Electrophysiological indices of information processing in methylphenidate responders

Electrophysiological Indices of Information Processing in Methylphenidate Responders Bertrand G. Winsberg, Daniel C. Javitt, and Gail Shanahan/Silipo

Event-related potential (ERP) studies report that the positive deflection following stimulus evaluation at 300 msec (P3) in hyperactive children is augmented by methylphenidate (MP). This study investigates P3 and preceding ERP components using an auditory oddball task in attention-deficit hyperactivity disorder (ADHD). Mismatch negativity, negativity at 100 and 200 msec, and positivity at 200 msec and 300 msec (P3) were obtained from 14 control and hyperkinetic children. ADHD children who responded to MP were tested on two separate days while receiving either MP or placebo. Controls were tested once. No differences were found between groups for ERP components preceding P3. P3 amplitude was significantly larger under MP than under placebo, but did not differ from controls. Under MP, differences in P3 amplitude unexpectedly occurred when no response was required. A P3 amplitude increase under MP and the unexpected P3 suggest that MP affects attention regulation. © 1997 Society of Biological Psychiatry

Key Words: Attention-deficit hyperactivity disorder, methylphenidate, auditory, eventrelated potentials, mismatch negativity, P3 BIOL PSYCHIATRY1997;42:434-445

Introduction The effectiveness of psychostimulant drugs for the control of hyperkinetic behaviors in children is universally appreciated. Stimulants also enhance clinical and laboratory measures of attention, decrease aggression, and improve performance on tasks of memory and information processing (see Solanto 1991 for a review). From the Department of Psychiatry, Brookdale Hospital Medical Center, Brooklyn, New York (BGW); Department of Psychiatry and Department of Neuroscience, Albert Einstein College of Medicine of Yeshiva University and the Bronx Psychiatric Center, Bronx, New York (DJC); and Department of Clinical Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York (BGW, GSS). Address reprint requests to Bertrand G. Winsberg, MD, Brookdale Hospital Medical Center. CHCI3, Linden Boulevard at Brookdale Plaza, Brooklyn, NY 11212. Received July 26, 1995" revised August 13, 1996.

© 1997 Society of Biological Psychiatry

Event-related potentials (ERPs) have been employed in efforts to gain knowledge about stimulant mechanisms of action and their relationship, if any, to performance and attention. ERPs provide the opportunity to study information processing in millisecond temporal reso]tution time locked to the stimulus occurrence. The present study examines ERP indices of preattentive and attentive auditory information processing, particularly early occurring negativity and late positivity in hyperactive children and controls as well as hyperactive children treated to achieve the maximum antihyperkinetic effect of methylphenidate (MP). A preattentive and an attention-dependent information processing component of the auditory ERP are mismatch negativity (MMN) and N2 (Naatanen 1990). These have been little studied with hyperactive children receiving MP. 0006-3223/97/$17.00 PII S0006 -3223(96)00429-5

Methylphenidate and ERP Components

MMN occurs with an onset latency of 50-150 msec following stimulus presentation. This waveform is elicited by infrequent, deviant stimuli ("oddballs") presented against a background of repetitively occurring standards. MMN is elicited even by deviant stimuli that are not consciously detected therefore leading to the suggestion that MMN is an automatic process (Naatanen 1990), which represents activation of neuronal structures within the primary auditory cortex (Sams et al 199l). A previous study (Satterfield et al 1988) suggested that MMN differentiated hyperactive children from controls; however, the derivation of the waveform did not optimize finding a true mismatch (cf. Naatanen 1990) (see below). Several recent studies investigating MMN and schizophrenia (Catts et al 1995; Javitt et al 1993, 1995; Shelley et al 1991) have reported decreased MMN amplitudes as indicative of an abnormality of preattentive mechanisms. The attentiondependent processing component N2 has a frontocentral negativity of approximately 200 msec and like MMN is elicited by deviant stimuli. The N2 waveform reflects information processing at the level of the auditory association cortex (O'Donnell et al 1993). It is also diminished in schizophrenic subjects, a finding that is interpreted as corroborating the existence of a subcortical information processing deficit. MMN and N2 are superimposed on N1 and P2, which are two information processing components that index stimulus registration within the auditory cortex (Naatanen 1990). These waveforms have received only limited investigation in ERP studies of hyperactive children receiving MP. Unlike the cognitive components, which are elicited by deviant but not standard stimuli, NI and P2 are elicited by standard and deviant stimuli. Also, the amplitude of these obligatory components is dependent on the physical characteristics of stimuli such as intensity and frequency, whereas the amplitude of cognitive components depends on the relationship between stimuli. N 1 has a frontocentral negativity of approximately 100 msec peak latency, and P2 has a frontocentral positivity of approximately 200 msec. Although MMN and N I may overlay temporally and spatially, magnetoencephalographic (Sams et al 1991) and electroencephalographic (Scherg et al 1989) dipole mapping have confirmed that MMN and N1 are generated from distinct regions of the supratemporal auditory cortex. Previous work on stimulant effects in brain electrophysieiogy has principally focused on visual information processing during a continuous performance task. Findings have indicated an increase in the amplitude of late wave positivity termed P3. P3 is a positive waveform deflection occurring approximately 300 msec after stimulus onset that indexes stimulus evaluation (Pritchard 1981). P3 amplitude is thought by some to be a reflection of the

