivity disorder, DBD disruptive behavior
disorders checklist, DISC diagnostic interview schedule for
children
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 symptoms
Inattention 7.5 (1.3)
Hyperactivity/impulsivity 6.1 (2.6)
Parent IOWA Conners ratings
Inattention/overactivity 10.6 (3.8)
Oppositional/defiant 6.9 (4.2)
Teacher DBD symptoms
Inattention 5.1 (3.4)
Hyperactivity/impulsivity 3.0 (2.5)
Teacher IOWA Conners ratings
Inattention/overactivity 8.8 (3.3)
Oppositional/defiant 4.2 (3.8)
ADHD subtype
Combined 76%
Hyperactive-impulsive 12%
Inattentive 12%
Co-morbidity
Oppositional-defiant disorder 41%
Conduct disorder 29%
Nocturnal enuresis 12%
Anxiety disorder 12%
Chronic motor tic disorder 6%
120
consent and participant assent were obtained, medication was
administered to ADHD participants. All other procedures were
identical between participants with ADHD and controls, and data
for the two groups were collected concurrently.
To reduce the strangeness of the environment and to increase
interest in the experimental task, each participant was asked to
pretend that he was an astronaut on a mission to decode a message
from outer space. Electrodes were attached and the child was left
alone in the subject chamber. Participants were monitored
throughout the session via a hands-free intercom and a video
camera. As part of their astronaut training, participants listened to
series of tones to ensure that both tone pitch and duration were
discriminated. Participants were then presented with two test startle
probes.
The experimenter returned to the subject room to provide
instructions for the task, as adapted from Jennings et al. (1996).
Participants were instructed to attend to either low or high tones
and to press a hand-held button at the offset of a longer-than-usual
presentation of the attended pitch. They were informed that
detection of longer-than-usual tones of the attended pitch would
determine the amount of bonus money they were paid. Perfect
performance earned US $5.00, with each error of omission or
commission resulting in a loss of US $0.50.
Each of the 72 trials of the tone discrimination task consisted of
a 5-s or 8-s tone and a 15-s to 29-s intertrial interval (ITI). Within
each block of 24 trials, there were 12 high tones (1200 Hz) and 12
low tones (400 Hz). Within each pitch, there were eight 5-s tones
and four 8-s tones. Startle probes were presented during two-thirds
of tones (two probes each at 120-, 240-, 2000-, and 4500-ms SOAs
in each trial block) as well as during one-third of the ITIs, with an
average of 26 s between startle probes. Six pseudorandom orders of
stimuli were used to counterbalance across participants the
sequence of SOAs and tone pitches. Attended pitch was counter-
balanced across sessions and the order in which pitches were
attended (low during session 1 and high during session 2 vs high
during session 1 and low during session 2) was counterbalanced
between subjects.
Upon completion of the tone discrimination task, the sensors
were 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 was
then informed about his performance and paid for the session.
Session 2, completed 1 week later, followed the above
procedures, except that the medication condition was switched
for ADHD children, and all children attended to the opposite tone
pitch.
Data reduction and analysis
Prepulse inhibition
Startle eyeblink magnitude was the primary dependent variable.
Eyeblink EMG responses were digitally integrated offline (rectified
and low-pass filtered with an 80-ms time constant) and scored with
the algorithm of Balaban et al. (1986), as in prior work (Hawk and
Cook 2000; Hawk et al. 2002a).
Eyeblink EMG magnitude subject averages were computed for
each session SOA (120, 240, 2000, 4500) pitch (attended,
ignored) cell, as well as for the ITI for each session. Percent
prepulse modification for each SOA was computed as [(M
ITI

M
prepulse
)/(M
ITI
)]100. To reduce subject loss due to missing data in
one or more cells of the design, modification scores were averaged
across the right and left eyes and across trial blocks.
Three separate analyses of variance (ANOVAs) addressed the
major questions in this study, which focused on short-lead prepulse
inhibition.
