Cholinergic potentiation improves
perceptual-cognitive training of healthy
young adults in three dimensional
multiple object tracking
Mira Chamoun1, Huppé-Gourgues Frédéric1, Isabelle Legault2, Pedro Rosa-Neto3, Daniela
Dumbrava4, Jocelyn Faubert2, Elvire Vaucher1*
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École d’optométrie, Université de Montréal, Canada, 2École d'optométrie, Université de Montréal,
Canada, 3McGill Centre for Studies in Aging, Canada, 4École d'optométrie, Université de Montréal,
Canada
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Submitted to Journal:
Frontiers in Human Neuroscience
Article type:
Original Research Article
In
Manuscript ID:
230044
Received on:
22 Sep 2016
Revised on:
27 Feb 2017
Frontiers website link:
www.frontiersin.org
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest
Author contribution statement
EV: Lab Director, contributed in elaborating the project, providing the material, analyzing the data and writing the paper
MC: Contributed in elaborating the project, testing the participants, analyzing the data and writing the paper
FHG: Contributed in analyzing the data and writing the paper
IL: Contributed in elaborating the project and analyzing the data
JF: Contributed in elaborating the project, providing the material, analyzing the data and writing the paper
PRN: Contributed in elaborating the project, providing the donepezil pills, writing the paper
DD: Contributed in the medical examination of the participants
Keywords
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Acetylcholine, Attention, 3D-multiple object tracking, Acetylcholinesterase (AChE) inhibitor, donepezil (Aricept), sensory training,
cognitive enhancement, Visual Perception
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Abstract
Word count:
203
A large body of literature supports cognitive enhancement as an effect of cholinergic potentiation. However, it remains elusive
whether pharmacological manipulations of cholinergic neurotransmission enhance complex visual processing in healthy individuals.
To test this hypothesis, we randomly administered either the cholinergic transmission enhancer donepezil (5 mg P.O.) or placebo
(lactose) to young adults (n = 17) 3 hours before each session of the 3D multiple object tracking (3D-MOT) task. This multi-focal
attention task evaluates perceptual-cognitive learning over five sessions conducted 7 days apart. A significant amount of learning
was observed in the donepezil group but not the placebo group in the fourth session. In the fifth session, this learning effect was
observed in both groups. Furthermore, preliminary results for a subgroup of participants (n = 9) 4–14 months later suggested the
cholinergic enhancement effect was long lasting. On the other hand, donepezil had no effect on basic visual processing as measured
by a motion and orientation discrimination task performed as an independent one-time, pre-post drug study without placebo
control (n = 10). The results support the construct that cholinergic enhancement facilitates the encoding of a highly demanding
perceptual-cognitive task although there were no significant drug effects on the performance levels compared to placebo.
Funding statement
This work was supported by: Canadian Institutes of Health Research (Grant number: MOP-111003, to EV) and Natural Sciences and
Engineering Research Council of Canada (Grant number: 238835-2011, to EV). MC received financial support from the School of
Optometry, Université de Montréal. We would like to thank the Centre for Interdisciplinary Research in Rehabilitation of Greater
Montreal for financial resources support
Ethics statements
(Authors are required to state the ethical considerations of their study in the manuscript, including for cases
where the study was exempt from ethical approval procedures)
Does the study presented in the manuscript involve human or animal subjects:
Yes
Please provide the complete ethics statement for your manuscript. Note that the statement will be directly added to the
manuscript file for peer-review, and should include the following information:
Full name of the ethics committee that approved the study
Consent procedure used for human participants or for animal owners
Any additional considerations of the study in cases where vulnerable populations were involved, for example minors, persons with
disabilities or endangered animal species
As per the Frontiers authors guidelines, you are required to use the following format for statements involving human subjects:
This study was carried out in accordance with the recommendations of 'name of guidelines, name of committee' with written
informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki.
The protocol was approved by the 'name of committee'.
For statements involving animal subjects, please use:
This study was carried out in accordance with the recommendations of 'name of guidelines, name of committee'. The protocol
was approved by the 'name of committee'.
If the study was exempt from one or more of the above requirements, please provide a statement with the reason for the
exemption(s).
Ensure that your statement is phrased in a complete way, with clear and concise sentences.
The procedures were in accordance with the Helsinki Declaration of 2013 and the ethical standards of the Comite d'ethique de la
recherche en sante, Universite; de Montreal, approval #12-084-CERES-P
Information and consent form
Donepezil effect on visual attention and perceptual learning in healthy young adults
Taking place at the school of Optometry of the University of Montreal
Laboratory of psychophysics and visual perception
3744, rue jean Brillant
Montreal, Quebec, H3T1P1 CANADA
Mira Chamoun
Ph.D student in Sciences de la vision
[email protected]
(514) 343-6162
RESEARCH COORDINATOR:
Isabelle Legault, Ph.D
[email protected]
(514)-343-6111 #8764
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RESEARCH DIRECTOR:
Elvire Vaucher, Ph.D., doctor in neuroscience
[email protected]
(514) 343-7537
RESEARCH CO-DIRECTOR:
Jocelyn Faubert, Ph. D., doctor in psychophysics
[email protected]
(514) 343-728
NEUROLOGIST ASSOCIATED TO THE PROJECT:
Dr Pedro Rosa Neto, M.D., Ph.D. Douglas hospital
(514) 766-2010
You are invited to participate in our research project studying the effect of the medication Aricept, usually used to treat
Alzheimer’s disease to improve memory and cognitive functions. In the present project, the medication Aricept is tested for its
capacity to improve the perceptual learning during visual training. Aricept is only made by Pfizer, but the company is not involved
in the project.
Before accepting to participate to this research project, please read carefully this consent form. It explains the objective, the
procedures, the risks, the benefits and the inconveniences of this study. It also provides coordinates of the key people to contact in
case you have any question or concern. This form may contain words you may not understand. Please feel free to ask all the
questions you might have and clarifications you might need.
1. Project description
The purpose of this project is to study the effect of stimulation of a certain type of neurons (cholinergic) of the brain on the visual
training and the perceptual learning. The cholinergic system stimulation is induced by administrating a medication, Aricept, 5mg.