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effortfulness of the stimulus response, whereas P3 latency is taken as a reflection of the speed of information processing (Johnson 1986). P3 is most pronounced when a stimulus is unpredictable, or task relevant, or related to response selection. ERP studies thus suggest that hyperactivity is associated with deficits that index cortical information processing (Holcomb et al 1995; Loiselle et al 1980; Zambelli et al 1977). Research findings on stimulant effects indicate that amplitude and latency changes in the visually engendered P3 index clinical response and performance (Halliday et al 1983; Klorman et al 1983, 1988); however, a study with normal stimulant-treated adolescents suggests that these changes may be nonspecific (Peloquin and Klorman 1986). Only a few studies have investigated stimulant effects during audi~Lory information processing on P3 (Prichep et al 1976; SwaLnson et al 1983; Syrigou-Papavasiliou et al 1988; Young et al 1995), and one proposes that the amplitude increase found is associated with the clinical response (Young et al 1995). The present study investigates the neurophysiological action of MP by evaluating information ]processing measures MMN, N2, P3, NI, and P2. In contrast to other studies, hyperactive children were treated to achieve an experimentally defined response criterion and were documented individual responders to treatment. Further, we excluded those children with any other Axis I diagnosis. In so doing it becomes possible to explore MP's effects on stimulus registration and cognitive levels of cortical information processing in a homogenous group of hyperactive children. Thus this investigation asses:ses information processing differences between hyperactive and controls and the effect of MP on information processing in MP responders.

Methods Hyperkinetic children were recruited from a hospital pediatric clinic, where they were referred for psychopharmacologic treatment for behavior problems. Controls were recruited from the children of hospital staff. All subjects were between the ages of 7 and 12 years and were paid an honorarium for their participation in the study. A clinical assessment, behavioral ratings, and psychoeducational testing were obtained for all children. Fourteen hyperkinetic children selected to participate in this study met DSM-III-R (American Psychiatric Association 1987) criteria for attention-deficit hyperactivity disorder (ADHD) and had no other Axis I diagnosis based on the Diagnostic Interview for Children and Adolescents-Revised (DICA-R) structured interview (Welner et al 1987). These children also exhibited current behavioral problems as evidenced by a baseline mean hyperactivity score of greater than or equal to 1.5 on the Conners Teacher Rating

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2.5 mm

HYPERACTIVrlY INATTENTION

2.0

1.5

1.0 i

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0.5

0.0

CONTROL

H A / BL

H A / MP

Figure 1. Conner Teacher Rating Scale (CTRS) hyperactivity and inattention unadjusted mean factor scores for the control group, the hyperactive group (HA) at baseline (BL), and hyperactive group (HA) on methylphenidate (MP).

Scale (CTRS), which has been reported by Goyette et al (1978) to be 2 SDs above age norms. This score is often used to identify hyperkinesis. Fourteen control subjects selected to participate in this study met no DSM-III-R criteria based on the DICA-R interview and had no past or current behavioral problems based on clinical history and teacher ratings as evidenced by their mean CTRS hyperactivity score (see Figure 1). All subjects were administered the Slosson Intelligence Test (SIT-R) for Children and Adults (Slosson 1991) to establish that each child's IQ was within the normal range. Children diagnosed with A D H D were treated with commercially available 5 mg MP (Ritalin) tablets, and their behavior was monitored biweekly at home and in the classroom using the Conners Abbreviated Rating Scale (CARS) and the CTRS, respectively. Depending on the child's response, MP was adjusted to achieve a response within the manufacturer guidelines of up to 60 mg per day. MP was administered in the AM and at noon (b.i.d.). A clinical response to medication was defined as a score of less than or equal to 1.0 on two consecutive CTRS hyperactivity ratings. Once a clinical response was reached the child was randomly assigned to one of two drug conditions: MP-placebo or placebo-MP. A D H D children received an electroencephalogram (EEG) on two separate days. The parent was told to withhold the AM dose

of medication the morning of each EEG. When the child arrived, he/she was given either his/her current MP dose or matching lactose placebo tablet, depending on which condition the child was assigned to. If the child received MP, he/she would receive placebo the morning of the subsequent EEG session. If the child receiw~d placebo he/she would receive MP on the subsequent se,;sion. EEG recording commenced approximately 1 hour after medication/placebo had been administered under supervision to insure compliance. For the ADHD children, all EEG testing was accomplished 1 8 - 2 4 hours after the last dose of MP. MP has a half-time of 6 hours; consequently the interval was adequate for washout (Hungund et al 1978). Controls were examined on one day and no medication was given.

