Anti-malaria drug mefloquine induces motor learning deficits in humans

Abstract

Mefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive. We were therefore interested in assessing whether mefloquine might induce similar effects in humans. The main aim of this study was to investigate the effect of mefloquine on olivary-related motor performance and motor learning tasks in humans. We subjected nine participants to voluntary motor timing (dart throwing task), perceptual timing (rhythm perceptual task) and reflex timing tasks (eye-blink task) before and 24 h after the intake of mefloquine. The influence of mefloquine on motor learning was assessed by subjecting participants with and without mefloquine intake (controls: n = 11 vs mefloquine: n = 8) to an eye-blink conditioning task. Voluntary motor performance, perceptual timing, and reflex blinking were not affected by mefloquine use. However, the influence of mefloquine on motor learning was substantial; both learning speed as well as learning capacity was impaired by mefloquine use. Our data suggest that mefloquine disturbs motor learning skills. This adverse effect can have clinical as well as social clinical implications for mefloquine users. Therefore, this side-effect of mefloquine should be further investigated and recognized by clinicians.

Keywords: cerebellum; eye-blink conditioning; gap junctions; mefloquine; motor behavior.

Figure 1

Dart throwing precision is not affected by the intake of mefloquine. (A) Schematic representations of two arms at the time of releasing the dart. Vertical throwing precision is more complex than horizontal throwing precision; it depends more on the moment of release and the speed of the throw. (B) Participants threw darts at a dartboard and for each throw the horizontal (E_x) and vertical deviations (E_y) from the center of the bull's eye were determined. (C) The vertical and horizontal precision were not altered by the intake of mefloquine (n = 9). Under both conditions, the horizontal component of the throw is more precise than the vertical component (*both p < 0.05, n = 9, t test). (D) The normalized vertical deviation from the target (n = 9) and (E) the normalized standard deviation of vertical deviation from the target (n = 9) were not affected by the intake of mefloquine. Blue bars indicate mean + SEM (error bar) before mefloquine intake and red bars indicate mean + SEM (error bar) 24 h after mefloquine intake.

Figure 2

Perception of complex rhythms is not impaired by the intake of mefloquine. (A) Schematic representation of the rhythm perception task. Two rhythms consisting of four tones are separated by a pause of 2 s. One of the rhythms has a timing perturbation of the second tone. This perturbation varies in size (0, 10, 25, 50, and 100 ms). The subject has to determine whether the rhythms are identical or different. (B) The ability to distinguish complex rhythmic stimuli as a function of perturbation length (ms) is reflected in the number of errors made per type of perturbation. Blue squares indicate mean % of errors ± SEM (error bars) before mefloquine intake and red squares indicate mean % of errors ± SEM (error bars) 24 h after mefloquine intake (n = 9).

Figure 3

Reflex blinking is not affected by the intake of mefloquine. (A) Left panel: Schematic drawing of eye-blink recording system. A gold plated neodymium magnet was attached to the edge of the upper eyelid (red circle), while a magnetoresistive sensor was attached at the edge of the orbit below the right lower eyelid (green circle). A blink was induced by a small air-puff (unconditioned stimulus: US). An increased magnetic force is detected by the sensor during closure of the eyelid. Right panel: eyelid movement recording of an unconditioned response (UR). Three temporal aspects of the reflex blink were determined: the onset, peak time velocity and peak time amplitude (red arrows). Figure is adopted from Smit et al. (2008). (B) Histogram of eye-blink timing parameters before (blue bars) and 24 h after the intake of mefloquine (red bars). (C) Histogram of standard deviations of the measured eye-blink timing parameters before (blue bars) and 24 h after the intake of mefloquine (red bars). Histograms show mean and SEM (n = 9).

Figure 4

Eye-blink conditioning is impaired by the intake of mefloquine. (A) Left panel: Schematic drawing of eye-blink conditioning. Right panel: eyelid movement recording of a response before (UR: unconditioned response) and after conditioning (CR: conditioned response). (B) Example of 48 eyelid recordings of a control subject (i.e., no mefloquine use; left panel) and a mefloquine user (right panel) during the acquisition. The conditioned stimulus (CS) is indicated by the light-blue bar, ranging from 500 to 1020 ms. The unconditioned stimulus (US) is indicated by the vertical black line, ranging from 1000 to 1020 ms. (C) Histogram of the total number of CRs in % observed in control subject (blue, n = 11) and mefloquine users (red, n = 8; *p < 0.05, t test). (D) The average percentages of CRs in each acquisition block is plotted for the control group (blue squares) and mefloquine group (red squares). Learning curves were used to fit both data sets ($R_{\text{control}}^{\text{2}}=0.98\text{and}{R}_{\text{mefloquine}}^{\text{2}}=0.87$).