Improving executive functioning in patients with Mild Cognitive Impairment by transcranial alternate current brain stimulation

MCI is characterized by changes in cortical neural networks related to decline
in EF. Executive functioning (EF) refers to the set of cognitive functions
involved in controlling or guiding behaviour, involving among others attention,
working memory and inhibition, in addition to planning ability and mental
flexibility (i.e. being able to switch between tasks). MCI is a prodromal phase
of neurodegenerative diseases of aging. Approximately 27-49% of MCI patients
develop full AD within 30 months. This is however, not limited to AD, some
types of MCI develop in other forms of dementia.

In addition to the EF impairment, MCI patients have brain network changes
intermediate between healthy elderly and AD patients. This is why a treatment
that could improve the brain network function should be addressed also to MCI
patients. By improving EF in MCI patients, one might delay the onset of
neurodegenerative diseases. Working memory abilities, a critical component of
EF, have been shown to contribute significantly to functional status in MCI .
This affects the prognosis of MCI and AD. Furthermore, effective treatment can
be used to decrease the severity of symptoms in AD and other dementias. This
directly reflects on the everyday functioning of MCI patients .

The deficiencies in EF in MCI patients are coupled with compromised brain
functioning visible from electroencephalography (EEG). Particularly, decreased
power in the theta range (6-8Hz) of the EEG during working memory and cognitive
control seem to be specific for MCI patients who progress to AD. Brain
oscillations and fronto-parietal synchronization in the theta range are
associated with various aspects of EF. Therefore, improving the fronto-parietal
theta synchronization in patients with MCI has the potential to improve EF.

tACS affects brain function such as memory and EF in healthy adults by
targeting specific brain oscillations at specific frequencies. The tACS
delivered at a specific frequency affects the brain rhythms at that frequency.
This is called entrainment.
We will base our two experimental conditions of tACS stimulation on the study
by Polania et al. (2012) and the study by Vosskhul et al. (2015), respectively.

We hypothesize that synchronous tACS in the theta range will cause an
enhancement of fronto-parietal brain synchronization and improvement in EF of
MCI patients.

We aim to apply tACS in the theta range over the left frontal and parietal
areas of patients with amnestic MCI (aMCI) to improve their executive
functioning (EF). We will assess the effect of two types of tACS by
investigating brain synchronization, cognitive abilities and daily activities
of patients on several time points during one year after the treatment.

To investigate effectiveness of the tACS treatment and to find the most
effective stimulation type, three groups of amnestic MCI (aMCI) patients (n=90)
will randomly receive either tACS active treatment (two groups; n = 30 for each
active group) or a placebo (n=30), daily for two weeks. Active group 1 will
receivetACS at 6 Hz (protocol by Polania et colleagues (2012)). Active group 2
will receive tACS at the individual relevant frequency as used by Vosskuhl
(2015). Synchronous tACS (1mA peak-to-peak amplitude) will be delivered on the
frontal and parietal lobe symoultaneously (F3 and P3) while performing a
two-letter delayed task, which is a task suitable for patients with cognitive
problems and the digit span task (forward and backward condition.
We will assess the following at day 1 and month 12:
- EEG resting state (5 mins; for measuringsynchrony).
- N-back working memory task. This task will be different from the task used
during tACS stimulation. In stead of using letters, numbers will be used.
- Vienna Reaction time task (VRTT)
- The Mini Mental State Exam (MMSE)
- Instrumental activity of daily living (IADL) and functional activity
questionnaire (FAQ) (for daily activities).
- Face-name-associative memory test (FNAME)
- Neuropsychological evaluation (NPE) will consist of:
- 15-word memory test (immediate and delayed recall; 4
different versions).
- WAIS Digit Span test: Forward, Backward and arithmetic
- Trail making test
- Verbal fluency tasks (semantic and letter
fluency).
- Stroop test
- Digit span
- Symbol digit substitution test
- Amsterdamse korte termijn geheugentest (AKTG) -
short version
- Key search (BADS)
- Mild Behavioral Impairment Checklist (MBI-C)
Nederlandse versie (MBI-C-NL)