Demographics Control subjects were significantly older, [t(26) = 2.11, p = .045] (mean age = 126.71 - 20.45 months) than the A D H D children (mean age = 111.36 _+ 17.96 months), and the control children had higher Slosson IQ scores [t(26) = 2.63, p = .017] (118.21 +- 10.94) than the A D H D children (99.79 -+ 23.78). The A D H D group had a mean MP clinical response dose of 0.45 + 0.26 mg/kg/dose with a range of 0.15-0.90 (5-30 mg per dose).

Methylphenidate and ERP Components

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Clinical Measures The DICA-R (Welner et al 1987) is a structured interview that has been shown to discriminate between normal and psychiatrically disordered children. A DSM-III-R diagnosis can be made on the basis of this interview.

Behavioral Measures The CTRS (Conners and Barkley 1985) was used to measure classroom behavior and was completed by each child's teacher. This scale contains 39 items that describe aggressive, inattentive, and hyperactive behaviors. Hyperactive items include "Constantly Fidgeting" and "Restless or Overactive." Examples of inattentive items are "Inattentive, Easily Distracted" and "Daydreams." Each item is rated on a 0 (not at all) to 3 (very much) scale. The hyperkinetic and inattentive subscales of this measure are reported in the present study.

EEG Parameters MATEaIALS. Electrophysiological data were obtained using a Grass electroencephalograph interfaced to a Neuroscan (Hemdon, VA) stimulus presentation and data acquisition system. Electrical activity was amplified relative to a nose reference with low and high pass filters set at 0.3 and 35 Hz, respectively. Stimuli consisted of frequent 1000-Hz standard tones and infrequent 1024-Hz deviant tones presented binaurally through auditory brain stem response (ABR) type intraaural stimulators. Tones were presented in pseudorandom order with a 5-msec rise/fall time and a nominal intensity of 75-dB sound pressure level (SPL). PROCEI~UR~. Two paradigms were used during the EEG session: a passive auditory paradigm and an active auditory attention task. In the passive auditory paradigm subjects were instructed to ignore the presented tones. Tones were 25 msec in duration and were presented at an interstimulus interval (ISI) of 50 msec (the passive short ISI condition) and 50 msec in duration with an ISI of 1.3 sec (the passive long ISI condition). For the passive short ISI task 9000 tones were presented in total. Deviant stimuli occurred on an average of every 9 sec (sequential probability of 0.6%). For the passive long ISI condition, 667 tones were presented. Deviant stimuli occurred on an average of every 9 sec (sequential probability of 15%). An ADHD subject was dropped from analysis in the short ISI condition due to a malfunction in equipment. Novel orders of stimuli were not used for each session. In the active auditory attention task (active long ISI condition), subjects were instructed to press a designated key on the computer in response to the deviant "oddball"

tone. In this paradigm there were 667 tones presented and deviant stimuli occurred on an average of every 9 sec (sequential probability of 15%). Tones were 50 msec in duration and presented at an ISI of 1.3 sec. Novel orders were not used for each active auditory session. Correct detections, omission, and commission responses were recorded for this auditory continuous performance task (CPT), as well as the reaction time (RT) lo the "oddball" tone. Before the active auditory task commenced, a practice session was given to all subjects. The ADHD group was given a practice session before each test session. The practice session consisted of 100 trials. No subject was excluded because of poor performance on the practice session. ERPs were recorded using gold cup electrodes at four midline sites (Fpz, Fz, Cz, and Pz) as well as the left and right mastoids. Neuroelectric activity was recorded continuously along with 0.01-msec duration timing pulses and digital stimulus recognition tags. In the passive short ISI condition, 500-msec epochs, incorporating a 50-msec prestimulus interval, were constructed off-line. In the passive long ISI condition and in the active condition, 1000-msec epochs incorporating a 100-msec prestimulus interval were constructed. Digitization rales were 256 Hz in the passive short ISI condition and 128 Hz in the passive long ISI and in the active condition. Because of limitations in the number of recording channels available, eye movements were monitored only using an electrode located above the left outer canthus. Artifact rejection thresholds for all electrodes were set at ___ 100 IxV for the short ISI condition and ± 125 IxV for the long ISI condition and for the active condition.