The long-term goal is to improve, for re-adaptation purposes, the visual performance of people having a visual or attentional
deficit. The visual training and the perceptual learning will be tested in an attentional task consisting of visual tracking of moving
spheres in a 3 dimensions (3D) environment (sitting position). This study will count 34 participants randomized into two equal
groups: an Aricept administred group and a placebo-administred group - providing a control group. The placebo is a lactose pill
having no effect on the body. This study thus involves taking medication.
2. Nature of participation and duration of study
If you agree to participate in this study, you will have to be present at l’ecole d’optometrie de l’Universite; de Montreal, 3744, rue
Jean-Brillant, Montreal (Quebec), H3T 1P1, room 210-10, once a week for 5 consecutive weeks (one 1h-session and four 4h-sessions).
Each session is independent and there is a 5 to 7 days interval between each session, depending on your availability. To participate
in the study, you must have had a complete eye exam within one year prior to the study. Moreover, we will ask you a written
consent in order to have access to your visual examination medical file and this, only during the period of participation. Before
the study, you must have a general medical examination, to know your health state and make sure you do not have cardiac or
respiratory problems. This exam will be conducted by Dr Dumbrava. In addition, you will have to pass an electrocardiogram
(placement of electrodes on the chest), in the premises of the university, which will be then analyzed by a cardiologist. Before and
after each session your blood pressure and heartbeat will be monitored by a qualified person. Women should pass a urine
pregnancy test before each session to make sure they are not pregnant. During the first session, you will have to answer a few
questions and go through some visual tests to make sure you fit the participation criteria. Afterwards, you will perform an
exercise of target tracking in immersive virtual reality environment, called C.A.V.E. This environment consists of four screens
(one at the front, one on each side and one on the ground) on which images are projected. These screens form a cubic space of 8
feet in length, width and heights and are open at the rear.
During this exercise, you will be seated on a chair and wear 3D glasses. The object tracking exercise, called 3D-M.O.T., consists in
tracking four virtual spheres moving in a set of 8 identical spheres. This set of spheres is presented in a virtual cubic volume.
Before the movement of the spheres, 4 of them are indexed via changing color for a five seconds period in order to be identified
as the target. The 4 spheres return to their original color and the 8 spheres start moving within the restricted 3D virtual space.
You will have to maintain your attention on the appointed target and when the spheres stop moving, you will have to identify the
targets (the spheres that were initially indexed with change of color). The main task starts at a given speed, and if all four
spheres are not correctly identified, the next trial will be slower. If the four spheres are correctly identified, then the next trial
will be faster. Trials are repeated like this following a staircase procedure, and ultimately, a speed threshold is established. Your
speed threshold will be saved in a computer file. During the 4 other sessions you will perform the same exercise done in the first
session after ingesting the medication (Aricepte or placebo) 3h before the test. During the 3h wait you will have to stay in the
building and activities will be proposed for the waiting period. The study will be double-blind which means neither you nor the
person who passed the tests will know which group you belong to or what medicine you have been taken. Your group ‘’placebo’’ or
‘’medication’’ is predetermined randomly by the research director. The group membership will be revealed in case of emergency
(loss of consciousness, emergency of taking a medicine that is incompatible with the criteria of inclusion…).
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The testing and follow-up will be performed by Mira Chamoun who is currently a Ph.D student in Vision Sciences, Universite de
Montreal.
3. Conditions of participation and constraints
In order to participate in this study, it is essential to meet the following conditions:
1. You are aged between 20 and 35 years
2. You are in good health (you do not take drugs or natural products, you do not suffer from heart failure or arrhythmia, you do
not suffer from epilepsy, you do not suffer from chronic obstructive pulmonary disease (asthma), you do not suffer from
gastrointestinal disorders, you do not suffer fainting?
3. Your body mass index (BMI) is between 17 and 25
4. You do not suffer from visual impairment uncorrected by glasses or contact lenses
5. You have a good vision in 3D
You cannot take part of this study if:
1. You have already participated in a target tracking study
2. You suffer from ocular pathology
3. You have an attention problem
4. You smoke
5. You are pregnant or breast-feeding
6. You seek to procreate
7. You are lactose intolerant
We ask you to use a method of contraception throughout the study until 30 days after the last session. During the study, you
cannot drink grapefruit juice or syrup dextromethorphan (DM) as it is contraindicated with Aricept. In addition, you need to ask
your pharmacist each time you buy health products (nutritional supplements, vitamins, ...) to double check that they do not
interact with Aricept (show reporting card).
4. Risks, inconveniences and disconforts
You have to come to the test site five times for experimental sessions with an interval of about a week. Each test takes about 4
hours including waiting time (3h) between drug administration and experience.
Entering a virtual reality room can sometimes cause slight discomfort (dizziness, heart pain, slight loss of balance). These
symptoms have no long-term effect and stop as soon as you exit the virtual environment. To date, no side effects have been
reported following experiments in our virtual reality room.
Medication (5mg) or placebo is administered in a small dose. This dose has been used in other studies in which no side-effect has
been reported. The possible side-effects, which should not occur at the dose used in this study, are listed below:
Very Frequent (10%): Diarrhea, nausea, headaches.
Frequent (1% to 10%): cold, anorexia, hallucinations, agitation, dizziness, insomnia, vomiting, abdominal discomfort, skin rash and
itching, muscle cramps, urinary incontinence, fatigue, pain.
Infrequent (0,1% to 1%): convulsions, bradycardia, gastrointestinal bleeding, gastric and duodenal ulcers, increase of muscle enzyme
creatine kinase levels.
Rare (0,01% to 0,1%) : liver disease, atrioventricular block, sinoatrial block, extrapyramidal symptoms
All these effects are mild and are reversible after or during the drug effect (1 week).
It should be noted that an allergic reaction is possible. However, in case you feel any discomfort, the experiment will be stopped
immediately and a doctor on call will take care of you.
5. Advantages and benefits of the study
Although there is no direct benefit associated with your participation, you will contribute to the advancement of knowledge on the
improvement of visual perception. More specifically, your participation will help us determine if this medication associated with
this type of testing can improve the training and visual perceptual learning. This knowledge will benefit people who have
undergone visual trauma.
