The effects of nr-TMS on the HD-EEG measurements while conducting a language test in healthy subjects.

People with a brain tumour often need brain surgery. A brain tumour may be
close to areas of the brain that are responsible for speech, reading and
writing. To make sure that these areas are not damaged during surgery, patients
sometimes need to be awake during the operation. During the operation, the
surgeon can temporarily disrupt the brain's function using small pulses of
electricity, while the patient takes a speech test. This allows the surgeon to
know whether the part being stimulated contains important language function. If
so, the stimulated part of the brain cannot be removed. This awake brain
surgery is often very exciting and tiring for patients. There are also other
drawbacks to this technique, which is why it is important to have a better idea
before surgery of which part of the brain is needed for speech and language and
therefore cannot be removed. We hope that with better information before
surgery, we will be able to reduce the time patients spend awake and perhaps
even eliminate the need for surgery altogether.

One way to map the exact location of language function in the brain is to
measure brain function using navigated repetitive transcranial magnetic
stimulation, or Nr-TMS for short. Nr-TMS uses short magnetic pulses to
stimulate the brain. A coil containing a strong magnet is placed on the head.
This magnetic field can create a small electrical current in the brain. This
can temporarily disrupt the functioning of a small part of the brain. To
measure these disturbances, we use a film of the brain called an
electroencephalogram (EEG). We use an EEG with more electrodes than normal.
Because we have more points, we can measure the brain's electrical signals more
accurately. In this study, we will use the n-TMS device to disrupt speech. At
the same time, we will use EEG to measure how the brain responds to this
disruption. During the disruption, we will give language tests. Our ultimate
goal is to perform this nr-TMS-EEG study in patients with a brain tumour before
surgery. In this way, we hope to improve the outcome of the surgery.

In this study, we will investigate what changes in brain activity when we test
language function and if this can be detected on a High-Density
electroencephalogram (HD-EEG). As part of this study, we will also temporarily
disrupt brain activity through brain stimulation. We will use navigated
repetitive transcranial magnetic stimulation (nr-TMS). During this scan, we
will test the language function by asking the subject to name pictures on a
screen at the same time. an MRI-scan will be made of brain of the subject.

The examination requires you to come to the hospital twice and will take up to
4 hours. The intake interview and the MRI scan will take about half an hour in
total. The experiment itself will take about 3 hours.
We will do the following during the study:
- Before the first visit, you will receive an information letter along with a
questionnaire with exclusion criteria. After 2 weeks, you will be called by a
researcher asking if you want to participate in the study. The researcher will
also go through the exclusion criteria questionnaire with you and then schedule
an appointment.
- During the first visit, the researcher will have an intake interview with
you. Here, the researcher will briefly explain the study again and you can ask
any further questions. This will take about 15 minutes. Next, You undergo an
MRI scan of your head. The MRI scan will also take about 15 minutes, of which
the scanning will only take 5 minutes.
- The MRI scan will be reviewed by a neuroradiologist or neurosurgeon. If no
abnormalities are found here, you will be invited to the second visit.
- During the second visit, the examination will be performed, which will take
about 3 hours. Before the examination, we ask you to remove your jewellery,
especially necklaces and earrings. We also ask you to put aside bank cards and
any electronic devices, such as phones. The TMS device works with strong magnet
which can cause damage if metals, electronic devices or bank cards are nearby.
- During the examination, you sit on a comfortable chair and are first given a
'cap' (a bathing cap with holes) with electrodes on your head. These electrodes
are filled with a paste and record the brain video. The skin under the holes
will be scratched a little to make the brain video as good as possible. This
can be slightly uncomfortable, but not painful.
- When this cap is connected, we will show you pictures on a screen and ask you
to name them as quickly as possible in a sentence. For example; if the picture
shows a cat, you say: "This is a cat". If a dog is shown: "This is a dog" and
so on.
- Next, an instrument with reflective balls will be attached to the EEG cap.
This is needed for the navigation device. The examiner will also prepare the
TMS device for the further examination, during which you will be asked to sit
relaxed and still.
- Before the stimulation starts, the intensity of the stimulation will be
determined. During this determination, an attempt will be made to induce muscle
movements in the hand with the TMS device. You will not notice anything, except
that involuntary muscle movements may feel a little strange.
- When everything is ready, you will again be asked to name pictures that you
see on a screen. During this second part of the examination, we will switch on
the TMS device, which will emit magnetic pulses during the measurement. These
magnetic pulses may cause you to have difficulty naming the pictures you see,
but this effect only lasts a few seconds. These magnetic pulses do not hurt.
Sometimes some muscles in the face may tighten, which can be bothersome. If so,
we can stimulate in a different way that makes this less present.
- After a number of naming pictures and stimulation with the TMS device, the
measurement is finished and you are able to leave the hospital on your own.

Participants will receive nr-TMS pulses, the effect of which will be measured
using HD-EEG. these pulses will be administered on the left fronto-temporal
region of the brain. Stimulation will take place for 1 second at a frequency of
5 Hz at an intensity of 100% of the resting Motor Threshold (rMT). This is
followed by a 3-second rest period. This amount, frequency, and intensity of
the TMS pulses falls published safety standards are (Rossi et al., 2009, Clin
Neurophysiol).

MRI
There are no known risks associated with having an MRI scan. You may find it
uncomfortable to lie still for a long time during the scan. Lying in the
scanner may also make you feel claustrophobic. However, you should be aware
that unexpected abnormalities may be found on the MRI scan. If this is the
case, your doctor will be informed.

EEG
There are no known risks associated with having an EEG. You may feel
uncomfortable if you have to wear the EEG cap for a long time or if the paste
remains in your hair after the examination.

TMS
The risk of nr-TMS can be considered negligible to minimal. You may hear the
TMS pulse, which sounds like a loud clicking sound. The TMS device may cause
the muscles around your face to contract. This may feel uncomfortable, but will
only last a short time. If it becomes too uncomfortable, you can tell us at any
time and the session can be adjusted or stopped. You may experience mild,
short-term side effects during stimulation. The most common side effects are
neck pain/discomfort (±40%), localised scalp discomfort (±39%), tension
headache during and immediately after stimulation (±28%) and dizziness. Rarely,
seizures have been reported in nr-TMS studies in patients (e.g. with epilepsy)
or in studies using particularly intense (non-standard) stimulation. The most
serious - but very rare - side effect of nr-TMS is the occurrence of a single
seizure. This occurs in 0.08 per 1000 sessions and the chance is virtually zero
if you do not have epilepsy or any other neurological condition. For this
reason, a neurologist or neurosurgeon will be present at the trial or in a
nearby trial unit to provide appropriate assistance. In addition, a KNF lab
technician (student) will often be present at the trial. To minimise these
risks, you will be given a full pre-test screening. See Appendix D for a full
list of contraindications to nr-TMS.
On one occasion, superficial burns were also described as a result of the TMS
stimulator overheating. There is a temperature-protection system in our
equipment: every 4 seconds the temperature of the stimulator is measured and if
it exceeds 40°C, the TMS device is automatically switched off. This risk is
present in all TMS treatments.


Computer program for displaying images and timing TMS.
To ensure that the images are displayed at exactly the same time as the TMS
pulses are delivered, we use a computer program. This programme was developed
and tested at the UMCG. Because this computer program is new, it carries
possible risks. The program may crash, a cable may break, or the stimulation
values may be entered incorrectly. This can cause you to perhaps get more TMS
pulses that you are meant to. However, there is a safeguard in the system that
ensures the pulses are always within safe stimulation norms. At least two
researchers are present during each measurement to minimise the risk of
negative consequences for you. This is because the stimulator can be removed
directly from the head by one examiner and, in addition, the person standing by
the computer can also directly ensure that the computer, i.e. the TMS
equipment, is switched off. In addition, there is a large stop button on the
TMS device itself through which the equipment can be switched off.