Data Analysis Epoch waveforms for standards and deviants were averaged for each subject for each condition. Peak amplitude and latency values were determined for each component and averaged across groups. Intervals used for peak selection were based on grand averages guided by previous ERP research. MMN was defined as peak negativity at Fz during the 75-175-msec latency range in the passive conditions difference (deviant minus :~tandard) waveforms. MMN is known to revert in pohtrity between Fz and the left and right mastoids. Therefore, prior to peak detection, this waveform was rereferenced to a mathematically computed average mastoid derivation. N2 was defined as peak negativity at Fz to deviant stimuli in the active auditory attention task occurring in the 150-250msec latency range. N 1 was defined as peak negativity at Fz to standard stimuli in the passive (long ISI) and active auditory conditions occurring 50-150 m,;ec after stimulus onset. As with MMN, for both N2 and N1 each waveform

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was also rereferenced to a computed average mastoid derivation prior to peak detection. P2 was defined as peak positivity at Cz to standard stimuli in the passive (long ISI) and active auditory conditions occurring in the 150-250msec latency range. P3 was defined as peak positivity at Pz to deviant stimuli in the active auditory attention task occurring 2 5 0 - 5 5 0 msec after stimulus onset. Amplitude and latency comparisons were performed between groups. For all analyses except where indicated analysis of covariance ( A N C O V A ) was employed to control for the age difference found between the control and A D H D groups (see Demographics above), and paired t-test comparisons were employed to analyze differences between the A D H D group on placebo and on MP. Statistical analyses were done using the SPSS/PC statistical program. Power analyses were performed for latency and amplitude differences that did not reach statistical significance. Beta ([3) indicates the power to which a significant or nonsignificant between-group difference could be rejected, that is, given the sample means and standard deviations, the percent chance that the difference in the sample would be smaller than the required difference and nonsignificant. Power analyses were performed using the Statistical Power Analysis program (Erlbaum Associates, Hillside, NJ). Values in the results represent the mean --+ standard deviation where indicated.

Results Behavioral Measures The CTRS behavioral data are depicted in Figure 1. Following MP treatment there is a significant decrease in hyperactive behaviors [t(13) = 15.74, p < .001] (means: A D H D at baseline = 2.24 vs. M P = 0.58). Controls are significantly less hyperactive than the A D H D group prior to treatment [F(1,27) = 111.11, p < .001] (adjusted means: controls = 0.42 vs. A D H D at baseline = 2.17; unadjusted means: 0.35 vs. 2.24) but are not following MP treatment [F(1,27) = 0.58, p = ,455] (adjusted means: controls = 0.40 vs. A D H D on M P = 0.52; unadjusted means: 0.35 vs. 0.58). Although the A D H D group were not selected for inattentive behaviors, it is clear that these children are more inattentive before treatment with MP. For the A D H D group, MP produced a significant decrement in inattentive behaviors [t(13) = 5.51, p < .001] (means: A D H D at baseline = 1.31 vs. MP = 0.55). The A D H D group prior to treatment is also more inattentive than controls [F(1,27) = 13.56, p = .001] (adjusted means: controls = 0.51 vs. A D H D at baseline = 1.25; unadjusted means: 0.45 vs. 1.31) but does not differ from controls when treated with MP [F(1,27) = 0.03, p = .872]

Table 1. Unadjusted Means (Standard Deviations) by Group for the Auditory CPT Measures CPT measures Percent correct detection Percent omission errors Percent commission errors Reaction time (msec) A' (sensitivity)

Placebo

MP

Control

79,6 (22.0) 20,4 (22.0) 1.8 (1.9)

94.1 (8.5) 5.9 (8.5) 0.9 (0.9)

95.1 (8.9) 4.9 (8.9) 0.5 (0.7)

594 (116) .941 (.060)

482 (88) .982 (.024)

518 (104) .987 (.023)

MP, methylphenidate.

(adjusted means: controls = 0.51 vs. A D H D on MP = 0.48; unadjusted means: 0.45 vs. 0.55).