6. Free consent and freedom to withdraw
Your participation in this study is voluntary. You are free to refuse to participate. You can also withdraw from the study at any
time without giving any reason. You simply have to notify the research team by a simple verbal notice.
In case a participant withdraws from the study, its experimental data will be removed from our analyses and all data concerning
him will be destroyed.
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The lead researcher of the study may also decide to withdraw you from the study if:
• You are not able to respect the instructions given to you ;
• You experience severe symptoms related to the experimental environment;
• Following changes in your health conditions, your participation may expose you to a certain risk.
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7. Protection of Privacy
All data (including names) collected during the study will be kept confidential and will be used for research purposes only. They will
be destroyed after a period of seven years after the end of the project.
All of this information will be kept in a binder in the laboratory of Dr. Faubert at the School of Optometry. Access to the file is
restricted and accessible only to the student-researcher, Mira Chamoun, her research supervisor, Isabelle Legault, laboratory
directors Elvire Vaucher and Jocelyn Faubert. Research records will also be available to any person authorized by the Committee
of Ethics and Research of the University of Montreal for verification. The pharmaceutical company will not have access to any data
from participants. For reasons of confidentiality, a number will be assigned during the transcription and analysis of data. No
names or identifiable information will be associated with the data obtained during the experiment. Therefore the data are coded,
each participant may be identified but his identity will not be disclosed in the literature. Each participant can see his file to take
note of the research results or to modify certain information.
8. Compensation and Indemnity
This project is financed by funds of research.
A 10 $ the first session and 40 $ / 4h-session will be awarded as compensation for your time and traveling. In case of withdrawal
from the study, the total amount will be prorated for your participation. In case a session is interrupted by you or the responsible
of the project the amount given for the session would still be delivered.
If you suffer any damages whatsoever resulting from the administration of a drug or other procedure related to the study, you
will receive all the care and services required by your state of health, without any cost from your behalf.
9. Results diffusion
At the end of the study, the results may be published in scientific journals. If you make a request, information on the progress or
outcome of the research project will be sent by email.
10. Contacts
If you have any questions regarding the scientific aspects of the research project, please contact: Mira Chamoun, studentresearcher via telephone at (514)-343-6162 or email [email protected].
If you wish to withdraw from the study, please contact: Isabelle Legault, research coordinator via telephone at 514-343-6111 poste
8764 or email
[email protected].
If you are experiencing health problems related to medication after completion of the study, please contact: Dr Rosa Neto at
514-766-2010
For information on ethical conditions under which unfolds your participation in this project, please contact the coordinator of the
Comit d’ethique de la recherche en sante (CERES) via email: [email protected] or telephone at (514) 343‐6111 poste 2604.
For more information on your rights as a participant, you can consult the Participant Portal of the University of Montreal at the
following address:
http://recherche.umontreal.ca/participants.
Any complaint regarding this research may be addressed to the Ombudsman of the University of Montreal at (514) 343‐2100 or via
e-mail [email protected]. The Ombudsman accepts collect calls. They speaks french and english and take calls from 9h to
17h.
11. Monitoring ethical aspects of the research project
The Committee of Research Ethics of Health Sciences approved this research project and monitors it. In addition, it will consider
any changes to the consent form and the research protocol.
12. Clinical Trials Registry
Under Canadian and U.S. regulatory requirements, a description of this clinical trial will be recorded in an electronic register
available online at the following address:
http://www.clinicaltrials.gov.
No information about you is included on this website. At most, some research results will be presented. You can consult the
register at any time. The identification number of this clinical trial is: NCT01738295, Donepezil effect on visual focus and training.
Note that the site ClinicalTrials.gov is in english only.
Donepezil effect on visual attention and training
Consent
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I have read the information and consent form. I acknowledge that I have been explained the project and answered to my questions
to my satisfaction and that I was given the time to make a decision. I agree to participate in this research project to the
conditions set forth. A signed and dated copy of the information and consent form will be given to me.
By signing this form, I do not give up any of my rights nor release the researcher’s legal or professional responsibility.
In
________________________________________
Name and signature of participant
___________________________
Date
I certify that the terms of the information and consent form has been explained to the participant and that all the questions has
been answered and that we made it clear he remains free to terminate his participation, and without any negative consequences.
I agree with the research team to respect what was explained in the information and consent form and give a signed copy to the
participant.
________________________________________
___________________________
Name and signature of the lead researcher
Date
I explained to the participant the terms of the information and consent form and I answered the questions that he asked.
________________________________________
___________________________
Name and signature of the person getting the consent Date
n/a
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Cholinergic potentiation improves perceptual-cognitive training of
healthy young adults in three dimensional multiple object tracking
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Mira Chamouna, Frédéric Huppé-Gourguesa, Isabelle Legaultb, Pedro Rosa-Netoc,
Daniela Dumbravad, Jocelyn Faubertb and Elvire Vauchera*
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Laboratoire de neurobiologie de la cognition visuelle, École d'optométrie, Université de
Montréal, Montréal, Québec, Canada
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Laboratoire de Psychophysique et de Perception Visuelle, École d'optométrie, Université
de Montréal, Montréal, Québec, Canada
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McGill Centre for Studies in Aging, Montréal, Québec, Canada
Laboratoire des neurosciences de la vision, École d'optométrie, Université de Montréal,
Montréal, Québec, Canada
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*
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Elvire Vaucher
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[email protected]
Corresponding author:
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Keywords: 3D-multiple object tracking; acetylcholine; acetylcholinesterase inhibitor;
attention; cognitive enhancer; donepezil; sensory training; visual learning.
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Abstract
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A large body of literature supports cognitive enhancement as an effect of cholinergic
potentiation. However, it remains elusive whether pharmacological manipulations of
cholinergic neurotransmission enhance complex visual processing in healthy individuals.
