Applying transcranial magnetic stimulation concurrently with functional MRI: investigating disturbed transcallosal signalling in patients

Transcranial magnetic stimulation (TMS) is a technique to safely and reversibly
stimulate brain areas in human patients or healthy volunteers. Using a coil
with a high current, a brief magnetic field pulse perpendicular to the surface
of the head is generated that penetrates the skull almost unattenuated. In the
brain, this brief magnetic pulse then generates a current locally that
interferes with neuronal processing.
This technique is increasingly used to diagnose or even treat neurological and
psychiatric disorders. However, at present the exact effects TMS has on the
brain are unclear. Recent research shows that not only the brain areas directly
underlying the TMS coil are affected, but entire connected neuronal networks.
Furthermore, local cortical architecture can alter the deployed current
considerably.
Very recently, it became possible to apply TMS during functional MRI scanning.
This allows researchers to follow the effect TMS has on brain activation, in
order to verify whether the intended TMS treatment or diagnosis is indeed
having the effect on brain activation that is often assumed. The dept. of
Psychiatry at the UMCU recently assembled a concurrent fMRI/TMS setup.

The objectives of this proposal are twofold. First, we intend to test the
feasibility of the new concurrent fMRI/TMS setup on real brains of a small
group of healthy volunteers. That is, can we indeed evoke fMRI BOLD responses
in several functional networks in the brain with TMS? The setup has been
extensively tested on phantoms, and all technical issues have been solved (see
section 5.2.2 of the protocol text). Second, we aim to investigate the
(dys)functioning of two pathways in a small group of schizophrenia patients.
The first part of the proposed research will give us a fundamental new insight
to what the actual effects of TMS on brain function are, and allow us to
improve brain stimulation techniques and possible future treatments such that
the brain areas of interest are influenced in the most efficient way possible.
In a small group of healthy volunteers we will stimulate (pre)motor and
language regions known to be incorporated in a functionally coupled cerebral
network. The aim of these experiments is to establish whether we can indeed
visualize TMS induced proximal and distal brain activation in these established
motor networks. Besides yielding scientifically interesting results on the
nature of these networks, these experiments will allow us to further optimize
our concurrent fMRI/TMS setup. When the concurrent fMRI/TMS setup yields
reliable activation in known networks, our first objective is achieved. We will
report to a Data Safey Monitoring Board (DSMB), established for this particular
study, about the outcome of this first concurrent fMRI/TMS pilot study when 5
out of 10 subjects and 10 out of 10 subjects have been tested before proceeding
with the second objective (see also section 9.3 of the protocol text). As we
are aware of the fact that this is a new technique within the UMC Utrecht, we
want to give the DSMB the opportunity to judge on the application of this
technique after the experiences of a small number of volunteers (mainly the
applicants and 5 of naive subjects recruited externally) are fully evaluated.
In the second part of the proposed research the objective is to investigate the
functioning of two pathways in a small group of schizophrenia patients. The
second objective will be carried out when the first objective, testing the new
setup on healthy volunteers, is achieved. It has been hypothesized that the
symptoms in a special group of schizophrenia patients, namely patients with
persistent auditory verbal hallucinations (i.e., 'hearing voices'), are caused
by an imbalance in neuronal pathway functioning. With the setup perfected and
tested on brain networks of healthy volunteers, we can now stimulate a cortical
starting point of such a possibly affected pathway, while simultaneously
reading out fMRI BOLD signals at another end of such a pathway. These readout
measures can then be compared to the same measures in healthy controls. The
first pathways we intend to investigate this way are the transcallosal
connection between the language areas of Broca and Wernicke in the left
inferior frontal cortex and temporor-parietal cortex and their respective
homologues in the right hemisphere. Broca*s and Wernicke's area in one
hemisphere will be stimulated, and BOLD fMRI in the contralateral hemisphere
read out. Imbalances in both the transcallosal and intrahemispheric networks
under investigation have been implicated as the cerebral pathology underlying
auditory verbal hallucinations in schizophrenia. Testing these hypotheses in
vivo for the first time can greatly improve our understanding of this disabling
disease and offer new therapeutic interventions in the future.

The study is comprised of 2 experiments, and is a combination of an
observational study (fMRI) with an 'invasive' component (TMS). The first study
is a feasibility study of this new technique on 10 healthy volunteers. The
second study is a study on schizophrenia patients and matched controls, testing
hypotheses on disturbed transcallosal signaling in these patients (see above
paragraph).

The risk associated with participating in an fMRI/TMS experiment is minimal. It
is not considered greater than when doing an fMRI or TMS experiment in
isolation. The potential risks of bringing a TMS coil into the bore of an MRI
scanner have been eliminated by the special setup that is designed by the
applicants (see methods, chapter 5 of protocol text). A comparable setup has
been in use for at least 8 years at University College London (UCL). This group
advised us regarding our setup, most parts are identical as at UCL. In the
first study 10 subjects will be tested during brief visits. 5 of these subjects
will be the applicants and co-workers that are used to such experiments. 5
subjects for experiment 1 will be recruited from campus, to guarentee objective
reports of feasibility and burdon by questionaires. The patients are recruited
in-house, and matched controls recruited externally. For potential risks of
fMRI and TMS, the usual precautions are taken (proper screening, see D5).