CPT (Auditory Attention) Performance Measures Unadjusted means and standard deviations are presented in Table 1. The effect of MP on performance is evident in the comparison between placebo- and MP-treated A D H D subjects. Paired t-test analyses employing a Bonferroni correction show that MP-treated subjects are Easter [t(13) = 5 . 5 7 , p < .001], more accurate [t(13) = 2 . 9 8 , p = .011], and have fewer omission errors [t(13) = 2.98, p = .011]. There was, however, no significant difference in percent commission errors. A measure o f sensitivity A ' (Grier 1971) was calculated for all groups. Paired t tests revealed a significant effect o f A ' for the A D H D children on MP compared to placebo [t(13) = 3.09, p = .009]. The data were repaired by session (session 1 and 2) and then by order (there were two orders assigned: placeb o - M P and M P - p l a c e b o ) to assess practice and order effects, respectively. Paired t tests for session and t tests for order were performed. There were no significant differences in performance between session 1 and 2 and between order. Multivariate analyses of variance ( M A N O VAs) were performed to assess drug-by-session and drugby-order effects on auditory CPT performance. No significant interactions were found. As can be seen from Table 1, the means for the control and placebo group appear quite disparate. In fact, when t-test comparisons were performed, the control and placebo groups significantly differed in percent correct detections, omission, commission errors, and A ' . "]'here were no differences in CPT performance measures between controls and the A D H D group treated with MP. Since the controls and A D H D children differ in age, the appropriate analysis is an analysis of covariance, covarying for age. Results of the A N C O V A s revealed there were no significant differences between controls and the A D H D group when treated with placebo for percent correct detections [F(1,27) = 1.75, p = .198] (adjusted means: controls 91.0 vs. placebo = 84.0), RT to correct detections [F(1,27) = 0.22, p = .640] (adjusted means: control = 548 msec

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Table 2. Unadjusted Mean (Standard Deviation) Peak Latencies and Amplitudes for Information Processing Components of the ERP Placebo N1 Passive Latency Amplitude Active Latency Amplitude P2 Passive Latency Amplitude Active Latency Amplitude MMN Passive short ISI Latency Amplitude Passive long ISI Latency Amplitude N2 Active Latency Amplitude P3 Active Latency Amplitude

MP

Control

105.25 (23.6) -2.18 (4.6)

96.4 (34.9) -2.76 (2.6)

110.04 (21.1) -3.14 (2.4)

115.29 (29.4) -3.15 (3.2)

104.24 (37.6) -4.12 (4.4)

120.65 (24.5) -4.68 (2.6)

170.65 (25.0) 4.55 (4.2)

181.92 (29.6) 4.07 (3.7)

162.92 (13.9) 5.66 (6.4)

185.72 (32.2) 5.67 (3.8)

181.81 (31.2) 7.22 (3.7)

173.44 (25.6) 6.71 (5.5)

130.89 (25.2) -5.00 (5.1)

137.28 (27.1)) -4.64 (6.4)

146.15 (25.4) -6.54 (4.5)

122.65 (30.9) -5.17 (4.3)

123.35 (38.2) -4.55 (3.7)

136.33 (31.9) -4.19 (3.2)

213.62 (32.3) -8.84 (5.8)

215.85 (36.2) - 10.24 (6,711

201.34 (37.7) - 10.52 (4.7)

450.78 (86.6) 16.27 (9.7)

379.91 (69.0) 24.30 (10.6)

417.85 (95.5) 22.38 (11.5)

MP, methylphenidate.

vs. placebo = 564 msec), and A ' [F(1,27) = 2.35, p = .138] (adjusted means: control = 0.975 vs. placebo = 0.952). The A N C O V A , however, did reveal that percent commission errors between controls and the A D H D group on placebo closely approaches significance [F(1,27) = 4.16, p = .052] (adjusted means: controls = 0.5 vs. placebo = 1.7). The control group did not differ with the A D H D group when on M P for all CPT performance measures except RT. The MP-treated A D H D children have significantly faster RTs than controls [F(1,27) = 6.72, p = .016] (adjusted means: controls := 542 msec vs. MP = 459 msec).

439

P2 follows N1, with a peak latency of approximately 200 msec after stimulus onset. There were no group differences for P2 latency or amplitude in the passive or active conditions. The nonsignificant results found for N1 and P2 were tested for power. The nonsignificant result for N1 amplitude in the active condition for the control group and A D H D group on placebo was analyzed with a [3 = .74. All other 13 > .80. M M N . Peak M M N latency and amplitude were determined for each subject by the deviant minus standard difference waveform at Fz for the short and long ISI passive conditions (see Table 2 and Figure 3). No significant peak latency differences were found between groups, placebo vs. MP [t(12) = - . 6 9 , p = ..503], control vs. placebo [F(1,26) = 0.03, p = .870] (adjusted means: control = 145.84 msec vs. placebo -- 1131.20 msec); and there was no significant amplitude differences found [t(12) = - 0 . 2 3 , p = .822] and [F(1,26) = 0.12, p = .729] (adjusted means: control = - 6 . 1 1 IxV vs. placebo = - 5 . 4 2 ~V). An analysis of the long ISI condition found no differences as well in either latency for placebo vs. MP-treated A D H D [t(13) -- - 0 . 0 6 , p = .957], controls vs. placebo-treated A D H D [F(1,27) = 0.113, p = .749] (adjusted means: controls = 131.45 msec vs. placebo = 127.54 msec), or for amplitude between these groups [t(13) = - 0.45, p = .659] [ F (1,27) = 1.31 = p = .263] (adjusted means control -- - 3 . 8 0 txV vs. placebo = - 5 . 5 6 IxV). All M M N nonsignificant results were screened for power. The nonsignificant result for latency in the short ISI condition for the control group and the A D H D group on placebo was analyzed with a [3 -- .68. All other 13 > .80.