To test this hypothesis, we randomly administered either the cholinergic transmission
enhancer donepezil (5 mg P.O.) or placebo (lactose) to young adults (n = 17) 3 hours
before each session of the 3D multiple object tracking (3D-MOT) task. This multi-focal
attention task evaluates perceptual-cognitive learning over five sessions conducted 7 days
apart. A significant amount of learning was observed in the donepezil group but not the
placebo group in the fourth session. In the fifth session, this learning effect was observed
in both groups. Furthermore, preliminary results for a subgroup of participants (n = 9) 4–
14 months later suggested the cholinergic enhancement effect was long lasting. On the
other hand, donepezil had no effect on basic visual processing as measured by a motion
and orientation discrimination task performed as an independent one-time, pre-post drug
study without placebo control (n = 10). The results support the construct that cholinergic
enhancement facilitates the encoding of a highly demanding perceptual-cognitive task
although there were no significant drug effects on the performance levels compared to
placebo.
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1. Introduction
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Sensory training has recently emerged as a promising field in the improvement of
perception and cognition (Seitz, 2010). The enhancement of perception and cognition
would alleviate sensory shift due to aging or sensory diseases or simply improve daily
and sport-related performance. Various training procedures, such as the repetitive
presentation of a specific set of stimuli, have been proposed for computer, tablet or 3D
environment (Faubert and Sidebottom, 2012; Kim et al., 2015). Moreover, recent
evidence shows that stimulation of the neuromodulatory brain systems may potentiate
perceptual learning (long-term improvement of perception induced by sensory training)
(Rokem and Silver, 2010; Kang et al., 2015).
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It has been shown that the cholinergic system improves the efficiency of cortical
processing of visual stimuli. Acetylcholine (ACh) optimizes the gain of pyramidal cells
in response to sensory stimuli and reduces sensory noise in humans (Moran et al., 2013).
This contributes to visual attention and learning processes (Yu and Dayan, 2002; Sarter et
al., 2005; Hasselmo, 2006; Herrero et al., 2008). This also increases both sensory
precision and the strength of the representation of stimuli. Moreover, in cases of visual
training it has been shown that ACh aids cortical processing, improving both its speed
and efficiency (Ricciardi et al., 2013). Therefore, combining visual training of a specific
stimulus with cholinergic potentiation, namely electrical or pharmacological stimulation
of the cholinergic system, induces enhancement of visual perceptual learning (Rokem and
Silver, 2010; Beer et al., 2013; Kang et al., 2014a; Kang et al., 2014b).
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Animal studies investigating electrical stimulation of cholinergic neurons paired
with visual stimulation demonstrate a strong effect on cortical responses in the primary
visual cortex (V1), cortical plasticity and visual performance (Goard and Dan, 2009;
Kang and Vaucher, 2009; Bhattacharyya et al., 2013; Kang et al., 2014a). However, there
are certain issues with implementing this electrical stimulation technique in a human
clinical setting. A worthwhile alternative to this cholinergic enhancement is the use of
acetylcholinesterase inhibitors (AChEIs), drugs used in Alzheimer’s disease to block the
breakdown of ACh at the synapse and prolong its action. Accordingly, AChEIs improve
performance of people in visual attention tasks (Demeter and Sarter, 2013) and
behavioral tasks that require voluntary attention (Bentley et al., 2004). In rats, donepezil
(DPZ), the AChEI most universally used for the clinical treatment of Alzheimer’s
disease, has been demonstrated to increase the amplitude of visually evoked potentials
when administered during a visual training period (Chamoun et al., 2016). Donepezil also
improves performance in diverse cognitive behavioral tasks (Wise et al., 2007; Cutuli et
al., 2008; Soma et al., 2013). Pharmacological therapy with AChEIs combined with a
behavioral intervention is therefore a potentially interesting therapeutic approach to
enhancing perceptual-cognitive visual performance in humans.
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Therefore, we used the 3D-multiple object tracking (3D-MOT) task to evaluate
the effect of cholinergic potentiation on the perceptual-cognitive capacity of healthy
young adults. In the 3D-MOT test, tracking of several targets among distractors is done in
a three-dimensional environment to increase stereoscopy and demands on attention
tracking (Parsons et al., 2016). 3D-MOT thus entails multi-focal attention and requires a
high level of processing (Pylyshyn and Storm, 1988; Cavanagh and Alvarez, 2005;
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Faubert and Sidebottom, 2012; Legault and Faubert, 2012) which encompasses the
capacity of the brain to ignore distractors and noise. The task is performed weekly over
five weeks (a 30-minute session once a week). A significant increase in tracking
performance is usually measured during the fifth session. 3D-MOT is usually used to
improve vision in athletes (Faubert, 2013) and aging persons (Legault and Faubert, 2012;
Legault et al., 2013). Since 3D-MOT requires a high attentional load and induces
perceptual and cognitive learning, it falls into the range of possible cholinergic
involvement and thus should be sensitive to cholinergic potentiation.
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We therefore administered DPZ during 3D-MOT perceptual-cognitive training
and calculated speed thresholds for tracking moving balls. Moreover, the acute effect of
DPZ on basic visual processing was further evaluated with orientation and visual motion
discrimination (Hutchinson and Ledgeway, 2006; Allard and Faubert, 2013). We
demonstrated that the tracking ability was improved at an earlier time point in healthy
young adults taking DPZ, which could be related to attention and efficiency of cortical
processing. Moreover, preliminary data suggest a long-lasting effect on performance.
This study supports the possibility of using DPZ to improve training of perceptualcognitive function in humans.
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2. Materials and Methods
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2.1 General methods
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2.1.1 Participants
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Twenty healthy young adults participated in the study. Two participants were excluded
due to a time conflict, and one was excluded due to unsatisfactory baseline performance.
The participants (10 men, 7 women; age: 23 ± 1 years; BMI: 23 ± 1 kg/m2, mean ± SEM,
see Table 1) were randomly assigned to either the DPZ (n = 9) or placebo (lactose pills, n
= 8) group. Only some participants were available to perform long-term 3D-MOT task
testing (Table 1). Ten participants were independently tested with motion or orientation
discrimination tasks (more than 6 months after the 3D-MOT task) using a cross-over
design experiment (see Table 1 and below). The sample size (n = 10 per group) was
determined based on previous studies on the 3D-MOT task (Legault et al., 2013) and
visual perception tasks (Allard and Faubert, 2013).
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All participants were naive to the purpose of the experiment and met the inclusion and
exclusion criteria (Table 2): normal or corrected-to-normal vision, no history of
neurological, psychiatric or toxicological problems, no history of smoking, etc. Body
mass index measurements had to be 17–26 kg/m2 in order to ascertain a similar
distribution of the drug across subjects. A standard clinical and neurological examination,
a stereoacuity test and an ECG recording were performed before the beginning of the
experiment. All participants completed a written informed consent form prior to the
beginning of the experiment. All data were collected and kept secured in the laboratory of
Drs. Vaucher and Faubert at the School of Optometry. The participants were enrolled by
the student researcher, Mira Chamoun, and their random allocation sequence was carried
out by Elvire Vaucher by assigning drug/placebo in numbered containers. Numbers were
assigned to participants in order of participation. Subjects received financial
compensation to cover travel expenses and time spent participating in the experiment.
The procedures were in accordance with the Helsinki Declaration of 2013 and the ethical
standards of the Comité d’éthique de la recherche en santé, Université de Montréal,
approval #12-084-CERES-P. The study was registered on ClinicalTrials.gov
(NCT01738295).
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2.1.2 Donepezil Pharmacological Enhancement
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DPZ is a reversible, non-competitive, highly selective AChEI with a half-life of 80 hours
and a peak plasma level of 4.1 ± 1.5 hours after intake (Rogers and Friedhoff, 1998). The
5 mg dose was selected because it is the lowest prescribed dose which induces beneficial
cognitive effects with very low adverse reaction incidence (Prvulovic and Schneider,
2014). This dose has been shown to be effective in improving visual attention and neural
plasticity in young adults (Rokem et al., 2010; Rokem and Silver, 2010). Three hours
before each session, subjects were administered one capsule containing either 5 mg DPZ
(ARICEPT®, Pfizer, Canada) or lactose placebo with water (Rokem and Silver, 2010).
The experimenter and subjects were naive to the experimental conditions. We used
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commercially available DPZ tablets (ARICEPT®, Pfizer, Canada) but this company has
no financial interest in this study.
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2.2 Experiment 1: 3D-Multiple Object Tracking
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The goal of this experiment was to determine if acute administration of DPZ at each
weekly session of the 3D-MOT task over 5 consecutive sessions could improve the
tracking of 4 objects either in terms of performance threshold or learning rate. An
additional test of the 3D-MOT task was carried out with the available participants 4–14
months after the end of training without drug intake (n = 5, DPZ group; n = 4, control
group, 9 participants from the original 17, see Table 1) to assess the preliminary results of
the long-lasting effect of cholinergic enhancement on this perceptual-cognitive task.
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2.2.1 Experimental design
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All subjects were tested on the 3D-MOT task once a week for five consecutive weeks.
The first week was used as a baseline measurement and was done without administering
the drug or placebo. This was a double-blind placebo controlled intervention. The study
drug or placebo was administered P.O. 3 hours before the testing for the next four weeks.
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2.2.2 Procedure
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The task consisted of 8 yellow spheres projected in the Cave Automatic Virtual
Environment (CAVE). The CAVE is a fully immersive virtual environment consisting of
an 8 x 8 x 8 foot room that includes three canvas walls (one frontal and two lateral walls)
and an epoxy floor that serve as the surface for image projection (Fig. 1A). Each
participant sat 177 cm from the central wall of the CAVE with eye height set at 160 cm
from the ground. They were asked to wear stereoscopic goggles to visualize the 3Denvironment and to fixate on a point located straight ahead of them. Four of the balls
turned orange for identification. Then all spheres turned back to yellow and followed a
linear trajectory with a selected speed. The spheres moved in a 3D-volume space,
sometimes bouncing off of or occluding one another or bouncing off the virtual wall (Fig.
1A). This movement activity lasted 8 seconds and then stopped. Next, participants had to
identify the target spheres. They received feedback as to their correct or incorrect
response. The next speed was determined using a 1-up-1-down staircase procedure
(Levitt, 1971; Legault et al., 2013). The staircase was interrupted after 8 reversals. The
speed thresholds were established from the mean of the last 4 staircase reversals. Each
testing session consisted of 3 repetitions of the same block, each of which lasted
approximately 10 minutes.
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As previously described (Legault et al., 2013), four high-resolution projectors were
synchronized and the image was updated in real-time to maintain the observer’s true
viewing perspective (i.e., no false parallax). A magnetic motion tracker system (Flock-ofBirds) was used to measure head position, which was used to correct the viewing
perspective of the observer in real-time. The CAVE was under the control of a SGI
ONYX 3200 computer (two Infinite Reality 2 graphic cards), which produced a
stereoscopic environment. The stereoscopy was generated with Crystal Eyes 2 active
shutter glasses synchronized at 96 Hz (48 Hz per eye). Before testing, subjects were
familiarized with the virtual environment and stimuli.
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2.3 Experiment 2: Orientation and Motion Visual Perception
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The goal of this experiment was to test whether DPZ alters basic visual processing, tested
in a motion and orientation discrimination task. This task was tested independently from
the 3D-MOT task (at least 6 months after the last drug intake).
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2.3.1 Experimental Design
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Ten healthy young adults (6 men, 4 women; age: 24 ± 1 years; BMI: 23 ± 1 kg/m2; mean
± SEM, 9 participants from the original 17 and 1 new participant; see Table 1) took part
in a pre-post drug study without placebo control. All subjects were tested on the
orientation and motion visual perception task once before and 3 hours after receiving
DPZ at the peak DPZ plasma concentration. However, the subjects were told that they
could receive either placebo or DPZ.
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The task was performed as previously designed and validated (Allard and Faubert, 2013).
The observer was positioned in a dark room 114 cm from the display and familiarized
with the task. A trial consisted of identifying the motion or the orientation of a sine-wave
grating of 0.3 CPD, by pushing arrow keys on a keyboard (Fig. 2A). A feedback sound
indicated whether the response was correct or incorrect. Motion stimuli were composed
of either a luminance or a contrast modulation of a sine-wave grating drifting in a random
direction (either left or right). All modulations were vertically oriented. First-order
motion stimulus (luminance modulation) drifted at 15 Hz and the second-order motion
stimulus (contrast modulation) at 2 Hz. The orientation task was a horizontal or vertical
display of the sine-wave grating. The contrast or luminance modulation was controlled by
a 2-down-1-up staircase procedure (Levitt, 1971; Allard and Faubert, 2008a) and the
luminance or contrast threshold obtained for the stimulus discrimination was estimated
for the last 6 reversals of the staircase. The testing consisted of 3 repetitions of 4 blocks
of trials; each block presented one of the 4 conditions (first- and second-order motion and
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first-and second order orientation) in a randomized manner. The testing duration was
approximately 30 minutes.
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2.3.3 Experimental Setting
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Stimuli were presented on a gamma-linearized 22’’ Formac ProNitron 22800 CRT
monitor with a mean luminance of 42 cd/m2 and a refresh rate set at 120 Hz. The spatial
window was circular with a diameter of 4 degrees. The presentation time was 500 ms.
The noisy-bit method (Allard and Faubert, 2008b) was implemented to improve the
screen luminance resolution and make it perceptually equivalent to a continuous
resolution. The noise was dynamic, spatiotemporally extended and presented over the
entire screen and visible at all times. The noise was binary and elements were 2 X 2
pixels wide (i.e., 0.028 X 0.028 degrees).
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2.4 Statistical Analysis
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For the motion and orientation visual perception tests, mean luminance/contrast threshold
were analyzed using a Wilcoxon test between the testings performed before and after the
intake of DPZ. The progression of the speed thresholds in the MOT task was analyzed in
each group separately using a Friedman test with Bonferroni correction (p < 0.01) for
multiple comparisons of speed threshold values between the baseline (Week 1) and the
training weeks (Weeks 2–5). An additional comparison was conducted to examine the
difference in performance between both groups (control and DPZ) using the KruskalWallis test to compare speed thresholds at each time point (Weeks 1–5). Long-term
testing of the 3D-MOT speed threshold was compared to the speed threshold of the first
week (baseline) from the returning participants using a Wilcoxon test. Statistical analyses
were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA).
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3. Results
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3.1 Donepezil effect on 3D-MOT training
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The 3D-MOT task is a training task conducted over 5 consecutive weeks during which
participants gradually improve their tracking performance. The subjects taking DPZ were
able to successfully track 4 balls with significantly greater speed as early as the fourth
session (p = 0.003) compared to their baseline values (measured during the first session).
This result was maintained in the fifth session (p = 0.001) (Fig. 1). In contrast, the control
group only showed a significant improvement in speed threshold during the fifth training
session (p = 0.002) (Fig. 1). However, the speed threshold for which the subjects were
able to track balls was not significantly different between the DPZ and control group at
any time point (Kruskal-Wallis test, p > 0.05) although percentage of change from
baseline was 20 to 50% higher for the DPZ group compared to the placebo group for each
session after week 3.
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3.2 Donepezil Effect on the 3D-MOT Task is Long-lasting
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Performance of the 3D-MOT task was also measured 4–14 months following the last
testing session depending on participant availability (Fig. 1C, D). The average amount of
time between the last training session and the retesting session was not significantly
different between the two groups (Kruskal-Wallis, p = 0.711). A significant increase in
the speed threshold (86 %) obtained by the initial DPZ group was observed at this late
time point compared to baseline values (Week 1) (Wilcoxon test, p = 0.043). The control
group maintained good tracking skills but the increase in speed threshold (45 %)
compared to baseline values was not significant at that point (Wilcoxon test, p = 0.068).
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3.4 Acute administration of donepezil does not affect first- and second-order stimuli
discrimination
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To evaluate the acute effect of DPZ on basic visual processing, motion and orientation
discrimination abilities were tested before and 3 hours after DPZ administration. The
motion discrimination threshold was not affected by DPZ either in terms of first-order
stimuli (p = 0.878) or second-order stimuli (p = 0.878) (Fig. 2B, C). Additionally,
orientation discrimination was not affected by DPZ for either first-order stimuli (p =
0.515) or second-order stimuli (p = 0.386) (Fig. 2B, C). Together these results suggest
that acute cholinergic potentiation does not influence basic visual processing of
orientation and motion. The fact that no difference was observed for both levels of
processing might be explained by the lack of repetitive training/DPZ administration that
could not induce an optimal recruitment of cholinergic neurons or by an optimal
performance of the young subjects, which might not be further increased.
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4. Discussion
This study demonstrates that an increase in cholinergic transmission by the
acetylcholinesterase inhibitor, DPZ, has no significant effect on the tracking skills in the
3D-MOT task compared to placebo but may improve the learning in this 5-week
perceptual-cognitive training procedure (1 session / week). In addition, preliminary
results suggest that the training effect was maintained after 4–14 months in the DPZ
group but not in the control group. This long-term result is preliminary, due to the small
sample of returning participants. The basic visual discrimination of first- or second-order
stimuli did not seem to be affected by cholinergic potentiation as measured in an
additional one-time, pre-post drug study without placebo control. Together, these results
suggest the role of the cholinergic system in fine-tuning complex visual perceptualcognitive processing. The discussion emphasizes how this DPZ effect might be due to the
role of ACh in attentional processes, optimization of visual efficiency (refining of cortical
circuitry and increase in sustained neural firing), improvement of the signal/noise ratio,
repetitive training, or all these effects combined.
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4.1 Cholinergic enhancement improves training but not performance in a multifocal attention task in healthy young adults
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The present results showed that DPZ facilitates the learning in a 5-week multi-focal
attention 3D-MOT training procedure. The overall maximum performance measured at
the fifth session was however not significantly improved by DPZ administration,
suggesting a learning effect rather than an improvement of performance per se. This
learning effect could be due to a potentiation of the attentional capacities by increased
brain concentrations of ACh. This result is in line with previous studies showing that
ACh is involved in visual attention processes in primates (Voytko et al., 1994; Bentley et
al., 2004; Herrero et al., 2008) and that DPZ potentiates performance in attentional tasks
(Rokem et al., 2010). As well, the cholinergic enhancement by physostigmine (another
cholinesterase inhibitor) potentiates selective attention by improving selectivity to the
relevant stimuli (Furey et al., 2000; Ricciardi et al., 2009). In the 3D-MOT task, both
selective and divided attention are involved (Cavanagh and Alvarez, 2005; Doran and
Hoffman, 2010) and could be potentiated by a higher ACh concentration.
