Effects of osmotic-release methylphenidate in attention-deficit/hyperactivity disorder as measured by event-related potentials

Abstract

Aim:  Attention-deficit/hyperactivity disorder (ADHD) is a relatively common central nervous system disorder in school-age children, which may involve a specific disorder in cognition and/or information processing. Event-related potentials (ERP) are commonly used as physiological measures of cognitive function as they are easily measured and non-invasive. Thus, in the present study, we examined the effects of osmotic-release methylphenidate (MPH) (Concerta), a common treatment for childhood attention-deficit/hyperactivity disorder (ADHD), in ADHD children as measured by ERP.

Methods:  Ten ADHD children participated after giving consent. Based on the guidelines for evoked potential measurement, mismatch negativity (MMN) and P300 were obtained by auditory odd-ball tasks. We measured both MMN and P300 in the drug-naive condition and after intake of osmotic-release MPH.

Results:  The MMN amplitudes after intake of osmotic-release MPH were significantly greater than those in the drug-naive situation at Pz and C4. The P300 amplitudes after intake of osmotic-release MPH were significantly greater than those in the drug-naive situation at Cz and Pz.

Conclusion:  MMN and P300 are sensitive tools for measuring the pharmacological effects of osmotic-release MPH in ADHD children.

ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) is a central nervous system (CNS) disorder estimated to occur in 3–7% of school-age children,¹ and is considered to involve a specific disorder in cognition and/or information processing. Event-related potentials (ERP) are commonly used as physiological measures of cognitive function as they are easily measured and non-invasive. For instance, ERP have been used to examine cognitive disturbance in children with developmental disorder, and an early negative ERP has been shown to be strongly-related to attention deficit.

The mismatch negativity (MMN), which functions in a distinctive stimulus discrimination process that utilizes sensory memory of prior stimuli, is considered an important mechanism for rapid detection of changes in the outer world, except those concerning consciousness.² As such, MMN reflects an automatic cerebral discrimination process, not under-attentive control. We previously reported that the amplitudes of both P300 and MMN were smaller in ADHD patients than in healthy subjects.³

With respect to the impulsivity observed in ADHD patients, we previously reported that the Hyperactivity-Impulsivity subscale score of the ADHD Rating Scale-IV-Japanese version (ADHD RS-IV-J) (Home Version)⁴ had a significantly strong positive correlation with the latency of MMN, and had a significant strong negative correlation with the amplitude of MMN, in predominantly hyperactive-impulsive type ADHD subjects.⁵ In other words, the more severe the impulsivity of ADHD subjects, the longer the MMN latency and the lower the MNN amplitude. Thus, ADHD children may have difficulty in referring to previous stimuli, causing increased sensitivity to and augmented anxiety about stimuli, which may account for the exhibited impulsivity.

Stimulating medications are commonly used for treatment of ADHD symptoms. Methylphenidate (MPH), for instance, has been used in ADHD children since 1937.⁶ In Japan, osmotic-release MPH (Concerta) was recently accepted as a treatment medication for ADHD children. Several studies have demonstrated a reduced P300 in ADHD children, which was normalized following MPH medication.^7–9 However, to the best of our knowledge the effects of osmotic-release MPH on MMN in ADHD children have not been described. Thus, in the present study we examined the effects of MPH on MMN and P300, and on ameliorating cognitive function, especially attention function, in ADHD children.

METHODS

Subjects

Ten children (nine boys, one girl) aged 7–13 years and diagnosed as ADHD based on DSM-IV,¹⁰ participated in the present study. The subjects with ADHD, who had no history of developmental disorder treatment, consulted an experienced pediatric psychiatrist (M. S., T. O., or H. N.) at the Department of Psychiatry of Nara Medical University with the chief complaint of attention deficit, hyperactivity, or impulsiveness. The subjects with ADHD underwent a standard clinical assessment comprising a psychiatric evaluation, a structured diagnostic interview, a cognitive battery, and a medical history. Two experienced pediatric psychiatrists (J. I., H. N.) confirmed the diagnosis of ADHD according to DSM-IV.¹⁰

The Wechsler Intelligence Scale for Children-Third Edition (WISC-III) full IQ scores of all subjects were over 70. All patients were Japanese and right-handed. In ADHD subjects, the severity of ADHD symptoms and latencies and amplitudes of ERP (MMN, P300) were estimated both before and after (8–12 weeks) osmotic-release MPH treatment at the same time of day (10.00–11.00 hours). ADHD subjects were treated with osmotic-release MPH as soon as possible after baseline ERP. The dose of osmotic-release MPH treatment ranged from 18 to 54 mg (mean ± SD, 33.3 ± 10.4 mg). The characteristics of the subjects can be seen in Table 1. This study was approved by the Institutional Review Board of Nara Medical University Hospital. Written informed consent was obtained from all subjects and/or their parents prior to the study.

Table 1.  Subjects characteristics

Sex (n = 10)	Boy 9	% 90	Girl 1	% 10
	Mean		SD
Age (years)	9.3		1.9
WISC-III	100.5		15.3
Concerta dose (mg)	33.3		10.4

	Before Concerta treatment		After Concerta treatment		t value (d.f. = 9)	P-value
	Mean	SD	Mean	SD
ARF, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Japanese version full scores; ARH, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Japanese version hyperactivity-impulsivity subscale scores; ARI, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Japanese version inattention subscale scores; WISC-III, Wechsler Intelligence Scale for Children-Third Edition.
ARF	31.1	8	11.9	5.6	9.826	<0.001
ARI	17.5	5.5	8.3	3.1	6.209	<0.001
ARH	13.6	3.6	3.6	3.8	8.135	<0.001

Procedures

ADHD assessment

We used the ADHD RS-IV-J (Home Version)⁴ to evaluate ADHD symptoms in ADHD children. It is generally considered that the higher an ADHD RS-IV-J score, the more severe the ADHD symptoms. All subjects underwent ADHD RS-IV-J assessment before and after osmotic-release MPH treatment (Table 1). In ADHD children the ADHD RS-IV-J full scores (ARF), ADHD RS-IV-J inattention subscales scores (ARI), and the ADHD RS-IV-J hyperactivity-impulsivity subscales scores (ARH) were significantly higher before osmotic-release MPH treatment than those after osmotic-release MPH treatment.

Event-related potentials

Measurements

Based on the guidelines for evoked potential measurement, MMN and P300 were obtained by auditory odd-ball tasks. An NEC Multi Stim II (NEC, Tokyo, Japan) was used as the auditory stimulus system.

MMN

Tone bursts at 1000 Hz standard stimuli (P = 0.9) and at 1100 Hz deviant stimuli (P = 0.1) (each stimulus lasted 50 ms) were presented at 500-ms intervals and at 80-dB intensities. The infrequent and frequent stimuli were given in random order via headphones. The MMN was measured while the children, as instructed, were reading books or magazines of their choice, without paying particular attention to the auditory stimuli given.

P300

Infrequent target stimuli were presented as tone bursts at 2000 Hz (P = 0.2) and frequent non-target stimuli as bursts at 1000 Hz (P = 0.8), with each stimulus lasting 50 ms. Both types of stimuli were given at intervals of 1.5 s and an intensity of 80 dB. The infrequent and frequent stimuli were given in random order via headphones. The children were instructed to pay attention to the target stimuli with their eyes open, and to press the button as quickly as possible when each target stimulus was delivered.

Recording and analyses

ERP were recorded with an MEB 2200 (NIHON KOHDEN, Tokyo, Japan). Electroencephalograms (EEG) were obtained at Fz, Cz, C3, C4, and Pz positions on the scalp using disk electrodes. The bilateral ear lobes were used as the reference electrode sites. The resistance of the electrodes was set at ≤5 kΩ. MMN was analyzed during the period between the 30-ms pre-stimulus and the 360-ms post-stimulus. P300 was analyzed during the period between 50 ms pre-stimulus and 750 ms post-stimulus. Artifact-free responses to the stimuli were added and averaged after EEG amplitude data ≥100 µV and eye movements were removed. To prevent the subjects from getting tired of, or used to, performing the tasks, each trial was conducted only once.

MMN

Fifty responses to infrequent deviant stimuli and 450 responses to frequent standard stimuli were averaged separately. The waveform of the frequent standard stimuli responses was subtracted from that of the infrequent deviant stimuli responses. From the subtraction waveform, MMN was identified as a negative wave with a peak latency from 100 to 250 ms. MMN latency and amplitude were measured.

P300

Thirty responses to infrequent target stimuli were averaged. Of the ERP obtained, P300 was identified as a positive wave with a peak latency from 250 to 550 ms. P300 latency and amplitude were also measured.

Statistical analyses

Statistical comparison of subject characteristics between the two groups was performed by two-tailed paired t-test. The latencies and amplitudes of both P300 and MMN were compared between before treatment and after treatment by two-tailed paired t-test. spss 17.0 J for Windows (spss, Tokyo, Japan) was used for all analyses.

RESULTS

MMN

The grand average MMN from ADHD children after osmotic-release MPH treatment was greater than that before treatment (Fig. 1). The exact figures of amplitudes and latencies are listed in Table 2. The mean MMN amplitudes from ADHD children at Pz and C4 after osmotic-release MPH treatment were significantly greater than those before treatment (Table 2).

Figure 1. Grand average mismatch negativity (MMN) from attention-deficit/hyperactivity disorder children () before and () after Concerta treatment conditions. MMN is shown by arrows. *P < 0.05.

