GABA, excitability and plasticity in the human motor cortex, an explorative study

GABA is an important neurotransmitter playing a pivotal inhibitory role in the
human central nervous system. It is hypothesized to have a critical function in
shaping the excitability and plasticity of the cortical motor system. Recently,
non-invasive techniques have come available to modulate and record the GABA
concentration in the human primary motor cortex. In this study, we aim to
employ these techniques to investigate the relationship between GABA
concentration, excitability and plasticity in the human cortical motor system.

We aim to investigate the relation between cortical excitability, GABA
concentration and plasticity in the human motor cortex. We plan to modulate the
functional integrity the primary motor cortex by using well-known repetitive
transcranial magnetic stimulation (rTMS) protocols, that differentially affect
the cortical excitability. We will index the GABA concentration at site of
stimulation using magnetic resonance spectroscopy (MRS), and its functional
connectivity coupling with other cortical regions using resting-state
functional magnetic resonance imaging (rs-fMRI). The first objective of this
study is to investigate the relationship between local changes in GABA
concentration, excitability, and connectivity. Second, we aim to track the
changes in GABA concentration, excitability and connectivity over time. This
will give insight into mechanisms supporting the recovery and plasticity of the
motor system following a functional perturbation. Lastly, we aspire to validate
GABA spectroscopy as an objective measurement to index TBS efficacy.

The study consists of one intake session and three experimental sessions in
which the excitability of the primary motor cortex will be differentially
modulated by one of three off-line rTMS protocols: continuous theta-burst
stimulation (cTBS: decreasing excitability), intermittent TBS (iTBS: increasing
excitability), and 5 Hz stimulation (120 seconds: ineffective). The
experimental sessions will take place 1 week apart of each other. Both before
and after rTMS application we will record motor evoked potentials (MEP) to
index cortico-spinal excitability, and determine the short-interval cortical
inhibition (SICI) to index cortico-cortical excitability. Additionally, in the
MR scanner we will acquire rs-fMRI and measure GABA concentration. This will be
done both before rTMS application, and afterwards at three subsequent time
points (at ~16 minutes, ~42 minutes, and ~63 minutes after TMS).

During the intake session, participants will be screened and informed on the
study in general and the TMS application in particular. During the following
three experimental sessions, each participant will receive (in counter-balanced
order) cTBS, iTBS and 5 Hz stimulation all consisting of 600 pulses during
separate sessions at 80% of the active motor threshold (AMT) over the primary
motor cortex.

TMS is safe and not painful. In rare cases, participants might report a (light)
headache (2-4%), which can be treated easily with paracetamol. Based on
incidental epileptic seizures triggered by TMS in early 90*s, safety-guidelines
were established, in order to set up the maximum duration of TMS stimulation
(Wassermann 1998; Anderson et al. 2006) . Updating these TMS guidelines,
resulted in guidelines including safety information about repetitive TMS (e.g.
TBS) (Rossi et al. 2009; Oberman et al. 2011). The protocols, intensities and
site of stimulation we chose to employ in this study are particularly
well-known to be safe and pose a minimal burden and risk to the subject. The
protocols all fall well within these safety TMS guidelines. (See attached
appendix for the (Wassermann 1998) and (Oberman et al. 2011) guidelines and
for the TMS safety report (v1.0 Augustus 2011)). Furthermore, all participants
will be pre-screened for relevant medical history, epilepsy, drug abuse, head
trauma, neurological or psychiatric illness, pregnancy, heart disease, cardiac
pacemakers, medication pumps, tricyclic antidepressants, neuroleptics and a
family history of neurological illness, psychiatric illness or epilepsy.
Because the risk associated with participation can be considered negligible and
the burden can be considered minimal, we do not expect adverse events during
the project.