EEG Measures

N2. Peak N2 latency and amplitude were determined by analysis of Fz in the active deviant condition (see Table 2 and Figure 2) for each group. Latency did not differ between the A D H D group when on placebo and MP [t(13) = - 0 . 3 0 , p = .771] nor did it differ between controls and the A D H D group on placebo [F(1,27) =: 0.42, p = .523] (adjusted means: control = 202.76 msec vs. placebo = 212.19 msec). Amplitude also did not differentiate between groups [t(13) = 0.80, p = .44] [F(1,27) = 0.07, p = .793] (adjusted means: control = - 9 . 4 3 I~V vs. placebo = - 9 . 9 3 pN). Power analysis for all N2 nonsignificant results revealed 13 > .80.

N1 ANO P2. Peak N1 and P2 latency and amplitude were determined by response to standard stimuli in the passive and active conditions at Fz and Cz, respectively (see Table 2 and Figure 2). There were no significant between-group differences in peak N1 latency in either the passive or active condition. Peak N1 amplitude, also, did not significantly differ among groups in either condition.

P3. Peak P3 latency and amplitude were determined by analysis of Pz in the active deviant condition (see Table 2). This waveform is depicted in Figure 2. The A D H D group on M P shows a significantly earlier peak P3 to the deviant in the active condition It(13) = 2.99, p = .011], and peak amplitude also shows a significant MP-associ-

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ated increase [t(13) = - 2 . 2 8 , p = .04] over placebo. The data were repaired by session (session 1 and 2) and then by order (two orders: placebo-MP and MP-placebo) to assess session and order effects, respectively. Paired t tests for session and t tests for order were performed. There were no significant differences in P3 latency and amplitude between session 1 and 2 and between the two orders. M A N O V A s were performed to assess drug-by-session and drug-by-order effects on P3 latency and amplitude, and no significant interactions were found. The control group's peak P3 latency and amplitude did not significantly differ from the placebo-treated A D H D children [P3 latency, F(1,27) = 0.31, p = .585, adjusted means: control = 423.95 msec vs. placebo = 444.68 msec; P3 amplitude, F(1,27) = 0.40, p = .535, adjusted means: control = 20.60 IxV vs. placebo = 18.06 txV]. Power analysis for these nonsignificant latency and amplitude results indicate t3 = .85 and 13 = .69, respectively. Placebo-treated A D H D subjects showed a significantly lower percent correct detections as well as a slower RT to correct detections than when treated with MP (see Table 1). The lower accuracy of the A D H D group when treated with placebo compared to their performance when treated with MP raises the

possibility that this group difference in P3 amplitude might reflect differential performance. Therefore, correlations were performed between percent correct detections and P3 amplitude. P3 amplitude did not correlate with percent correct detections for the A D H D group on placebo (r = .45, p = .108) and the A D H D group when on MP (r = .35, p = .217). A correlation using the unadjusted means for P3 amplitude and percent correct detections was found for the control group (r = .57, p = .035). The relevance of this correlation is unclear, since means were adjusted for by the ANCOVA, and no significant differences were found for P3 amplitude and percent correct detections between the control group and the A D H D group on placebo or MP. Satterfield et al (1994) argue that significant amplitude and detection relationships are unclear unless one separately analyzes the P3 amp]Litude data for correct detections. Satterfield et al found this procedure did not alter their findings with respect to P3 amplitude difference. Limitations in our computer software did not allow for the separate analysis of P3 amplitude data for correct detections, and this may have influenced the P3 amplitude difference found. We feel future studies should separately analyze by correct detections. Correlations were