Table 2.  Amplitudes and latencies of mismatch negativity (MMN) and P300

	Before Concerta treatment		After Concerta treatment		t value (df = 9)	P-value
	Mean	SD	Mean	SD
* P < 0.05.
MMN amplitude (uV)
Fz	4.2	4.2	9.1	9.1	−1.79	0.107
Cz	3.6	4	6.4	11.5	−0.829	0.429
Pz	2.2	5	8.1	6.4	−2.442	0.037*
C3	3.5	4.8	5.6	6.6	−0.88	0.402
C4	4.5	3.5	9	5.4	−2.718	0.024*
MMN latency (ms)
Fz	173.1	36.3	188.1	33.2	−1.096	0.302
Cz	185	36.4	193	30.1	−0.558	0.591
Pz	192.8	34.2	192.4	32.3	0.033	0.974
C3	191.4	35.9	191	27.9	0.038	0.97
C4	187.5	31.6	180.9	33.4	0.613	0.555
P300 amplitude (uV)
Fz	−8.5	16.3	−20.8	16.8	1.643	0.135
Cz	−11.2	11.2	−28.1	17.7	2.785	0.021*
Pz	−17	6.7	−33.3	19.8	2.317	0.046*
C3	−10.7	9.2	−19.2	11.3	2.056	0.07
C4	−11	10.5	−20	12.3	2.192	0.056
P300 latency (ms)
Fz	376.7	68.1	383.4	54.4	−0.36	0.727
Cz	388.7	67.8	383.4	57.4	0.366	0.723
Pz	357.8	58.2	360.9	68.4	−0.233	0.821
C3	355.1	55.5	373.2	57.5	−0.882	0.401
C4	361.8	53.8	358.7	58.1	0.181	0.861

P300

The grand average P300 from ADHD children after osmotic-release MPH treatment was greater than that before treatment (Fig. 2). The exact figures of amplitudes and latencies are listed in Table 2. The mean P300 amplitudes from ADHD children at Cz and Pz after osmotic-release MPH treatment were significantly greater than those before treatment (Table 2).

Figure 2. Grand average P300 from attention-deficit/hyperactivity disorder children () before and () after Concerta treatment conditions. P300 is shown by arrows. *P < 0.05.

DISCUSSION

In the present study, although there seemed to be visual differences in most electrodes for both MMN and P300 following osmotic-release MPH treatment in ADHD children, significant increases in MMN or P300 amplitudes after osmotic-release MPH treatment were only observed in Pz and C4 or Cz and Pz. These discrepancies may relate to the small sample size and large standard deviation in the present study.

P300 is a potential generated in the final stage of sensory and cognitive processing. The improvement in P300 following osmotic-release MPH treatment in ADHD children is consistent with previous studies.^7–9 As disturbance of the P300 component has been previously suggested as an indicator of impaired cognition,^11,12 these data suggest that cognitive function in ADHD children was ameliorated by osmotic-release MPH treatment. However, P300 is likely to be affected by the cognitive factors present prior to P300 generation, thus limiting the significance of investigations employing solely P300 recordings. As such, we also evaluated MMN in ADHD children in the present study, the pre-P300 potentials that reflect information processing itself.^3,5

In the present study, we reported that MMN amplitudes were increased after osmotic-release MPH treatment in ADHD children, suggesting that the automatic cerebral discrimination process might be ameliorated by osmotic-release MPH treatment, which in turn may have reduced the impulsiveness and hyperactivity in ADHD children.

With respect to the laterality of cerebral dysfunction in ADHD, it was proposed that ADHD children exhibit dysfunction in a right-sided frontal-striatal system.¹³ This comprehensive morphometric analysis was consistent with the hypothesized dysfunction of right-sided prefrontal-striatal systems in ADHD children.¹⁴ Furthermore, in an event-related functional magnetic resonance imaging (fMRI) study, ADHD children exhibited less right-sided activation in the anterior cingulate gyrus during alerting (one of the attentional networks) relative to controls.¹⁵

In the present study, there was no difference between the left (C3) and right (C4) P300 amplitudes or MMN amplitudes either before or after treatment, and there was no difference between the left (C3) and right (C4) P300 and MMN latencies either before or after treatment. However, the MMN amplitude after osmotic-release MPH treatment was significantly greater than that in the drug-naive situation at C4. Thus, we suggest that the right hemisphere may be competent following MPH treatment with respect to MMN.

There were two limitations to our study. First, the sample size was small. However, we examined 10 ADHD children who had no history of developmental disorder treatment, and our data showed significant changes. Second, we had no placebo-control subjects. Future studies with large samples and placebo-control subjects as measured by ERP are required to determine whether cognitive function in ADHD children was ameliorated by osmotic-release MPH treatment. In conclusion, the results of the present study suggest that both MMN and P300 are sensitive tools for measuring the pharmacological effects of osmotic-release MPH in ADHD children.

ACKNOWLEDGMENTS

This work was supported by a Grant for International Health Research (127-A) from the Ministry of Health, Labor and Welfare, Japan.