Introduction 1994 2005 2000 1997 2005 2005 2001 2002 2005 2003 2001 2005 2004 2003 2005 2004 2003 2001 2002 2005 2003 2001 2005 2004 2005 2003 2005 2005 2005 1996 1994 1997 1999 2003 1996 2003 2006 2007 2005 2002 2006 2003 1998 1996 2003 1998 1985 1973 1985 2006 2003 1997 2000) 2005 2006 2000 2002 1999 2003 2006 2005 2007 2007 Method Participants 2006 1 2 Table 1 Distribution of family sizes Number of siblings within a family ADHD Control n n n n 1 0 0 51 51 2 177 354 72 144 3 53 159 20 60 4 8 32 4 16 Total 238 545 147 271 Note: Table 2 Distribution of affected and non-affected siblings within ADHD-families Total number of children within a family Diagnostic status n n n n 2 1 1 – 62 1 – 1 115 3 1 2 – 7 1 1 1 24 1 – 2 22 4 1 3 – 2 1 2 1 1 1 1 2 4 1 – 3 1 Total 238 Note: All children were between the ages of 5 and 19 years and were of European Caucasian descent. Participants were excluded, if they had an IQ < 70, a diagnosis of autism, epilepsy, brain disorders or known genetic disorders, such as Down syndrome or Fragile-X-syndrome. 2006 1996 1997 1986 1999 3 Table 3 Sample characteristics  Probands Affected siblings Non-affected siblings Normal controls F 3,812 Contrasts n n n n M SD M SD M SD M SD Age in years 12.0 2.5 12.0 3.4 11.5 3.6 11.6 3.2 ns  % Right handed 91.1  87.5  89.2  85.5  a  % Male 84.5  56.3  45.1  40.6  a 1 > 2,3,4 2 = 3 & 2 > 4 3 = 4 Estimated full scale IQ 97.9 13.0 100.7 10.6 103.8 10.9 106.0 10.2 23.5* 1 = 2 & 1 < 3 = 4 2 = 3 & 2 < 4 3 = 4 Conners’ parent DSM-IV     Inattentive 71.1 8.4 66.0 11.6 47.9 7.0 46.5 4.8 585.4* 1 > 2 > 3 = 4     Hyperactive-impulsive 79.1 9.2 67.8 13.6 49.0 6.9 47.3 5.1 767.3* 1 > 2 > 3 = 4     Total 76.9 8.6 68.3 11.6 48.2 6.8 46.5 4.5 875.7* 1 > 2 > 3 = 4 Conners’ teacher DSM-IV     Inattentive 66.0 9.1 61.7 10.2 48.3 6.0 46.4 4.6 386.3* 1 > 2 > 3 = 4     Hyperactive-impulsive 70.2 10.7 63.5 13.3 48.3 6.5 47.2 5.0 378.1* 1 > 2 > 3 = 4     Total 69.8 9.8 63.8 11.4 48.3 5.8 46.4 4.5 485.8* 1 > 2 > 3 = 4 ADHD diagnosis     Inattentive –  28  –  –        Hyperactive-impulsive –  20  –  –        Combined 238  64  –  –    Note ADHD = Attention-Deficit/Hyperactivity Disorder; DSM-IV = Diagnostic and Statistical Manual for Mental Disorders (4th edition) P a 2 p Measures Motor Timing Task 2005 2005 Baseline Speed task 1999 A practice session (10 trials) and an experimental session (32 trials) were administered for both hands separately. The task was first practised and executed with the index finger of the non-preferred hand, thereafter practised and executed with the index finger of the preferred hand. Dependent measures were the speed (mean reaction time in ms) and variability (SD of reaction times in ms) of responses. Tapping task 1999 A practice session (5 s) and an experimental session (18 s) were administered for both hands separately. The task was first practised and executed with the index finger of the non-preferred hand, thereafter practised and executed with the index finger of the preferred hand. Dependent measures were speed (mean intertap interval in ms) and variability (SD of intertap intervals in ms) of motor output. Intelligence 2002 2000 1997 Procedure 1999 Analyses 2001 r w w r w 1975 F max  F max  2001 1988 2 2007 Results Testing of possible confounders Main effects of hand, gender, IQ, and age F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P F P F P Interactions between group and possible confounders F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 F P p 2 3 4 Table 4 Means and standard deviations of the motor measures in ms Dependent variable Proband Affected sibling Non-affected sibling Control p 2 Contrasts M SD M SD M SD M SD Motor timing     Accuracy 981 99 997 96 1,007 114 1,020 100 .03 1 = 2 > 3 = 4     Variability 389 265 375 265 344 260 295 218 .10 1 = 2 > 3 > 4 Baseline Speed     Speed 355 75 356 85 353 81 351 78 .02 1 = 2 > 3 = 4     Variability 132 85 131 87 123 82 117 75 .03 1 = 2 > 3 = 4 Tapping     Speed 239 39 248 48 256 51 249 48 .01 ns     Variability 46 20 48 23 45 20 44 18 .01 ns Note Scores were averaged across hands for the Baseline Speed and