2
In all analyses, pitch (attended vs ignored) and SOA
(120 ms vs 240 ms) were included as within-subjects factors, and
attend 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 tested
whether methylphenidate increased prepulse inhibition among boys
with ADHD; medication was included as a within-subjects factor.
The third ANOVA contrasted startle modification between ADHD
boys during the methylphenidate session and controls (session 1).
All interactions were followed up with simple main-effects
analyses. To determine under which conditions the prestimuli
reliably inhibited startle, intercept tests were also examined in the
controls versus ADHD-placebo and ADHD-placebo versus ADHD-
methylphenidate analyses.
One potential problem in the comparisons between ADHD and
controls is that attentional modification may decrease over time
(Schell et al. 2000; Hawk et al. 2002a). Because the primary
comparisons of ADHD and controls did not control for possible
session effects, a supplemental set of analyses were completed. The
control data were again from session 1. The first ANOVA
contrasted the controls with ADHD boys during the placebo
session but was restricted to ADHD boys who received placebo
during session 1 (n=8). Similarly, the second ANOVA examined
prepulse modification among controls and ADHD boys during the
methylphenidate session, but only those ADHD boys who received
methylphenidate during session 1 (n=9).
ITI startle magnitude
Paralleling the prepulse inhibition analyses, three ANOVAs were
conducted on ITI startle magnitude to determine whether any
differences in prepulse inhibition might be due to differences in the
degree of baseline (i.e., ITI) startle responding.
Task performance
As for prepulse modification, task performance was examined
using ANOVA, with separate ANOVAs examining controls versus
ADHD-placebo, ADHD-placebo versus ADHD-methylphenidate,
and controls versus ADHD-methylphenidate. Percent misses (errors
of omission; there were 12 attended target tones) and percent false
alarms (errors of commission) were examined separately. The
analysis of percent false alarms included attend (attended vs
ignored tone pitch; there were 24 attended non-targets and 36
ignored non-targets) as a within-subjects variable.
2
A parallel series of analyses were conducted on percent prepulse
facilitation at the long-lead SOAs (2000 ms and 4500 ms). Because
prepulse inhibition is of primary interest, these results are
summarized here. As expected (Filion et al. 1993; Jennings et al.
1996; Hawk et al. 2002a), long-lead prepulse facilitation was robust
in all analyses (P values <0.001). However, there were no group
differences in long-lead prepulse facilitation (all P values >0.20).
While there was a reliable medication drug order attend
interaction among the ADHD group (P<0.04), further examination
of the data suggested that the interaction reflected a session effect
rather than an interesting effect of methylphenidate. That is, when
the data were re-coded according to session (mathematically
equivalent to medication drug order), follow-up tests indicated
marginally greater facilitation during attended than ignored during
session 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 comparable
effect among the controls (Hawk et al. 2002a). Further details are
available from the authors
121
Results
Percent prepulse inhibition
Figure 1 presents mean percent prepulse inhibition for
ignored and attended prestimuli at the 120-ms and 240-ms
SOAs, separately for ADHDplacebo, ADHDmethyl-
phenidate, and controls. In the analysis comparing
ADHDplacebo to controls, group differences varied
across SOAs and attention conditions (group SOA and
group SOA attend F
1,28
values=10.7 and 6.3; P values
<0.005 and 0.02, respectively). Simple main-effects
analyses revealed the hypothesized pattern. At 120 ms,
ADHDplacebo exhibited less prepulse inhibition than
did controls during attended prestimuli, but not during
ignored prestimuli (F
1,28
values=6.5 and 0.2; P values
<0.02 and 0.67, respectively). At 240 ms, ADHDplacebo
and controls exhibited comparable prepulse inhibition
or lack thereof during both attended and ignored
prestimuli (F
1,28
values <1.8; P values >0.19). Intercept
tests conducted separately for ADHDplacebo and con-
trol participants demonstrated that percent prepulse
inhibition was reliably different from 0% only during
attended prestimuli at 120 ms among controls (F=25.2,
P<0.001). The pattern of findings was fully replicated in
the supplemental ANOVA that compared controls to only
those ADHD participants who received placebo during
session 1 (group SOA and group SOA attend F
1,19
values=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 F
1,14
=8.0, P<0.02; Fig. 1).
