Invited Symposium: What Can Genetic Models Tell Us About Attention-Deficit Hyperactivity Disorder (ADHD)?
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Materials and Methods
Subjects
7 clinically referred right-handed male adolescents aged 12 to 18 years (mean = 14.1 years), meeting DSM-IV criteria for ADHD participated in the study. The hyperactive adolescents scored above the conventional thresholds for hyperactivity on the act ivity scale of a standardized parental interview and on the Conners teacher rating scales. Exclusion criteria were neurological disease and comorbidity with any other psychiatric diso rder, such as learning and speech disorder, with the exception of conduct disorder which can be seen as a complication of ADHD. Patients were either unmedicated or medication-free for one week prior to scanning. Comparison subjects were 9 male adolescents aged 12 to 17 (mean = 14.7 yrs.) with corresponding non-verbal IQ, who did not meet any criteria for psychiatric disorders and scored below threshold on the parental interview and the Conners teacher rating scale. 8 male adults participated aged 26 to 35 years (mean = 2 9.8 years) No group differences in IQ were observed.Experimental design
Each experimental paradigm consisted of two main conditions (activation and control condition) lasting 33 seconds each. Control and activation conditions were periodically alternated 5 times in the course of a single experiment lasting 5.5 minutes.
Stop task
in the control condition, an airplane appears on the screen (inter-stimulus-interval (ISI) 1650 ms; duration of airplane 1000ms, followed by 650 ms blank screen; 18 stimuli per epoch). On 50 % of trials the airplane was followed by a zeppelin, which appea red 250 ms after onset of the airplane, replacing it for 300ms, and was then followed by a blank screen for 1100 ms. The subject was required to press a right-handed button whenever an airplane appeared, whether or not it was followed by a zeppelin (Rubia et al., 1998). The activation (stop) condition was identical, except that a bomb appeared on 50% of trials, instead of the zeppelin, 250ms after the airplane. The subject was instructed to press the button if the airplane appeared alone, and to press the button if the airplane was followed by the bomb.Delay task
In this parametric design two synchronization tasks were alternated, which differed exclusively in their ISI (short and long event rate condition). In the short event rate condition, a visual stimulus appeared on a computer screen with an ISI of 600 ms. The subjects had to produce high-frequency movements (tapping) in order to synchronize their motor response to the visual stimulus. In the long event rate (delay) condition a visual stimulus appeared with an ISI of 5s and the subjects had to synchronize their motor response to the visual stimulus, generating intermittent movements. In both conditions, the subjects were instructed to synchronize their motor response to the appearance of the stimuli by pressing a response button with their right hand at the same time or shortly after seeing the visual stimuli. In order to be able to synchronize, especially in the long event rate condition, subjects were instructed to monitor the time elapsed since presentation of the previous stimulus (Rubia et al., 1998). The computerized activation paradigms were visually presented to the subjects in the scanner via a mirror from an LCD projector. Throughout image acquisition, each subject's performance was monitored by right-handed button press and recorded by means of a MR- compatible interface to a PC.fMRI data acquisition and analysis
Gradient-echo echoplanar MR images were acquired using a 1.5 Tesla GE Signa System fitted with Advanced NMR hardware and software at the Maudsley Hospital, London. A quadrature birdcage head coil was used for RF transmission and reception. In each of 15 non-contiguous planes parallel to the anterior-posterior comissure, 100 T2*-weighted MR images depicting BOLD contrast were acquired with TE = 40ms, TR = 3000ms, flip angle = 90, in-plane resolution = 3.1mm, slice thickness = 5mm, slice-skip= 0. 5mm. At the same session, a 43 slice, high resolution inversion recovery echoplanar image of the whole brain was acquired in the intercommissural plane with TE = 40ms, TI = 180ms, TR = 16,000ms, in-plane resolution = 1.5mm, slice thickness = 3mm, slice-skip = 0.3mm.Methods used for fMRI time series analysis have been described elsewhere in detail (31,32). The power of periodic signal change at the frequency of alternation between control and activation conditions (1/60 Hz) was modelled by fitting a sinusoidal regression model to the movement-corrected tim e fMRI series at each voxel. The fundamental power quotient (FPQ) was estimated at each voxel of all images. A random permutation procedure resulted in 10 parametric maps (for each subject in each plane) of FPQ estimated under the null hypothesis that FPQ was not determined by experimental design. All parametric FPQ maps were transformed into the standard space of Talairach and Tournoux. To estimate the difference between healthy and hyperactive adolescents in the mean power of response to the activation condition, while controlling for the possibly confounding effects of variability in non-verbal IQ, we fitted an analysis of covariance (ANCOVA) model at each voxel which was generically activated by the activation condition in one or both of the groups. The voxel-wise probability of false positive activation was p < .05.
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