van Essen et al. Melfoquine induced motor deifcits 2002), perceptual timing (rhythm perception task: Xu et al., 2006), reflex timing (reflex blinking: Koekkoek et al., 2002; Smit et al., 2008), and an associative motor learning task (eye-blink condition- ing: Koekkoek et al., 2002; Smit et al., 2008). of the results with a memory trace. The eye-blink conditioning task was performed in a group of participants 24 h after the intake of their first mefloquine tablet and in an age- and sex-matched control group who did not use mefloquine. slairetamdn sdohtem yduts PPonoitaludn Pxelatnmires Pu We recruited volunteers, who were prescribed mefloquine (Roche, USA; the commercial name marketed as Lariam®) for malaria prophylaxis at the Travel Clinic Havenziekenhuis in Rotterdam, the Netherlands. Written informed consent was obtained from the participants or the parents of the participants when they were younger than 18 years. The experimental protocol was approved by the Erasmus MC Medical Ethics Committee (MEC-2004-205). Participants who had used mefloquine in the preceding 2 months, who had risk factors for concentration impairment (e.g., use of opioids, hypnotics or tranquilizers during the study period or use of alcohol 4 h before testing) or who had illnesses resulting in altered motor behavior were excluded from this study. From the participants information was collected on gender, weight, height, age, weekly physical exercise, and previous mefloquine intake by use of a questionnaire (Table 1). The participants were requested to take the standard dose of 250 mg mefloquine at the end of dinner, as food facilitates mefloquine absorption (Crevoisier et al., 1997). One day after the first mefloquine intake, users were carefully reviewed for adverse effects (by Thomas A. van Essen, see also Table 1). The experimental set up consisted of performance tasks: (a) dart throwing task, (b) perceptual timing task, and (c) reflex blinking task. To test motor learning, the eye-blink conditioning task was used. The performance experiments were executed 2–4 days prior to the intake of mefloquine (baseline) and 24 h after the intake of the first mefloquine tablet. The learning experiments were only per- formed once per (naïve) subject, in order to prevent contamination Table 1 | Characteristics participants. Characteristics Performance task (n = 9) Men/women Age (years) Age range (years) Weight (kg) Physical exercise (≥ 2 × /week) Adverse events Insomnia Head ache Abnormal dreams/nightmares 6/3 40.7 17–67a 74.2 6 (67%) 3 (33%)b 2 1 1 Learning task (no mefloquine; n = 11) 7/4 24.3 20–35a 65.5 7 (64%) – Mefloquine (n = 8) 4/4 25.0 17–40a 68.8 5 (63%) 3 (38%)b 1 1 2 Gender, mean age, age range, mean weight, amount of exercise level, and adverse events for each group. aAge range is different between the motor performance and the motor learning participants. bNumbers do not add up to total adverse events since some participants had more than one adverse event. PcnamofrePxstnmire Dart throwing task In this task participants threw 25 darts at a dartboard and were told to aim for the bull’s eye while holding their underarm vertically during the course of each throw. They were placed on a standard range from the dart board (2 m) and each throw was followed by a short pause of 5 s. Throwing imprecision can be divided in a horizontal and ver- tical component. The horizontal (Ex) and vertical deviations (Ey) of each dart from the center of the bull’s eye were determined manually (Figure 1B). Under normal conditions, imprecision in release timing or throwing speed is not the main source of throw- ing imprecision, but the imprecision in direction of motion at the time of release is considered the main cause of throwing impreci- sion (Smeets et al., 2002). However, when either speed or timing precision is affected by mefloquine, an additional error source is introduced that will affect the precision of the dart throw. This error source will only affect the vertical component, but not the hori- zontal component, of the throw (Figure 1A). Therefore, we would expect an enhanced variability in the vertical deviation compared to the horizontal deviation after the use of mefloquine. The speed and timing sensitivity of the dart throw was determined by dividing vertical deviation from the target (Ey) by the total deviation from the target (Ey + E ). The precision of the dart throw was determined by x dividing the standard deviation of the vertical displacement from the target (sdEy) by the total standard deviation of the displacement from the target (sdEy + sdEx). Rhythm perception task Functional MRI studies revealed that the IO is activated during perception of complex rhythms and perception of a single stimulus with unexpected timing, and that the IO is sensitive to the tempo- ral structure of sensory input (Xu et al., 2006; Liu et al., 2008; Wu et al., 2010). In this task participants have to compare successive auditory rhythms (Xu et al., 2006). Two successive rhythms were generated by two pairs of four tones. Each pair consisted of four tones of 500 Hz with a duration time of 5 ms and these tones were separated from each other by intervals of 333 ms. The pairs were separated by an interval of 2 s (Figure 2A). A rhythm asynchrony was introduced in either the first or second four-tone rhythm, consequently the other four-tone rhythm became the designated standard rhythm. Rhythm asynchrony was achieved by shifting the second tone of the rhythm closer to the first (i.e., shortening the inter-tone interval). This shortening of the inter-tone inter- val (perturbation) varied randomly throughout each test block between 0, 10, 25, 50, 75, and 100 ms. The task consisted of eight blocks and in each block the participants were exposed to all six perturbations. For each perturbation we determined the number of errors that were made per subject. The 0 ms perturbation served as a control of understanding the task and to asses to what extent the task was subject to guessing. After each series of two rhythms participants were asked whether the rhythms were identical or not. Frontiers in Neuroscience | Neuropharmacology November 2010 | Volume 4 | Article 191 | 2