As predicted, follow-up tests indicated that methylpheni-
date significantly enhanced prepulse inhibition during
attended prestimuli but not during ignored prestimuli at
120 ms (F
1,14
values=7.2 and 0.0; P values <0.02 and
0.95, respectively). At 240 ms, methylphenidate did not
reliably affect prepulse inhibition during attended or
ignored prestimuli (both F values <1). These findings did
not vary with the order of drug administration (F
1,14
=1.6,
P=0.23). Percent prepulse inhibition was statistically
different from 0% only at the 120-SOA during attended
prestimuli 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 to
controls revealed a statistically reliable attend effect
(F
1,28
=8.2, P<0.01), indicating robust enhancement of
prepulse inhibition during attended relative to ignored
prestimuli. While this effect did not vary with SOA, SOA
attend F<1, post-hoc tests revealed that attentional
modification was robust at 120 ms and was not evident at
240 ms (attend F
1,28
values=8.3 and 0.0; P values <0.01
and 0.84, respectively). Most importantly, there was no
evidence of differential prepulse inhibition between
controls 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 received
methylphenidate during session 1 revealed an identical
pattern of findings (attend F
1,20
=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 reveal
reliable differences between controls (meanSEM=
14.74.8 V) and ADHD participants during the meth-
ylphenidate session (12.12.4 V) or the placebo session
(13.82.5 V) both F values <1. Similarly, for the boys
with ADHD, methylphenidate did not significantly alter
ITI startle magnitude relative to placebo (F<1). Thus, the
findings for percent prepulse inhibition were not due to
differences in baseline ITI startle magnitude.
Task performance
Table 2 presents the task performance data separately for
ADHDplacebo, ADHDmethylphenidate, and controls.
As can be seen, performance was generally good and did
not differ across groups. In the analysis of ADHD
placebo versus controls, false alarms were more likely
following short attended tones than following ignored
Fig. 1 Mean percent startle eyeblink electromyogram (EMG)
magnitude modification, relative to inter-trial interval (ITI), for
boys with attention-deficit hyperactivity disorder (ADHD) follow-
ing both placebo and methylphenidate (MPH) administration, and
for controls. Error bars are within group and condition standard
error
Table 2 Mean (standard error) percent of false alarms and misses
for boys with attention-deficit hyperactivity disorder (ADHD)
following placebo and methylphenidate (MPH) administration, and
for controls
ADHDplacebo ADHDMPH Controls
False alarms
Ignored 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)
122
tones (attend F
1,28
=11.4, P<0.005), as would be expected.
However, the percentage of false alarms did not reliably
differ between controls and ADHDplacebo, group and
group attend (F values <1). An identical pattern of
statistically significant effects emerged in the analyses of
ADHDmethylphenidate versus ADHDplacebo and
ADHDmethylphenidate 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 F
values <1]. Methylphenidate did not reliably influence
false alarm rates, medication and medication attend (F
values <1).
Overall, misses were relatively infrequent. The number
of misses did not differ between controls and the ADHD
group 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 compare
attentional modification of short-lead prepulse inhibition
of startle among children with ADHD to that of a control
group of boys without behavior problems. The pattern of
findings both replicated and extended prior work on
ADHD. Two previous studies reported comparable pas-
sive prepulse inhibition among boys with and without
ADHD (Ornitz et al. 1992; Castellanos et al. 1996).
Similarly, we found that responses to ignored prestimuli
were equivalent for our participants with and without
ADHD. Thus, it appears that basic sensorimotor gating is
intact among boys with ADHD. More generally, the
findings for ignored prestimuli are consistent with the
proposition that ADHD is not associated with a deficit in
automatic information processing (Douglas 1999; Ser-
geant et al. 1999).
However, there was evidence of reduced controlled
attentional processing among the boys with ADHD.
Specifically, during the placebo session, the ADHD
group showed less prepulse inhibition than the control
group during attended prestimuli at the 120-ms SOA.
Prepulse inhibition at this SOA is believed to reflect the
operation of early controlled attentional resources, as the
distinction between attended and ignored stimuli is made
(Dawson et al. 1997). Thus, the present data suggest
impairment in this early discrimination process among
boys with ADHD. One possibility is that there is simply a
delay in the discrimination. Some support for this
hypothesis emerges from a re-examination of Fig. 1 and
an alternative decomposition of the reliable group SOA
attend interaction. When changes across SOAs are
examined for each group attend cell, an interesting
pattern emerges (Fig. 1). Controls exhibit the expected
reduction in prepulse inhibition during attended prestim-
uli from 120 ms to 240 ms (F
1,28
=9.7, P<0.005).
Conversely, ADHDplacebo participants demonstrate a
reliable increase in prepulse inhibition (F
1,28
=4.5,
P<0.05). It would be quite informative to examine
intermediate SOAs, such as 180 ms, to determine whether
ADHD boys exhibit the same degree of attentional
modification as controls, but with a delayed time course.
Alternatively, the observed pattern may reflect inconsis-
tent or erratic allocation of attention, a pattern which has
been observed in reaction time studies of ADHD (Dou-
glas 1999, p 125).
Whether due to an absolute deficit, change in time
course, or more variability, the data suggest ADHD is
associated with a problem with early selective, controlled
processing. 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 with
theoretical models of deficient inhibition in ADHD (Quay
1997), though further work is necessary to relate prepulse
inhibition to other laboratory-based indices of behavioral
inhibition (Quay 1997), self-regulation (Douglas 1999),
and/or executive function (Barkley 1999). Such work
remains in the early stages, even in the adult literature
(Filion et al. 1999). It will be of further interest to
determine whether prepulse modification is related to
ecologically valid indices of attentional disturbance
(Evans et al. 2001; Pelham et al. 2001a, 2001b) and
whether the results of the present study of Caucasian boys
generalize across sex and ethnicity.
It is important to note that the pattern of startle
modulation observed for boys with ADHD is not specific
to ADHD. Very similar findings have been observed
among adults with schizophrenia. Using the tone dis-
crimination paradigm, schizophrenia is associated with
normal prepulse inhibition during ignored prestimuli but
impaired modification during attended prestimuli (Daw-
son et al. 1993, 2000; Braff et al. 2001). While other
disorders of childhood are associated with reduced
passive prepulse inhibition (i.e., Tourettes and enuresis;
Ornitz et al. 1992, 2000; Castellanos et al. 1996), it
remains to be seen whether only ADHD will be associated
with diminished prepulse inhibition during controlled
attentional processing.
Conversely, it will also be of interest to determine
whether the absence of controlled prepulse modulation is
related to ADHD subtype. It is plausible that deficits in
sustained attentional processing may be most strongly
associated 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 ADHD
participants were of the combined subtype (involving
symptoms 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 to
examine the impact of methylphenidate, the most fre-
quently prescribed medication for ADHD, upon startle
modification in children with ADHD. To accomplish this
123
aim, we tested the effect of a commonly employed
therapeutic dose of methylphenidate (0.3 mg/kg) versus
placebo in a repeated-measures, double-blind design.
Methylphenidate did not influence prepulse inhibition
during ignored prestimuli. Instead, the drug specifically
enhanced prepulse inhibition during attended prestimuli at
the 120-ms SOA. As a result, methylphenidate completely
eliminated the difference that we had observed between
the ADHD group following placebo and the control group
(Fig. 1).
The finding that methylphenidate influenced prepulse
inhibition during attended, but not ignored, prestimuli is
consistent with Douglas (1999) conclusion that methyl-
phenidate affects the allocation of controlled resources,
including selective attention. Even more specifically, the
present data appear consistent with reaction time and
event-related potential data that suggest methylphenidate
can speed the discrimination of target and non-target
stimuli (Klorman et al. 1994). Again, further work with
SOAs between 120 ms and 240 ms would be useful for
determining whether methylphenidate alters the amount,
speed, and/or consistency with which early attentional
processes are engaged.
The robust effect of methylphenidate in the present
study supports the hypothesis that improvement in ADHD
often occurs with relatively low doses of methylphenidate
and that higher doses yield diminishing returns (Smith et
al. 1998; Evans et al. 2001; c.f., Rapport and Kelly 1991;
Schachar and Ickowicz 1999). However, it is important to
point out that all ADHD participants in the present study
had prior experience with methylphenidate. Indeed, these
participants had previously shown a good response to
methylphenidate at a dose similar to that used in the
current work (Pelham et al. 2001a), limiting the gener-
alizability of the findings. Future work should examine
the doseresponse relationship and include children who
are not necessarily methylphenidate responders.
It may also be informative to examine the effects of
methylphenidate on attentional modification of startle
among normal controls. This is important for two reasons.
First, it would address a methodological limitation of the
current work, namely that controls and ADHD partici-
pants were not tested under identical conditions. That is,
controls never took pills, and ADHD participants always
took either placebo or methylphenidate. Ethical concerns
regarding giving non-therapeutic stimulants to children
and prior data regarding the absence of expectancy effects
with methylphenidate (Pelham et al. 1997, 2001b, 2002)
provided the primary rationale for these procedures.
Nonetheless, the comparison of controls who took no pill
in either session to children with ADHD who took a pill
in both sessions is not ideal. Second, of greater theoretical
interest, there are limited data to support the hypothesis
that the cognitive effects of stimulants are not specific to
ADHD (Rapoport et al. 1980; see Mehta et al. 2001, for a
review). Both issues may be best addressed by examining
the effects of methylphenidate on prepulse modification
among adult controls, rather than children, both because
of 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, the
specific neurobiological mechanism responsible for the
effect of methylphenidate on prepulse modification is not
clear. Methylphenidate blocks the re-uptake of both
dopamine and norepinephrine, and both neurotransmitters
appear important in the therapeutic effect of the drug
(Castellanos 1999; Schachar and Ickowicz 1999; Mehta et
al. 2001; Pliszka 2001). For example, recent imaging
work in adults without ADHD indicated that 0.25 mg/kg
oral methylphenidate blocks more that 50% of dopamine
transporter in the striatum (Volkow et al. 1998), signif-
icantly increasing striatal dopamine (Volkow et al. 2001).
Importantly, alterations in striatal dopamine also
influence passive prepulse inhibition (Mansbach et al.
1988; Hutchison and Swift 1999). However, drugs that
increase mesolimbic dopamine generally disrupt, not
enhance, prepulse inhibition in rats and humans (for
reviews, see Braff et al. 2001; Geyer et al. 2001). This
discrepancy between the effects of methylphenidate in the
present study and the effects of many dopamine agonists
in rats could occur for several reasons. For example, the
observed effects of methylphenidate may be specific to
ADHD; studies of the effect of methylphenidate in adults
without ADHD would address this question. In addition,
there are many differences in the methods used in the two
types of work, including whether prestimuli are actively
or passively attended and the relative doses of drug
administered. While future studies may resolve the
discrepancy, at present the results of the current work
are not consistent with animal studies showing that
increases in mesolimbic dopamine decrease prepulse
inhibition.
