Contributions of the supplementary motor area and the pre-motor cortex to skilled sequential action: a TMS study.

The ability to execute movements in a fixed sequential order and thus to
develop sequencing skills is fundamental to human behaviour. Sequential skills
have often been studied in the domains of cognitive psychology as well as
neurology, and models on the production of such skill have been developed in
both domains. Cognitive psychology has distinguished three modes of sequence
execution, namely the reaction mode, the associative mode and the chunking
mode. Regarding the neural domain, two brain areas have been found to be
differently involved in sequential behaviour: the premotor cortex (PMC) is
thought to be responsible for externally guided and/or triggered behaviour,
while the supplementary motor area (SMA) is involved in internally guided
(i.e., self-initiated) behaviour. The present study aims to converge the
cognitive and neural domains - and their respective models of sequential action
- in order to better understand the foundations of skilled sequential action.
We hypothesize that the reaction and associative modes can be mapped onto PMC
function, due to the continued need for stimuli. Conversely, the chunking mode
seems to relate to SMA functioning, due to the highly internalized triggering
of movement.

The main objective is to investigate the involvement of the supplementary motor
area (SMA) and the premotor cortex (PMC) in skilled sequential action.

The study is an interventional study.

On the first day of the experiment, subjects practice two keying sequences in
the discrete sequence production (DSP) task. This practice phase will consist
of 10 blocks, so that subjects can take a short break (~2 minutes) between
blocks. The duration of the practice phase will be about 2,5 hours. On the
second day of the experiment, subjects will first practice the learned
sequences for two blocks. Next, they will undergo 20 minutes of low-frequency
(1Hz) rTMS and then have a 20 minute break - inhibitory effects of rTMS on
motor performance have been shown to be larger after a 20min. interval compared
to no interval (Verwey et al., 2002). Finally, subjects will complete the four
test blocks and fill out a questionnaire regarding the practice sequences. This
final phase will take about 2,5 hours.

Twenty minutes of repetitive transcranial magnetic stimulation (rTMS) targeted
to either the supplementary motor area (SMA group) or the premotor cortex (PMC
group), or twenty minutes of sham stimulation (control group).

The duration of rTMS application will be 20 consecutive minutes during the
second day of the experiment. During rTMS the subject will be seated in a
comfortable chair. Repetitive TMS is generally well tolerated. Possible
side-effects and risks are:
- Headache and/or local pain: The most common side-effect of rTMS is the
experience of pain. It is most frequently reported when rTMS is applied to
non-motor areas. We will warn subjects that rTMS may not be pleasant and may
cause some pain. If subjects do not tolerate rTMS, the experiment is stopped
and will not be continued.
- Hearing problems: Releasing the TMS pulse is accompanied by a clicking sound,
which may be experienced as quite loud by subjects. Therefore, subjects will
wear hearing protection.
- Syncope: When a subject reports nausea, dizziness or feelings of (almost)
fainting, the experiment is stopped and will not be continued. During the
experiment, the subject will be asked frequently if he/she experiences any of
these feelings.
- Seizures: There have (rarely) been reports of seizures during or after rTMS.
Rossi et al. (2009) describe two of such instances. However, these instances
either occurred when subjects were taking pro-epileptogenic medication, or may
have represented a syncope. Subjects in the present study will be screened and
excluded from the study if they are on pro-epileptogenic medication.

According to the guidelines provided by Rossi et al. (2009), the risk of an
epileptic seizure during or after rTMS is extremely low, especially if the
guidelines are followed. As the parameters that will be used in the study fall
within these guidelines, the risk of this study is low. Twenty minutes of rTMS
may be intense, but we believe that it will be well tolerated by the subjects.
We will make sure that the subject is comfortable, by providing a comfortable
chair and frequently asking the subject if he/she experiences any discomfort.

There are no risks involved in performing the motor sequencing task.