Integrating motivation, cognition and action: cortical control of striatal processing

Dopamine in the striatum is an important mechanism for the mediation between
motivation, cognition, and action. Neuroanatomical (animal) data have revealed
an arrangement of spiraling connections between the midbrain and the striatum
that seems perfectly suited to subserve a mechanism by which dopamine can
direct information flow from ventral/ ventromedial (VS), via central (caudate
nucleus; CN), to dorsolateral (putamen) regions of the striatum. Moreover,
these striatal regions are connected to distinct cortical areas [orbitofrontal
(OFC), dorsolateral prefrontal (dlPFC), and premotor cortex (PMC),
respectively] through cortico -striatal circuits.

Transcranial magnetic stimulation (TMS) of particular cortical areas is known
to affect dopamine release in distinct striatal regions. Therefore, with a
particular TMS protocol (continuous Theta Burst Stimulation; cTBS) we will
decrease the excitability of the OFC, dlPFC and PMC to infer the connections to
the VS, CN and putamen. We hypothesize that desensitizing these cortical areas
uniquely affects task-related brain activity in the distinct striatal areas and
the area(s) it projects to and behavioral performance on the functions
associated with these areas (i.e. the VS, CN and putamen are involved in reward
processing- cognitive flexibility - motor control, respectively).

We hypothesize that stimulation of particular parts of the human cortex changes
task-related brain activity in distinct striatal areas and performance on the
distinct components of a rewarded-task switching paradigm. This paradigm
measures cognitive flexibility, which is previously shown to improve after
anticipation of high (vs. low) reward.

This effect is thought to depend on individual differences in baseline levels
of striatal dopamine and the results will confirm that the interaction between
motivation, cognition, and action is mediated by dopamine in the striatum, as
will be measured with the dopamine transporter genotype (DAT1/SLC6A3).

The main objective is to assess the effect of decreasing cortical excitability
on task performance and striatal BOLD response as well as the effects on the
striatal areas that are connected through ventral - dorsal spiraling
connections.

We will also assess whether these hypothesized effects are mediated by striatal
dopamine, by taking into account individual differences in baseline levels of
striatal dopamine.

We furthermore look at cTBS induced changes in cortico-striatal connectivity
with resting state functional Magnetic Resonance Imaging (fMRI).

The study will consist of four sessions, each separated by at least a week.
During the first session, the motor threshold (MT)
will be determined (to determine the stimulation intensity in the later
TMS-sessions) and a structural MRI-scan will be made (in
order to localize the TMS coil in the other TMS-sessions).
Furthermore, during this first session, a short cTBS protocol (10 sec.) will be
applied on the PMC and OFC at a low intensity (at first 10% and later 80% of
the aMT). By this means, subjects can indicate whether they would like to
proceed with the experiment.

The study consists of one intake session and three experimental sessions in
which the excitability of three cortical regions will be inhibited with an
off-line TMS protocol by administering cTBS in counterbalanced order
(within-subject). To investigate the effects of cortical cTBS on task-related
brain activity in the striatum while participants perform a rewarded-switch
task during the measurement of brain activity with fMRI. Differences in
connectivity will be measured with high resolution resting state scans.
The off-line effects of cTBS will last approximately 60 minutes.

To measure the effects of cortical cTBS on task-related brain activity in the
striatum while participants perform a rewarded-switch task, we will measure the
task related BOLD-response with fMRI. Differences in connectivity will be
measured with resting state fMRI.

All participants will perform the task -related scan and resting state scan
twice during each session, once after cTBS and once without the application of
cTBS (i.e. before cTBS or more than 1 hour after its application).

During the intake session, participants will become accustomed to the sensation
of cTBS. During the following three experimental sessions, each participant
will receive continuous theta-burst stimulation of 600 pulses (three 50Hz
pulses every 200 ms) at 80% of the active motor threshold for 40 seconds over
the left OFC, left dlPFC and left PMC.

Furthermore, during this first session, a short cTBS protocol (10 sec.) will be
applied on the PMC and OFC at a low intensity (at first 10% and later 80% of
the aMT).

TMS is not painful at the level of intensity used in this project (i.e. at 80%
of active motor threshold). According to previous literature, it might be
possible that, in rare cases, participants could report a (light) headache,
which could be treated easily with paracetamol. On the basis of incidental
epileptic seizures triggered by TMS in early 90*s, safety-guidelines were
established to set up the maximum duration of TMS stimulation (Wassermann,
1998; Anderson et al., 2006; Rossi et al., 2008; Oberman et al, 2011).
Therefore, our protocols will follow these safety TMS guidelines. 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.