Impairment of Retention But Not Acquisition of a Visuomotor Skill Through Time-Dependent Disruption of Primary Motor Cortex

Subjects.

Fifty-two right-handed subjects (18- to 44-years-old, 23.9 ± 5.5 SD, 24 females) participated after providing written informed consent. Protocols were approved by the Johns Hopkins Institutional Review Board. All volunteers were screened for history of neurological disorders and other TMS contraindications.

Apparatus and general task procedures.

Subjects were seated in front of a vertically oriented monitor centered at the midline and at eye level. A sling supported the forearm in the horizontal plane, shoulder movement was restricted by a belt and the wrist was braced. Head movements were restrained with a custom-molded bite bar, and a shield prevented vision of the hand and arm.

Subjects performed rapid “shooting” reaching movements through targets displayed on the monitor while grasping the handle of a robotic arm. They were instructed to move a cursor from a central start position (depicted as a cross) to the center of the target in a straight line and with an appropriate speed. There was a 1:1 mapping between cursor and hand displacement. After a random wait time uniformly distributed between 2.5 and 3.5 s, a beep sounded as a target (1 × 1 cm) appeared. The target was located at one of three positions along a boundary circle with a 10 cm radius and the cross as the center (see below). As the cursor moved toward the target, a trace of the cursor path remained on the screen. At the moment the cursor passed through the boundary circle (trial end), the cursor was hidden, the boundary pass point (endpoint) was marked with a dot, and the robot exerted a dampening field to slow hand motion. If the cursor passed through the target, peak tangential velocity was within 130 ± 12.5 cm/s, and path curvature index (movement path length divided by the distance between cursor position at target onset and endpoint) was ≤1.01, an animation of target explosion and a tone were given as reward. The target turned red or blue if peak velocity was higher or lower than the desired range, respectively. A visual warning cue was given if the reaction time (time between target onset and movement onset) was >400 ms. The peak velocity feedback and the trace (up until endpoint) were displayed until the robot moved the handle back to the start position, at which point the cursor reappeared.

Experiment 1.

The experiment consisted of blocks of 48 trials, with a timed period of rest (1 min) between blocks (see Fig. 1). Targets were pseudorandomly ordered within one block, so that every set of three consecutive trials included one each of the three targets at 127.5, 135, or 142.5°. Before the experimental session, subjects performed three blocks of familiarization in the null condition (i.e., without any visuomotor transformation). The session began with a preadaptation block in the null condition. Subjects then performed four blocks of adaptation as a rotational transformation was applied to the cursor direction with respect to the hand direction. The first 12 trials of the first adaptation block were performed with 0° rotation, after which the magnitude increased by 1° clockwise for every 6 trials, so that the last six trials of the fourth block were performed with the maximal 30° clockwise rotation. The rotation was implemented gradually to decrease the likelihood that subjects would use cognitive strategies to improve performance (Mazzoni and Krakauer, 2006). Subjects were divided into four groups depending on the type of TMS received during the adaptation period (n = 9 per group). For the immediate-TMS group, we applied a single TMS pulse over M1 at the time of each trial end. For the delayed-TMS group, we applied a single pulse over M1 at 700 ms after trial end. Subjects in the dorsal premotor cortex (PMd) TMS group received a single pulse over PMd at the time of trial end. A fourth group of subjects did not receive TMS. After the adaptation period, all subjects performed a block of deadaptation (washout of adaptive movements back to baseline) in the null condition and in the absence of TMS.

For the delayed-TMS group, we chose the stimulation time of 700 ms after trial end as it was the latest time during the intertrial interval at which TMS could be reliably given without interfering with the next trial. Stimulation at later times than this tended to induce a twitch in the subject's arm that interfered with the process of placing the cursor on the cross and waiting for initiation of the next trial. For the PMd-TMS group, we sought to control for the possibility that any effects which were induced by TMS over M1 in the immediate-TMS group might be attributable to spread of the TMS-induced current from M1 to PMd. We were concerned about this because connections between the motor cortex and the premotor cortex are dense (Münchau et al., 2002), PMd plays a role in visually guided movements (Lee and van Donkelaar, 2006), and PMd cells display adaptation- and retention-related plastic changes in force field paradigms (Xiao et al., 2006). Therefore, to test this possibility, we applied TMS over PMd at an adjusted (reduced) intensity for subjects in this group (see TMS methods below).

Experiment 2.

Our aim here was to consider whether a period of TMS preceding a sudden large error (e.g., initially in the deadaptation period of experiment 1) induces a greater sensitivity to the error, and whether experiment 1 was influenced by this or other nonspecific effects. As before, after familiarization training, the experiment began with a preadaptation block (48 trials/block) performed in the null condition (Fig. 1). For 8 subjects, this was followed by four blocks with a single pulse of TMS applied at the time of each trial end, but unlike experiment 1, these blocks occurred in the null condition rather than with visual rotation. In 8 other subjects, no TMS was applied. After this period, four blocks of adaptation occurred where from the first trial onwards, a 30° counter-clockwise visual rotation was present. Finally, subjects performed a deadaptation block in the absence of TMS.