Alternatively, it may be more plausible to consider
influences beyond the striatum. Dopamine activation of
D1 receptors in the prefrontal cortex is important in
working memory (Arnsten 2001), which may be of
fundamental importance in ADHD (Barkley 1997, 1999).
In fact, there is evidence of prefrontal dopaminergic
abnormalities 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 Jentsch
2001), and such corticostriatal projections are hypothe-
sized to be important in the pathophysiology of ADHD
and the beneficial effects of methylphenidate (Grace
2001). In addition to dopamine, norepinephrine enhances
functioning of the prefrontal cortex (Arnsten 2001), and
prefrontal norepinephrine may be important in the
pathophysiology of ADHD (Russell et al. 2000). More-
over, increases in norepinephrine can facilitate neural and
behavioral responses to target stimuli, relative to irrele-
vant or ignored stimuli (Berridge 2001), precisely the type
of mechanism that could explain the selective effect of
methylphenidate on attended prestimuli that was observed
in the present study. Thus, dopaminergic and noradren-
ergic aspects of prefrontal cortical function may mediate
effects of methylphenidate on attentional processing in
124
ADHD, such as the effects on prepulse modification in
the present study.
Consistent with this hypothesis, data from both
humans and rats suggest that the prefrontal cortex is
important in the modulation of prepulse inhibition. In
humans, positron emission tomography (PET) data
acquired during a tone discrimination paradigm similar
to that used in the present study suggest the prefrontal
cortex is important in performing the task. Specifically,
Hazlett and her colleagues (1998) found that the degree of
attentional modification of prepulse inhibition was asso-
ciated with increased activation of several prefrontal
regions, including the medial prefrontal cortex. Lesion
studies, as well as dopaminergic stimulation and blockade
studies, suggest that the medial prefrontal cortex is also
part of the neural circuitry that regulates passive prepulse
inhibition in rats (see Swerdlow et al. 2001, for a review).
Thus, at present, the prefrontal cortex may be the
strongest candidate for further study in human and animal
work on prepulse inhibition in ADHD.
Methylphenidate is of great interest and will clearly be
important in future research in this area. However, more
selective agents should also be examined in order to
characterize the relative contributions of dopamine and
norepinephrine to alteration of prepulse modification in
ADHD. Drugs that have demonstrated at least some
efficacy in treatment of ADHD, such as the alpha-2A-
adrenoceptor agonist guanfacine (Scahill et al. 2001), may
be of particular interest.
Uncertainty about the neurobiological mechanism
notwithstanding, the present data provide preliminary
evidence that prepulse modification may be useful for
examining the attentional mechanisms by which treat-
ments for ADHD work. This may not be limited to
pharmacological treatments. Behavioral treatments play a
strong role in the management of ADHD (Pelham et al.
1998), and the results of an initial study in young adults
suggests that attentional modification of prepulse inhibi-
tion is sensitive to the effects of incentives. In that study,
prepulse inhibition was enhanced during attended relative
to ignored tone prestimuli among participants provided a
monetary incentive for task performance, but not among
participants who were simply asked to try to do their best
(Hawk et al. 2002b). Given the putative role of altered
responsivity to reward and punishment in ADHD (Haen-
lein and Caul 1987; Iaboni et al. 1997), the tone
discrimination prepulse paradigm may provide a useful
context for exploring both behavioral/motivational and
pharmacological influences on attentional processing in
ADHD.
Acknowledgements This research was supported by a Research
Development Award from the University at Buffalo to L.W.H.
Portions of this research were presented at the Thirty-Ninth Annual
Meeting of the Society for Psychophysiological Research, Granada,
Spain, 1999. We thank Barbara A. Church for generating the
acoustic stimuli, Alyssa M. Johnson and Joshua S. Redford for
assistance with data collection, and Elizabeth M. Gnagy, Lisa D.
Burrows-MacLean, and Adia N. Onyango for assistance with data
collection and data management.
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