Boosting a neuromodulatory system relevant to Alzheimer's disease to enhance memory.

The cause of Alzheimer's disease (AD), the most common form of dementia,
remains unknown. Neuropathological studies suggest that a small area in the
brainstem, the locus c½ruleus (LC), might be the site of the initial
neuropathologic changes. This area is the sole source of noradrenalin to the
brain, a neurotransmitter involved in arousal, but also various cognitive
functions. Animal and pharmacological studies have hinted towards an important
role of this area in memory and attentional processes. However, these studies
were hampered by the limited spatial resolution, making it hard to clearly
localize the locus c½ruleus in the brain. New developments in brain imaging
with ultra-high field magnetic resonance imaging (UHF-MRI) allow now to
visualize the brain with stunning precision. Furthermore, non-invasive new
stimulation methods, transcutaneous vagus nerve stimulation (tVNS) and exposure
to blue-enriched light, are believed to enhance locus c½ruleus activity and
thereby influencing related neuronal networks such as memory and attention
networks.

The 3 main concrete aims that we will investigate are:
i) The association between the locus c½ruleus brain activity and changes in
pupil size during memory and attention tasks;
ii) The overlap and non-overlap between locus c½ruleus-related neural
networks and other task-related brain areas during memory and attention tasks
in healthy older individuals;
iii) The underlying neural network changes during memory and attention
tasks when applying a non-invasive stimulation technique once (tVNS or
blue-enriched light).


As secondary objectives, we will investigate potential outlasting effects of
each stimulation method on memory performance and we will compare patterns of
functional activity during tVNS versus during exposure to blue-enriched light,
as performed at the University of Liège (ULiège).

This is an observational MRI study with a pseudo-randomized single blind
cross-over design (tVNS) and with a within subject design (blue-enriched
light).

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. The device and its use in the 7T scanner has been approved by the
Scannexus safety committee. 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,
respiration 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.
Blue-enriched light exposure as administered in this project does not
constitute a hazard for the eyes (e.g., any ultraviolet light is filtered out
of the light beam) and has been repeatedly used for research, including in
Liège*s lab. Headache is the only side-effect that participants may encounter
but it is rare and dissipates swiftly after the stimulation is ceased. The
light set up specifically designed and constructed for studies conducted at the
Cyclotron Research Center of the University of Liège by Dr. Gilles Vandewalle
was repeatedly used without any adverse event.
We are convinced that the risks are acceptable.