Mapping Sex-by-genotype Interactions in Brain Functions: Connectivity between Polymorphisms of Dopamine Related Genes and Sexual Dimorphism in Cognitive Flexibility and Inhibition

Polymorphisms of dopamine related genes (DRD2 and COMT), including Taq1A
(rs1800497), C957T (rs6277), and Val158Met (rs4680) are responsible for
differences in many human brain functions, including cognitive flexibility and
inhibition. With regard to Taq1A (rs1800497), a single nucleotide polymorphism
(SNP) on the gene DRD2, carriers of A1 allele of this polymorphism compared
with non-carriers (A1-) are characterized with a 30% reduction of D2 receptor
density (Noble, 2000), more processing advantage in task switching, and in
fact, more cognitive flexibility (Stelzel, Basten, Montag, Reuter, & Fiebach,
2010; Stelzel, Fiebach, Cools, Tafazoli, & Esposito, 2013); concerning C957T
(rs6277), another SNP on the gene DRD2, carriers of T allele are characterized
with higher striatal D2 receptor density (Frank, Doll, Oas-Terpstra, & Moreno,
2009; Ritchie & Noble, 2003). It has been suggested that response inhibition
can be predicted by this particular polymorphism and in fact, CT- and TT-
genotypes are associated with higher response inhibition accuracy, especially
in terms of outcome evaluation process (Beste, Stock, Epplen, & Arning, 2016).
With reference to Val158Met (rs4680), which mediates prefrontal dopamine
(Frank, Loughry, O*Reilly, 2001), a different dopamine related gene is at work.
Val158Met (rs4680) is an SNP on the gene COMT. This gene codes
catechol-O-methyltransferase (COMT) enzyme that is responsible for degrading
dopamine in prefrontal cortex (Lundstrom et al., 1995). In fact, Val allele of
this polymorphism is linked to higher activity of COMT which results in an
increase in the rate of dopamine degradation and decreased level of dopamine in
prefrontal cortex; however, Met allele is associate with lower level of COMT
activity, leading to a decrease in dopamine degradation rate and higher levels
of dopamine in prefrontal cortex. It has been suggested that carriers of Val
allele (homozygous) of this polymorphism have better performance in task
switching and in fact have superior cognitive flexibility, compared with
carriers of Met allele (Colzato, van den Wildenberg, & Hommel, 2013; Colzato et
al., 2010; Cools, 2006).

Neurotransmitter systems, such as dopamine, are influenced by sex hormones
(Riccardi et al., 2011); in fact, with respect to sex differences in
dopaminergic neurotransmission, it has been suggested that in dopamine
regulating genes, sexual dimorphisms can be expected in some aspects of
cognition (Riccardi et al., 2011); however, previous literature does not report
any investigations concerning sexual dimorphism in brain functions and
contribution of polymorphisms of dopamine related genes in that regard. In this
project, I will investigate sex-by-genotype interactions in brain functions, by
addressing the above-mentioned gap in the related state-of-the-art research.
Via such investigation, I would be able to detect sexual dimorphism in
cognitive flexibility and inhibition, in carriers of A1, T and Met alleles
(compared with non-carriers) of dopamine related genes polymorphisms Taq1A
(rs1800497), C957T (rs6277), and Val158Met (rs4680), via functional magnetic
resonance imaging (fMRI).

This experiment includes a standard structural T1-weighted MRI scan, a
Diffusion Tensor Imaging (DTI), a resting state fMRI, and three different
cognitive tasks. The experimental design is a 3 (Taq1A, C957T, Val158Met) x 2
(higher, lower cognitive function in each task) factorial design. This
experiment will take around one hour. The specifications of the cognitive tasks
are as follows:

a) Task Switching
The ability to adapt behavior flexibly to the changing environments, as an
index of cognitive flexibility, can be assessed by means of task switching
paradigms. In this project, the switching task includes reacting on number
stimuli; this reaction depends on a task cue that will be presented 300ms
before the number stimuli. If there is a circle cue, the participant should
decide if the number stimulus is larger or smaller than five; if there is a
square cue, the participant should decide if the number is odd or even. The
number stimuli will be presented for 1700 ms, and it will be followed by a
variable inter trial interval of 2, 4, or 6 seconds. In addition, cues can be
presented on the right or left side of the screen, which will indicate the
response hand for that trial. In case the stimulus is smaller than five or
even, participants will respond will middle finger of the respective response
hand and if the stimulus is greater than five or odd, participants will respond
with the index finger of the respective response hand. The trial sequence will
be pseudorandomized.