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The learning effect of DPZ on 3D-MOT training could also be due to a refinement of the
cortical circuitry sustaining the accomplishment of the task. 3D-MOT training increases
by itself attention, working memory and visual information processing speed. Moreover,
3D-MOT training induces changes in resting-state functional brain imaging and
electroencephalography, more specifically a decrease in the theta, alpha and gamma
frequencies in the frontal lobe and increased gamma frequency over the occipital lobes
(Parsons et al., 2016). It has been established that cholinergic activity during top-down
attention processes also influences interactions between the different brain areas
(Golmayo et al., 2003; Nelson et al., 2005). For instance, the improvement in working
memory performance following a steady-state infusion of the AChEI physostigmine was
accompanied by increased activity in the visual cortex associated with perceptual
processing, whereas activity in the prefrontal cortex was decreased, suggesting a
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reduction of attentional load to perform the same task (Furey et al., 2000). ACh also plays
a role in reducing the spatial spread of visual responses in early visual cortex tested in
fMRI (Silver et al., 2008). Given that 3D-MOT is a task that requires higher levels of
processing (Faubert and Sidebottom, 2012) and involves multiple brain areas (Culham et
al., 1998; Jovicich et al., 2001), coupling this task with cholinergic enhancement benefits
from the role of the cholinergic system in increasing the activation of the sensory cortex
and the refinement of processing. Improvement of the 3D-MOT performance by regional
activation has also been shown by transcranial current brain stimulation of certain
structures (anterior intraparietal sulcus, for example) in the visual pathway (Blumberg et
al., 2015).
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3D-MOT performance usually improves during training because of specific perceptualcognitive learning activity (Makovski et al., 2008). Given the role of ACh in learning,
pairing visual training with ACh enhancement may modulate the tuning of the neurons
for the trained stimuli (Rokem and Silver, 2010). In fact, studies in rats and humans have
shown the role of cholinergic enhancement of visual training on the potentiation of visual
capacities such as visual cortical responsiveness (Kang et al., 2014a; Chamoun et al.,
2016), contrast sensitivity (Soma et al., 2013; Boucart et al., 2015), motion direction
discrimination (Rokem and Silver, 2010) and texture discrimination (Beer et al., 2013). In
addition, given the role of the cholinergic system in attention and the role of attention in
perceptual learning (Ahissar and Hochstein, 1993), pairing visual training with ACh
enhancement may fine-tune the allocation of attention in this multi-focal attention task.
Therefore, perceptual-cognitive learning combined with DPZ administration might
optimize multi-focal tracking skills. The lack of effect of DPZ on the absolute
performance value could be indicative of a ceiling effect due to high performance and
cholinergic activity in young healthy subjects preventing further improvement of
performance.
An additional role of cholinergic potentiation in faster improvement of tracking skill of
participants is the possible modulation of the signal-to-noise ratio, thus making relevant
stimuli sharper. Some studies demonstrate that ACh can increase the processing of
relevant stimuli and suppress the processing of irrelevant input in a top-down attention
task. Human studies show that ACh allows a clearer perceptual representation of the
target by reducing background noise (Furey et al., 2000; Ricciardi et al., 2009). In rats,
cholinergic enhancement is associated with an improvement in the signal-to-noise ratio
therefore enhancing the rat’s response to a visual stimulus (Kang et al., 2014a).
Therefore, administering DPZ could have had an effect in reducing the noise level,
allowing the participants to have a clearer representation of the targets among the
distractors.
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4.2 The Cholinergic Enhancement Effect is Long-lasting
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The present study suggests that cholinergic enhancement has a long-lasting effect on
tracking performance. However, the long-term effect was tested on a smaller sample of
participants (n = 9) and further studies need to be conducted to verify such an effect. This
lasting effect would correspond with previous studies showing that an improvement in
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visual learning after training on a motion task lasts for months after the training (Ball and
Sekuler, 1982). However, the cholinergic enhancement doubled the amount of learning
compared to the control subjects at this time point, suggesting that the cholinergic effect
on visual learning and consolidation of the learning or recall mechanism (Zaninotto et al.,
2009) amplifies retention of performance skills. Likewise, in a previous study,
participants were trained on a texture discrimination task and were given an ACh agonist
(nicotine) at the end of the training session, indicating an effect of ACh on consolidation
processes (Beer et al., 2013). The present results indicate that an effect of AChEI on the
consolidation of learning of a trained task is possible. In animal models, long-term
potentiation-like effects of the cholinergic system have been observed on visual evoked
potentials after basal forebrain stimulation (Kang et al., 2014a), suggesting the formation
of memory traces in the visual cortex. Together these findings suggest a role of
cholinergic enhancement in the encoding and long-term perceptual-cognitive learning
processes following visual training.
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4.3 Limitation of the study
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This study was conducted with a relatively small sample of participants, reducing the
power of the statistical analysis. While this sample size is regularly used in corresponding
studies, we obviously need a greater sample size to more thoroughly assess possible
effects of DPZ on the performance level in the 3D-MOT task. Also, the long-term data
are for a smaller number of returning participants and should be further confirmed.
Further experiments will also be required to isolate the transfer effects of this cholinergic
potentiation on attention or perception. However, it is known that 3D-MOT training over
5 weeks can enhance cognition and changes in resting-state neuroelectric brain function
(Parsons et al., 2016).
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5. Conclusion
In conclusion, repetitive DPZ administration during perceptual-cognitive training led to
an earlier improvement of tracking ability and to a potential long-lasting effect. We
believe that this effect is due to a combination of the effect of ACh on attention,
perception and fine tuning of visual processing. These results suggest the importance of
boosting the cholinergic system in practicing visual tasks to enhance plastic changes and
efficacy of visual processing and memory traces. This effect would help in improving
rehabilitation strategies to help visually impaired people recover vision capacity.