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Figure 1.

Experimental design. Thick lines represent visual rotation magnitude. Arrows indicate the blocks with TMS.

Targets were located at 157.5, 165, and 172.5° and were pseudorandomly presented as in experiment 1. These locations were chosen so that the initial movements of the first adaptation block had the same hand path direction as the initial movements of the deadaptation block in experiment 1. Also, because of the counter-clockwise direction of visual rotation, the hand direction gradually shifted clockwise over the course of the block, again identical to experiment 1. We carefully matched the movements so that, given the fixed cortical area being stimulated by TMS, the results of this experiment could not be attributed to the use of different muscles from those in experiment 1.

Analysis and statistics.

We quantified performance in each trial using the angular endpoint error, defined as the angle between the line connecting the initial cursor position to the center of the target and the line connecting the initial cursor position to the endpoint. Trials were binned by three, and statistics were performed on the binned data using repeated-measures ANOVA with Tukey's correction for multiple comparisons. For calculating mean cursor trajectories, the cursor position data for each movement was resampled at 20 points evenly spaced over the movement duration (from movement onset to trial end), with linear interpolation between adjacent time points.

TMS and localization of stimulation sites.

A Magstim 200 monophasic stimulator (Magstim, Whitland, UK) and a figure-of-eight coil with 70 mm wing diameter were used. Surface electromyogram (EMG) recordings were taken from right biceps brachii, right deltoid, and right first dorsal interosseous (FDI) muscles. The coil was placed tangentially to the scalp with the handle pointed backwards at a 45° angle with respect to the anterior-posterior axis. Single pulses of TMS were applied to the left M1 to localize the FDI motor “hot spot,” defined as the site that elicited maximal motor evoked potentials (MEPs) in FDI at 40–50% of maximum stimulator output. The FDI resting motor threshold (RMT) at the motor hot spot was the minimum intensity which elicited MEPs of ≥50 μV amplitude in the FDI in ≥5 of 10 consecutive pulses applied to the motor hot spot for the FDI muscle. The mean FDI RMT measured at the M1 hot spot for the immediate-TMS, delayed-TMS, and PMd-TMS groups in experiment 1 was 41.78 ± 3.11, 40.11 ± 4.73, and 41.56 ± 6.89% (mean ± SD) of the maximum stimulator output respectively. Subsequently, single pulses were delivered to the left M1 to localize the biceps and the deltoid hot spots. During experiments which involved stimulation of M1, TMS was applied at 120% of FDI RMT at the midpoint between biceps and deltoid hot spots to stimulate the representation of muscles chiefly used in the present task (Thoroughman and Shadmehr, 1999). We observed TMS-induced MEPs in the right FDI, biceps, and deltoid muscles throughout the adaptation period (see Results).

For the PMd-TMS group in experiment 1, TMS was given over left PMd at an adjusted stimulation intensity to represent a coactivation of left PMd caused by current spread from TMS on left M1 (Gerschlager et al., 2001). This intensity was calculated by first finding the resting motor threshold of FDI when TMS was applied to left PMd, defined as the minimum intensity which elicited MEPs of ≥50 μV amplitude in the right FDI muscle in ≥5 of 10 consecutive pulses applied to the left PMd. The dorsal premotor cortex was localized by moving the TMS coil to a position 2 cm anterior and 1 cm medial to the M1 hot spot for the FDI muscle. This location is based on previous functional imaging studies which have demonstrated that PMd is located ∼1.5–2.5 cm anterior to the motor cortex hand area (Fink et al., 1997; Picard and Strick, 2001). The ratio of FDI RMT measured at the M1 hot spot to FDI RMT measured at the PMd site was then found, and this ratio (77.0 ± 4.4% SD) multiplied by the value of 120% of the FDI RMT at the M1 hot spot was used as the adjusted (reduced) intensity of TMS over PMd (which corresponded to 83–98% of the FDI RMT at the hot spot).

It is possible that any observed results in the immediate-TMS group are not caused by disruption of M1 activity by TMS, but are actually the result of significant sensory sensation induced by TMS (e.g., a loud clicking sound caused by discharging of the stimulator) that nonspecifically interferes with the task (nonspecific effect) (Robertson et al., 2003). There are a number of approaches which can be used to control for such nonspecific effects. One approach is to apply TMS at different sites with the same stimulation time point. This was the case for the PMd-TMS group in experiment 1, although it is possible that TMS over PMd induced a slightly different sensation compared with TMS over M1. Another method is to apply TMS at different time points over the same site, which was the approach taken in the case of the delayed-TMS group in experiment 1. A third approach is to use distinct tasks with stimulation at one site, which was the case for experiment 2. A final alternative is to use sham stimulation, in which the stimulator discharges with an audible clicking sound but the magnetic pulse does not traverse the skull. However, as currently available sham coils fail to produce a sensation similar to real TMS (Robertson et al., 2003), we favored the other approaches rather than a sham control.