b) Stop-signal Task
Response inhibition is considered as one of the main characteristics of
cognitive control (Logan, 1994). One way to assess the ability to inhibit a
response is via stop-signal task. In this task participants will be provided
with the image of a green arrow that signals a left- or a right-hand response
pseudo-randomly. The presentation of an arrow will be terminated when the
participant responds to the direction of an arrow (go signals). The intervals
between go signals will vary from 1,250 to 1,750 ms, randomly, in steps of 125
ms and during these intervals a fixation point will be presented. The color of
the arrow will change from green to red on 30% of the trials, upon which
participants should inhibit a response to the direction of the arrow (stop
trials). In order to adapt the task to the performance of the participant, a
staircase design for the stop signal delay (SSD) will be used. In order to
control inhibition probability, in such a design, the delay between the onset
of the go signal and the onset of the stop signal will be dynamically adjusted.
If the participant is unable to inhibit a response, the stop-signal delay will
decrease by 50 ms in the next stop trial; however, if a response is
successfully inhibited, stop-signal delay in the next stop trial will increased
by 50 ms, which decreases the likelihood of successful inhibition on the next
trial.

c) Go/Nogo task
A standard visual Go/Nogo paradigm will be applied (Beste et al., 2011). Each
of the 450 trials will consist of a 200 ms presentation of the target stimulus
(a white 5-letter word) followed by a white fixation cross on black background,
both in the center of the screen. Seventy percent of all trials will be GO
trials where participants will be asked to immediately press the space bar of a
regular keyboard with their right index finger in response to the word *PRESS*.
The remaining 30% of trials will be NOGO trials where the word *STOP* will be
presented as the target stimulus and participants will be asked to refrain from
pressing the space bar in those trials. Trials either will end after the first
button press or when 2200 ms has elapsed. The inter-trial interval (ITI)
consists of a white fixation cross presented in the center of the screen. It
randomly will normally vary between 700 and 1100 ms to avoid effects of
expectancy/time estimation. In combination with the 30/70 ration of GO to NOGO
trials, the short ITIs will induce a strong response tendency and hence a high
rate of false alarms. The trials will be presented in 5 blocks of equal length.


For more information please see section 3 of the research protocol.

Participating in an fMRI study has not been associated to any known risks. This
non-invasive technique involves no catheterizations or introduction of
exogenous tracers. Numerous children and adults have undergone magnetic
resonance studies without apparent harmful consequences. Some people become
claustrophobic while inside the magnet and in these cases the study will be
terminated immediately at the subject's request. The only absolute
contraindications to MRI studies are the presence of intracranial or
intraocular metal, or a pacemaker. Relative contraindications include pregnancy
and claustrophobia. Participants who may be pregnant, who may have metallic
foreign bodies in the eyes or head, or who have cardiac pacemakers will be
excluded because of potential contraindications of MRI in such subjects. There
is no direct benefit to the participants from this research; however, this
research by addressing the gap in the related state-of-the-art research,
provides insights on sexual dimorphism in brain functions and contribution of
polymorphisms of dopamine related genes in that regard; especially given that
the importance of the benefits gained from this research far outweighs the
minimal risks involved. In this study, participants will be protected against
any MRI procedural risks via a thorough pre-screening process. Information
obtained from the study will be strictly confidential, except as required by
law, and will be made available to the subject and his/her physician in
response to a specific request from the subject. There will be no personal
identification of subjects in scientific communications. Data will be stored in
a confidential manner both through the use of a coding system (a code will be
assigned to the data from a given subject instead of the subject*s name) and
through the security of the files and computer systems. All standard anatomical
images (i.e. localizer images) are routinely reviewed by a neuroradiologist.
fMRI studies are not given a clinical interpretation. In the event that a
significant abnormality is detected, a recommendation to seek further medical
consultation will be made. However, it is stressed that the MRI evaluation
performed for these studies does not represent a complete clinical MRI
evaluation, and it is not being performed for clinical diagnostic purposes.