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6. Funding and Disclosure
Grant sponsor: Canadian Institutes of Health Research; Grant number: MOP-111003, EV.
Natural Sciences and Engineering Research Council of Canada; Grant number: 2388352011, EV. MC received financial support from the School of Optometry, Université de
Montréal. We would like to thank the Centre for Interdisciplinary Research in
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Rehabilitation of Greater Montreal for financial resource support. JF is a Scientific
Officer for CogniSens, Inc. the producer of the commercial version of the 3D-MOT
system used in this study. In this capacity, he holds shares in the company. The other
authors declare no conflict of interest for this research. Aricept® is made by Pfizer, but
the company was not involved in the project.
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7. Acknowledgements
We are profoundly grateful to Maxence Lambert, O.D, MSc for her contribution in
setting up the study, Jean-Claude Piponnier, PhD for his technical help for the first- and
second-order visual perception task and Julie Lamoureux for her help with the statistical
analyses.
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8. Author contributions
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EV: Lab Director; contributed by designing the project, providing the material, analyzing
the data and writing the paper
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MC: Contributed by designing the project, testing the participants, analyzing the data and
writing the paper
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FHG: Contributed by analyzing the data and writing the paper
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IL: Contributed by designing the project and analyzing the data
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JF: Contributed by designing the project, providing the 3D-MOT and the Orientation and
Motion Visual Perception techniques and equipment, analyzing the data and writing the
paper
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PRN: Contributed by designing the project, providing the donepezil pills and writing the
paper
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DD: Contributed by performing the medical examination of the participants
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Tables
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Table 1. Demographic data: participant characteristics and involvement in the 3D-MOT
task and basic visual discrimination tasks
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Participant
n
Age
years
Height
cm
Weight
kg
BMI
kg/m2
MOT
17
23 ± 1 (20-31)
173 ± 3
(157-193)
69 ± 3
(47-95)
22 ± 1
(19-26)
DPZ group
9
22 ± 1 (20-26)
Placebo
8
24 ± 1 (20-31)
176 ± 3
(167-193)
169 ± 4
(157-192)
71 ± 4
(56-90)
67 ± 6
(47-95)
MOT, long-term
9
24 ± 1 (20-31)
173 ± 3
(159-193)
70 ± 4
(50-90)
23 ± 1 (19-25)
Visual
discrimination
10
23 ± 1 (20-27)
174 ± 2
(167-193)
69 ± 3
(68-90)
23 ± 1 (19-25)
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23 ± 1 (19-25)
Values represent the mean ± SEM (range) of participants in the MOT task, long-term
MOT testing and basic motion and orientation discrimination tasks (Visual
discrimination). Only a subset of participants could participate in the long-term MOT
retesting and visual discrimination task. BMI: body mass index; MOT: multiple object
tracking.
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593
22 ± 1 (19-26)
Table 2. Inclusion and exclusion criteria
Inclusion Criteria
Exclusion Criteria
Aged 20-35
Previous MOT task participant
Good health
Attention deficit
Body mass index between 17 and 26
Smoker
No visual impairment or ocular
pathology not corrected by glasses or
contact lenses
Pregnant, breast feeding or
planning a pregnancy
Good 3D vision
Lactose intolerance
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Figure captions
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Figure 1. 3D-multiple object tracking task: comparison of tracking performance in
the donepezil and placebo group. A) Example of the 3D-multiple object tracking task
(3D-MOT): 8 yellow spheres are randomly positioned in a virtual 3D environment; 4
randomly selected spheres turn orange for identification of the spheres to track (targets);
then all spheres turn back to yellow and move following a random linear trajectory
(arrows represent initial movement) at a defined speed; the spheres stop, are numbered
and the participant identifies the targets (orange border); finally, the targets turn orange
for correct feedback; the targets turn yellow with a red border for a wrong answer and the
targets turn light orange for a right answer not identified. The trial is then repeated,
changing the speed of the movement of the spheres using a 1-up-1-down staircase
procedure. The speed threshold for which the subjects are able to track balls is calculated
from the mean of the last 4 reversals of the staircase. B) Tracking performance in terms
of speed threshold (cm/s) for each participant every testing week (Weeks 1–5) in the
control group (blue-shaded squares) and donepezil group (purple-shaded circles). The
mean of the speed threshold (grey bar) is given. C) Speed threshold (percent change from
baseline) for tracking performance of subjects every testing week and during long-term
testing (4–14 months after the initial training) for the control group (in blue) and the
donepezil group (in purple). D) The significance table represents (a) the statistical
comparison of the mean speed threshold for each group using Friedman’s test with
Bonferroni correction (upper panel). Note that the donepezil group significantly
improved their performance (significant difference in speed threshold compared to
baseline value) at Weeks 4 and 5, while the control group only reached this level of
improvement at Week 5; (b) the statistical comparison of the mean speed threshold of
long-term testing to baseline values using the Wilcoxon test. There was a significant
sustained improvement in the speed threshold in the donepezil group but not in the
control group.
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Figure 2. Motion and orientation discrimination: acute effect of a one-time
administration of donepezil. A) Representation of the basic visual perception tasks of
motion (upper panel) and orientation (lower panel) discrimination of the stimulus. The
stimulus is a sine-wave grating of 0.3 cycles per degree modulated by discrete variations
of luminance, first-order luminance defined stimulus (left panel) or contrast, second–
order contrast defined stimulus (right panel). Average Michelson contrast thresholds are
shown for luminance-defined stimulus (B) for the discrimination of motion (left) or
orientation (right) before (open bar) and 3 hours after (black bar) donepezil intake, and
for the contrast-defined stimulus (C) for the discrimination of motion (left) or orientation
(right) before (open bar) and 3 hours after (black bar) donepezil intake. For both the
motion and the orientation discrimination tasks, neither the mean luminance modulation
threshold nor the mean contrast modulation thresholds reached by the participants were
altered by the intake of donepezil (Wilcoxon test, p>0.05). Error bars represent SEM
values.
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Figure 2.TIF
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