Tapping z Endophenotypic analyses Motor Timing task accuracy F P p 2 P P P M M M P P P 1 P P r P Fig. 1 Accuracy and variability of motor timing (adjusted for the linear effect of age) in probands, affected siblings, non-affected siblings and control children. Error bars represent 1 standard error from the mean  variability F P p 2 P P P P P P P r P 1 Baseline Speed task speed F P p 2 P P P P P P P P r P variability F P p 2 P P P P P P P P r P 2 Fig. 2 Speed and variability of Baseline Speed (adjusted for the linear and curvilinear effects age) in probands, affected siblings, non-affected siblings and control children. Error bars represent 1 standard error from the mean. Scores were averaged across hands  Tapping Task speed F P p 2 variability F P p 2 P P r P r P 3 Fig. 3 Speed and variability of tapping (adjusted for the linear and curvilinear effects of age) in probands, affected siblings, non-affected siblings and control children. Error bars represent 1 standard error from the mean. Scores were averaged across hands  Since there were group differences for speed and variability of externally cued motor output (Baseline Speed task), the issue was raised whether the deficits found on the Motor Timing task were primarily related to these group differences in basic motor output. Therefore, analyses were undertaken whereby the speed on the Baseline Speed task was used as an additional covariate in the analyses on accuracy on the Motor Timing task. The variability on the Baseline Speed task was used as additional covariate for the analyses on variability on the Motor Timing task. accuracy F P p 2 variability F P p 2 Discussion There was investigated whether accuracy and variability of motor timing were viable endophenotypic candidates as reflected by poor performance on these measures in children with ADHD (i.e. indicating an association between the deficits and the disorder), reflected by poor performance in non-affected siblings in between their affected siblings and controls (i.e. suggesting a relation between the deficits and a familial susceptibility for the disorder), and reflected by sibling correlations (i.e. signalling familial resemblance for deficits). We administered two motor tasks in addition to a motor timing task, in order to investigate whether deficits were specifically related to the timing of motor output or whether deficits were also observed in tasks requiring motor output without any timing demands. 2005 2006 2002 1999 2003 2006 2005 2005 1997 2000) 2006 1999 2006 1985 2003 1998 1996 2003 2006 Limitations 2006 2007 Conclusions Variability in motor timing appears a useful endophenotypic candidate: It is clearly associated with ADHD, it is also present in non-affected siblings, and it correlates within families. Accuracy (under- versus over production) in motor timing appears less useful: even though accuracy is associated with ADHD (probands and affected siblings have a tendency to under-produce compared to controls), non-affected siblings did not exhibit this tendency and sibling correlations were only marginally significant. There were group differences in motor speed and variability (Baseline Speed task): probands and affected siblings were slower and more variable in their motor output as response to an external cue. Even though siblings resembled each other in their speed and variability, non-affected siblings performed more like controls. These findings suggest that speed and variability of externally cued motor output are associated with having ADHD, but probably not related to a familial vulnerability for the disorder. Interestingly, the speed and variability in self-generated motor output (Tapping) is normal in probands and affected siblings, making it unsuitable to unravel underlying vulnerabilities leading up to ADHD. Deficits in motor timing cannot be explained by deficits already present in basic motor output without a timing component (Baseline Speed), suggesting abnormalities in motor timing are predominantly related to deficient timing operations but not to deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD.