Focus on the locus network with 7T MRI: link to memory (dys)function

The cause of Alzheimer*s disease, the most common form of dementia, remains
unknown. Neuropathological studies suggest that a small area in the brainstem,
the locus coeruleus, might be the site of the onset of the disease. This area
is the sole soure of noradrenalin to the brain, a neurotransmitter involved in
arousal, but also cognitive functions. Animal and pharmacological studies have
hinted towards an important role of this area in memory functioning. However,
these studies were hampered by the limited spatial resolution, making it hard
to clearly localize the locus coeruleus in the brain. New developments in brain
imaging allow now to visualize the brain with stunning precision. Furthermore,
a non-invasive new stimulation method, transcutaneous vagus nerve stimulation,
is believed to excite the locus coerulues and thereby influencing neuronal
networks and memory functioning.

There are three aims in this project:
1. To investigate how the functional interaction between the locus coeruleus
and other brain areas, in particular the medial temporal lobe areas, during
memory processes (encoding, consolidation and retrieval) change with
development of Alzheimer's disease.
2. To investigate associations between noradrenaline, memory performance and
brain functioning. We aim to investigate how acute noradrenalin levels change
during the different memory processes and whether or not this is beneficial for
performance. Furthermore, we will investigate whether this interaction between
noradrenalin, memory performance and brain functioning is different healthy
older individuals or patients with prodromal Alzheimer's disease.
3. To investigate the underlying neural network changes during transcutaneous
vagus nerve stimulation. We will focus on differences in functional
connectivity between the locus coeruleus and the medial temporal lobe areas in
healthy older individuals and prodromal Alzheimer's disease patients. An
experimental condition will be compared with a sham condition in a
pseudo-randomized cross-over design.

This is an observational MRI study with a pseudo-randomized cross-over design
for the stimulation part.

We do not expect that the participants are at any risk during this study and we
do not expect them to benefit from this study directly. Participants will be
screened for claustrophobia or related anxiety problems. In case of doubt, the
dummy scanner will be a check to investigate possible fears. The participants
will be informed about unexpected medical findings. In case the participant
does not wish to be informed, he is not allowed to participate in this study.
A static magnetic field of up to 14T or more does not harm biological tissue,
but the radiofrequency and MR gradient applied can influence the human body via
heating (specific absorption rate (SAR)). Just as with 1.5T and 3T MRI scanners
the limits of the radiofrequency (RF) and magnetic resonance (MR) gradient are
encoded in the 7T scanner. Therefore certified users will always stay below
these limits making 7T scanning harmless. Furthermore, just as with 1.5T and 3T
MRI scanners, metallic objects cannot be inserted into the scanner area of the
7T MRI scanner. Therefore, subjects with metallic prostheses, pacemakers, metal
clips on blood vessels, metal parts in the eye, an intrauterine device, metal
braces and other metal objects will be excluded from the study. Prior to
scanning all subjects will fill out a form to screen for these metallic
objects. Although 7T MRI is harmless if contra-indications are taken heed of
and if operated by certified users, a small amount of people (5%) may
experience vertigo or nausea while entering the scanner. However, these
symptoms will be minimised by slowing the subject*s entry and exit time into
the magnetic field.
As for the transcutaneous vagus nerve stimulation: The TENStem device is CE
certified and registered for this purpose and several studies have applied it
successfully in healthy subjects (including older participants), patients and
in the MRI environment. For the administration, we will adhere to the reported
parameters and location (left ear). Participants who do not tolerate these
parameters will be excluded from the study.
Even though, this device has been used previously in an MRI context, we will
not start this study before the safety committee of Scannexus has formally
approved its compatibility. Scannexus provides continuous support by trained
lab workers, who are also able to deliver medical support if necessary.
Transcutaneous vagus nerve stimulation has no known complications and no
long-lasting or serious adverse events. We will however monitor heart rate,
blood pressure, and enquire potential sensations after stimulation. For safety
reasons (both for the MRI and stimulation), we will exclude participants with
cardiac pathology or pace makers. The risk for the participant involves
temporary light dizziness (15%), concentration problems, fatigue or a tingling
sensation at the ear.
We are convinced that the risks are acceptable.