We will assess the following at day 11an month 1,
- EEG resting state (5 mins; for measuringsynchrony).
- N-back working memory task. This task will be different from the task used
during tACS stimulation. In stead of using letters, numbers will be used.
- Vienna Reaction time task (VRTT)
- Instrumental activity of daily living (IADL)
- Neuropsychological evaluation (NPE) will consist of:
- 15-word memory test (immediate and delayed recall; 4
different versions).
- WAIS Digit Span test: Forward, Backward and arithmetic
- Trail making test
- Verbal fluency tasks (semantic and letter
fluency).
- Stroop test
- Digit span
- Symbol digit substitution test
- Mild Behavioral Impairment Checklist (MBI-C)
Nederlandse versie (MBI-C-NL)
Salivary levels of lactoferrin will be collected at day 2.
Neuroimaging
We will use fMRI (day 2 and 11) to investigate brain network functioning during
working memory (n-back task, ~10 minutes) and resting state.Anatomical features
(used as cofounding variables) will be assessed using a T1 scan: diffusion
tensor imaging (DTI), magnetic transfer imaging (MTI) and Magnetic resonance
spectroscopy. MR-scans (including fMRI) will be made both at baseline and after
2 weeks of treatment.
EEG will be recorded for approximately 10 minutes. We aim to record a segment
of 5 minutes with minimum artifacts. This segment will be used for coherence
analysis. Coherence will be estimated using the weighted phase lag index which
has an advantage over other methods as not being affected by volume conductance
of independent sources, and increased power to detect changes in
phase-synchronization .
The outcomes on VRTT will be compared using repeated measures ANOVA with
factors: the condition (visual or auditory) and time of stimulus (pre or post).
If participants take part in the additional session, they will undergo a more
extensive EEG and psychological assessment including Cognitive Reserve Index
Questionnaire and the Behavioral dysexecutive syndrome inventory.

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Participants in the study will go through 13 session that will take place
across 1 year. The initial step will be NPE testing (70 minutes). If the
patients fulfill CI criteria, she/he will undergo the second step a
pre-stimulation an MRI scanning session (60 minutes). The same day patients
will undergo an EEG session (10 minutes recording and 20 minutes preparation
time, total 30 minutes). After the EEG, participants will fill perform
cognitive Vienna reaction time task (14 minutes). And eventually first tACS
session (18 minutes stimulation and 10 minutes preparation). On the third to
10th day, participants will undergo brain stimulation (tACS or sham tDCS). The
stimulation session will last 28 minutes (preparation: 10 minutes, stimulation:
18 minutes). On the 11th day, participants will undergo the brain stimulation
followed by brief EEG recording, VRTT, NPE and MRI. If patients express that
the second day or the tenth day last too long, we might split it in two days,
Further, we will offer participants a time to relax or have lunch in between
MRI and other measurements. This will be adjusted solely to decrease the burden
to patients as much as possible. Maximum 20 of 90 participants, that are not
MRI compatible, will not undergo the MRI sessions.
Further, we might offer participants, in case of too high burden of frequent
visits and if possible to research team, to deliver some tACS sessions at their
home. These issues were discussed with our expert by experience. It is
important to measure the post-stimulation EEG and the VRTT immediately after
the last stimulation thus the final tACS has to be coupled with the
post-stimulation VRTT and EEG. In addition, patients will come for follow up at
months 1 and 12. In addition, before and after the stimulation, patients will
fill in one questionnaire at their home - the
hybrid-computer-based-executive-function test which takes 55 minutes, and they
have to fill in TOPICS_MDS questionnaire that is complying with Memorabel grant
requirements.

The experiment will not involve more than minimal risks for the participants.
MRI is a standard brain imaging technique with no known negative effects on
health. The only risks are for subjects with cardiac pacemaker and metal
implants. These individuals will not be allowed to participate. In terms of
burden, MRI involves lying still in a confined environment during one hour. In
addition, during data acquisition, the MRI scanner makes a loud noise, and
although participants are provided with earplugs, the residual noise can be a
burden for some individuals. During the tACS procedure participants are exposed
to a very low electrical current of 2 mA. The use of tACS to date has not
resulted in adverse effects, apart from mild headache or a mild tingling
sensation underneath the electrodes. Finally, EEG involves a measurement of
brain currents and is not associated with any contraindication.
Salivary collection is quick and adds little extra burden to patients. In
addition, participants will be offered an optional additional session that will
take place before the first stimulation session and last for 2 hours.