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100'1J30

TIME (msec) Figure 3. Deviant minus standard waveforms in the passive short (50 msec) and long (1.3 sec) ISI conditions at Fz for 1:hecontrol group (thick lines), the hyperactive group treated with placebo (dotted lines), and the hyperactive group treated with methylphenidate (dashed lines). Waveforms are shown relative to a derived average mastoid reference. Vertical lines indicate MMN latency range. performed for P3 latency and RT by group and for P3 amplitude and RT by group. P3 latency did not correlate with RT for the placebo-treated (r = .32, p = .260) and MP-treated groups (r = .44, p = . 120). On the other hand, a significant negative correlation between RT to correct detections and P3 amplitude was found for the MP group (r = - . 7 4 , p = .002) but not for the placebo group (r = - . 4 8 , p = .077). Visual inspection of waveforms for the active standard and passive deviant conditions revealed apparent larger amplitudes under MP representing an unexpected P3 waveform (see Figure 2). Consequently post hoc analyses were conducted. Paired t test and A N C O V A analyses reveal significant differences for peak P3 amplitude to the standard in the active condition. MP-treated A D H D subjects have significantly larger peak P3 amplitudes for standards than when on placebo [t(13) = - 2 . 3 5 , p = .035] (means: MP = 12.09 txV vs. placebo = 7.79 IxV) and than do controls [F(1,27) = 11.33, p = .002] (adjusted means: MP = 13.12 txV vs. control = 6.07 IxV). Post hoc analysis also found differences in peak P3 amplitude to the deviant in the passive condition. Again MP-treated A D H D children have larger P3 amplitudes It(13) = - 2 . 6 3 , p = 0.21] (means: M) = 12.43 I~V vs. placebo = 6.17 lxV) [F(1,27) = 7.43, p = .012] (adjusted means: MP = 12.75 ~V vs. controls = 5.94 txV).

Discussion This investigation assessed sensory, early, and late information processing in A D H D children and the extent to which clinically effective doses of MP would be reflected in alterations in these components of the ERP. Of particular interest was the preattentive inforrnaion processing component MMN, which has not been studied in A D H D children. The clinical behavior scale measure (CTRS) shows the powerful and well-known MP effects on hyperkinesis and inattention for children treal:ed to response. In this respect our study differs from off~ers that fail to provide quantitative information on the behavior change in individual children. The within-subject improvement of MP on CPT performance measures replicates many previous studies; however, performance enhancement with stimulants also occurs among normal children (Peloquin and Klorman 1986), and this finding, therefore, may not be taken as unique to hyperkinetic children. The CPT has earned an accepted role in the diagnosis of attentional function and for monitoring drug response. Nevertheless, the value of the CPT has come under recent question (Corkum and Siegel 1993; Halperin et al 1991). In the present study, when age was controlled by covariance, all CPT measures with the exception of percent commission errors did not

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differentiate ADHD children from controls. Thus these results may be added to the accumulating body of literature questioning the usefulness of this measure. Our ERP results indicate there are no deficits in preattentive processes and attention-dependent processes for ADHD children who are MP responders compared to the control group. The absence of a drug-induced change and the lack of differences between controls and ADHD subjects indicates that information processing mechanisms are intact. MMN and N2, representing indices of obligatory preattentive and attention-dependent information processing, respectively, neither distinguished between the normal and ADHD children, or reflected changes in response to the therapeutic doses of MP. In a recent report (Winsberg et al 1993) with a subset of the sample used in the present study, apparent differences in MMN between the ADHD and control groups and apparent normalization of MMN under MP treatment were seen. The present findings, however, do not confirm these initial observations. Naatanen (1990) indicates the MMN, although elicited by deviant stimuli in active (attend) and passive (ignore) conditions, is best observed in ignore conditions. A separate measure of MMN in an active condition is difficult because of overlap from the N2, since MMN is best derived by subtracting the standard stimulus ERP from the deviant stimulus ERP under ignore conditions. Satterfield et al (1988) investigated MMN as a component of N2 in ADHD subjects and normal controls. These investigators found differences between ADHD and control subjects for the attend target-nontarget difference of N2 and inferred an abnormality of the mismatch. This, however, is difficult to assess since an attend (or active) condition was utilized confounding the N2 with mismatch. The ADHD literature is, otherwise, devoid of studies investigating the relationship among MMN, hyperactivity, and stimulant response. Screiber et al (1992) have reported on MMN among children at risk for schizophrenia. These authors reported MMN as a deflection occurring at 180360 msec following the mismatch stimuli, and consequently their data are not directly comparable to our own. These investigators failed to find any differences between risk group and controls. Although results were nonsignificant, these authors concluded, by visual inspection of the waveforms, that the reduction seen in amplitude and the increased variability was consistent with an interpretation of a processing deficit in at risk children. We find no difference in MMN between our ADHD children and the controls, nor is the MMN affected by MP. If children at high risk are indeed characterized by a preattentive processing deficit as proposed by Screiber and associates, our data would argue that ADHD children are less vulnerable. To the extent that this is so, it is consistent with the lack of effectiveness of stimulants for the treatment of schizo-

