We analyzed eighteen right-handed (Edinburgh Handedness Inventory; EHI; [19
]; laterality quotient mean value ± standard deviation 94.9 ± 10.2) children between 8 and 14 years (13 males and 5 females, mean age ± standard deviation 11.5 ± 1.9 years, mean IQ ± standard deviation 110.5 ± 18.8) who met the criteria of a hyperactive-impulsive or combined subtype of ADHD according to the semi-structured interview for DSM, K-SADS [20
All patients were recruited either in the Child and Adolescent Psychiatric Department of the University of Heidelberg or at a child psychiatrist's practice, were treated with multilayer-release or immediate-release MPH without other co-medication and suffered from no other psychiatric diseases. This includes that we assured that there were no neuropsychiatric disorders such as psychoses and autism or neurological diseases as epilepsy [21
], migraine [22
] and tic-disorder [10
], which are thought to lead to specific changes in contingent negative variation (CNV) parameters.
An IQ below 80 (4-subtest short version of HAWIK III [23
]), led to exclusion from the study.
As Quinn et al. [24
] found no significant difference between the concentration of multilayer- and immediate-release MPH within the first four hours after the intake, we included children treated with both immediate and extended release MPH in our patient group.
Twelve out of 18 ADHD children were treated with extended release MPH with a mean dosage of 0.85 mg/kg body weight (0.25 to 1.29 mg/kg), the other six with immediate release MPH with a mean dosage of 0.4 mg/kg (0.15 to 0.74 mg/kg).
Nineteen right-handed (EHI laterality quotient 97.3 ± 5.2) healthy, age-, gender- and IQ-matched children and adolescents (14 males and 5 females, mean age 11.6 ± 2.1 years, mean IQ 117.4 ± 13.0), who took no psychoactive medication and did not suffer from any neurological or psychiatric symptoms, were recruited as control group at Heidelberg's elementary and secondary schools.
In both groups we screened for visual impairments (corrected visus ≥ 0.8).
All subjects and their parents provided written informed consent according to the Declaration of Helsinki and the study was approved by the local ethics committee.
We recorded a CNV paradigm, using an auditory warning stimulus S1 (1000 Hz, 90 dB, 50ms duration) and a visual imperative stimulus S2 (image of a white hand, pointing towards the side of the required button press, presented for 150 ms on a black screen). The interstimulus interval was 3 seconds, intertrial intervals varied randomly from 7 to 11 seconds.
Subjects were instructed to correctly respond as fast as possible when S2 occurred on the screen by pressing a button on the STIM response pad (Neuroscan Inc, TX, USA) with the thumb of either the right or the left hand (quick, unilateral motor answer).
40 trials per hand were recorded in a counterbalanced order across subjects. Two runs were recorded: In the control group both runs, T1 and T2, were drug-free. In the ADHD group, the first one (T1) was drug-free (after at least 24 hours after the last intake of MPH), the second one (T2) after 70 minutes after the intake of the individual used dose of MPH. In other studies the same experimental period of 70 minutes after the intake of MPH was chosen, so comparability is ensured.
Participants fixated a cross on a computer screen in order to minimize eye artifacts. Neuroscan Synamp Amplifiers (Neuroscan Inc., USA) were used to record continuous DC 64-channel EEG with a sampling rate of 250 Hz. An anti-aliasing filter was set at 70 Hz (low-pass). Surface Ag-AgCl sintered electrodes were fixed using an equidistant electrode cap (Easycap, FMS, Germany) and are named according to an extended international 10-20 system. The vertical and horizontal electrooculogram (EOG) was recorded by electrodes 1 cm next to the outer canthi and above/below the left eye.
Impedances were kept below 5 kΩ. Data were recorded against a reference near Cz and transformed offline to average reference. Recordings 1 s before S1 served as baseline. For the analysis of PINV, the EEG-signal was digitally filtered (30 Hz high cut-off), segmented into epochs of 7.5 s (1 s pre S1 to 3.5 s post S2), corrected automatically for DC-drifts by linear regression (Brain Vision Analyzer, Brain Products GmbH, Germany), and for eye movements and blinks (algorithm according to Gratton and Coles as implemented in Brain Vision Analyzer Version 1).
Artifacts were rejected automatically if the signal amplitude exceeded 150 mV. This procedure was confirmed by visual inspection; only artifact free trials entered further analysis. Bad channels were interpolated using nearest neighbours. Trials were rejected from further analysis if subjects responded with the wrong hand or after more than 3.5 s after S2.
Two ADHD patients and one control child (out of originally n = 20 children in both groups) had to be excluded from further evaluation due to recording errors or excessive artifact-prone data. N = 18 ADHD children and n = 19 controls were included for further statistical analysis.
As a first step, planned comparisons for group differences between the PINV-amplitudes of unmedicated ADHD versus control children over the left and right ventrolateral prefrontal areas (pooled leads AF7, FP1, F9 and AF8, FP2, F10 during the time interval 2000 to 3000 ms after the imperative stimulus S2 in agreement with results of our previous study [18
]) were examined for right and left hand button presses by four t-tests. The significance level was set to p = 0.05/4 = 0.0125 (Bonferroni correction).
Next, in order to assess the influence of medication on PINV topography in more detail, results were examined by multivariate analysis of variance (MANOVA), using the between subject factor GROUP (ADHD versus healthy controls) and the within subject factors SIDE of the response movement (left vs. right hand), HEMISPHERE (left vs. right VLPFC), RUN (T1 vs. T2) and ELECTRODES (AF7/8, FP1/2, F9/10) followed by simpler separate MANOVAs for left and right hand response CNV tasks.
Significant main effects or interactions in the MANOVA were subsequently further examined by post-hoc tests (Newman Keuls).