Connections between the frontal lobe and the basal ganglia:
possible biomarkers for dopaminergic deviations

The frontal cortex plays an important role in imposing higher order volitional
control over automatic behavior. This allows us to react appropriately in
complex and dynamic environments. The frontal cortex involvement in higher
order control is eminent in response selection and motor control, but is
suspected to extend to decision making, cognition, language and reasoning.
For some time, connections from the frontal cortex to the basal ganglia, and
especially dopaminergic signaling therein, have been implicated in human
response selection and decision making, although most of our knowledge about
this system arises from work on animals. More recently, connections between the
frontal cortex and the cerebellum have been implicated in our control over and
learning of complex motor tasks.
Many neuropsychiatric diseases can be explained by defects in the
aforementioned networks, but the exact neuropathology remains poorly
understood. Response selection deficits occurring in schizophrenia, Parkinson's
and Huntington's disease have all been explained by corroborated neuronal
signaling in these networks, especially regarding dopaminergic metabolism in
the basal ganglia, but this has hardly been investigated directly in human
subjects. The present research proposal describes 2 experiments that
investigate the function of (parts of) these two networks in healthy
individuals. The techniques that are used are Transcranial Magnetic Stimulation
(TMS), functional MRI (fMRI) and 1-proton spectroscopy (1H-MRS).

The objective of this study is to determine the role of dopaminergic
neurotransmission in the basal ganglia in response regulation.
The outcome of the proposed studies is intended as proof of concept for our
future research initiatives on the dysfunction of the aformentioned networks in
neuropsychiatric patients using the same techniques. Especially, using 1H-MRS
as a technique to determine dopaminergic signaling deviations in the basal
ganglia and their influence on response regulation might be tested as a disease
biomarker.

This study investigates the role of fronto-basal connections in human response
selection.

The study will measure functional properties of the human fronto-basal network
in 4 visits by 40 healthy volunteers: 1) by determining the dopamine content in
the human striatum through lactate 1H-MRS; 1) by investigating activity in this
network using fMRI during simple response selection tasks (eye movements); 3)
by examining behavioral consequences of stimulating parts of this network with
TMS; and 4) by measuring response selection and decision making, functions
purported to be mediated by fronto-basal networks, using a series of behavioral
paradigms. Correlations amongst these four measures will be examined within
individuals. For example, will participants with low striatal dopamine levels
be more reflexive and automatic in their behavior and will this also be
reflected in reduced striatal fMRI activity? This series of experiments will
also provide insight into the normal range of fronto-basal functioning, to
provide a reference for examining dopaminergic dysregulation in psychiatric and
neurological populations with basal ganglia dysfunction, such as Parkinson's
and Huntington's disease, and schizophrenia.

The experiments are described in detail in chapter 5 (methods) of the protocol
text.

The risk and burden associated with participating in an MRI, fMRI or
TMS experiment is negligible, and are routinely performed in our
institute. For potential risks of fMRI and TMS, the usual precautions are taken 
(proper screening, see D5).