B.G.Winsberg et al

phrenia (see Carpenter et al 1992). Direct evidence that hyperkinesis does not predispose to schizophrenia has been provided by Jones et al (1994). These attthors report behaviors such as delayed motor milestones, speech problems, and isolated play but not disruptive behaviors to be associated with the subsequent occurrence of schizophrenia. No difference in the N2 waveform between clinical and control children nor in response to treatment was found in our study. Several studies have found N2 not to differentiate clinical and control groups (Holcomb et al 1986; Zambelli et al 1977); however, Satterfield et al (1994) recently reported that auditory and visual N2 amplitude differs between clinical and control children. Halliday et al (1983) did not find N2 sensitive to MP, whereas a recent study by Verbaten et al (1994) employing one.-tailed tests reported increased N2 amplitude under MP treatment. Further, Syrigou-Papavasiliou et al (1988) and Taylor et al (1993) report an MP effect on N2 latency bul: not amplitude. Given our nonsignificant findings with respect to MMN, which is an index of attention-depende.nt information processing, the N2 waveform in MP response and in differentiating clinical from control children is uncertain. There are no N1 and P2 differences found between the ADHD group and controls, nor is there an effect of drug. It is noted that the status of N1/P2 findings is dependent on the physical characteristics of the stimuli. In an almost identical task, one of the present authors found N1 not to differentiate schizophrenic adults from norrnals, while finding a decreased P2 latency (Javitt et al 1995). Some previous investigators have found N1 and/or P2 to differentiate clinical and control groups (Holcomb et al 1986; Loiselle et al 1980; Prichep et al 1976; Satterfield et al 1994), others have found them sensitive to MP (Halliday et al 1983; Klorman et al 1990; Prichep et al 1976), while still others have found no differences in N1 and/or P2 (Holcomb et al 1986; Klorman et al 1990; Satterfield et al 1988; Verbaten et al 1994). Contradictions in research findings may be related to differences in interstimulus interval, type of stimuli, and intensity of the stimulus. Our data may be added to the literature reporting no differences in both of these waveforms of premformation processing, indicating that this physiological aspect of the nervous system is intact in our hyperkinetic sample. Investigations have reported the P3 to differentiate ADHD subjects from normals for both visual and auditory tasks. In contrast to those reports, this was not tound in the present study. Several studies (Callaway et al 1983; Satterfield et al 1988) have reported no diffen~nces in P3 when ADHD and control groups performed comparably, indicating that P3 deficits are detectable in ADHD children under conditions that elicit performance deficits. In the present study, the ADHD group did not differ from the

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control group on all but one measure of CPT performance; this may then explain why no differences in P3 were evident between A D H D and control children. Our results, however, are consistent with those of others who report decreased P3 latency and increased amplitude differences in hyperkinetic children receiving MP (Klorman 1991), and also confirm the Young et al (1995) finding of a P3 amplitude increase in the auditory waveform. RT, the index of the speed of decision making, is not correlated with the MP-induced P3 latency decrease. A decrease in P3 latency has been previously reported for P3a elicited in a visual CPT paradigm (Coons et al 1987; Klorman et al 1991). Although not all studies have found this component of the ERP to reflect stimulant effects, our findings when coupled with the visual CPT-related results support the notion that MP enhances evaluation and motor response. On the other hand, Halliday et al (1983), employing a visual RT paradigm, did not find any stimulant effect on P3 latency but report a significant correlation with RT. Thus future work will need to clarify these seemingly contradictory findings. The significant negative correlation found between P3 amplitude and RT in MP-treated children has not been previously reported. This finding suggests that under MP the A D H D child is more physiologically alert and more accurate than on placebo. An intriguing finding is the unanticipated P3 found for MP-treated A D H D children in the active condition for standard stimuli and in the passive condition for deviant stimuli, indicating that the children are unable to ignore nonsignificant stimuli. This suggests MP-induced physiological hypervigilance. The clinical implication of this finding is not immediately clear. We

speculate that under MP there may be an inability to regulate the biological mechanisms underlying attention. Consequently it should prove of interest to explore the degree to which this unanticipated P3 serves as a physiological marker for the clinical response state. We designed this study to include n~sponders only. Previous reports have included both clear responders and undoubtedly equivocal responders or at the very least these studies have not provided quantitative individual response data. A recent report by Young et al (1995) proceeds in the direction required for demonstrating the usefulness of electrophysiological research to explain the response state. These authors report P3 ~Lmplitude increments to identify a large proportion of responders; however, although encouraging, the specific hyperkinetic criteria are not presented, and the mean age of 13.3 years suggests that many of these subjects did not have classroom hyperactivity, which typically characterizes A D H D children. Future studies will be required that provide specific diagnostic and response criteria. Caution is indicated, since MP increases P3 amplitude., and decreases latency robustly in both A D H D and normals (Peloquin and Klorman 1986). In this regard our finding; of an unanticipated P3 response to MP points toward another ERP approach to investigating clinical response and nonresponse.

The authors wish to thank Dr. Anne Marie Shell,ey for her valuable contributions to the conduct of this study. We also wish to thank Owen Charles, who helped with data collection and Drs. P.J. Noel and J. Golfarb of Brookdale Hospital, who provided helpful clinical support.

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