The impact of dopamine on functional and structural connectivity

Dopamine (DA) plays a key role in the regulation of human cognition. For
instance, from a cognitive perspective DA is thought to modulate the balance
between stable versus flexible cognitive representations, whereas from a
biological perspective it is thought to regulate the interplay between the
prefrontal cortex (PFC) and the striatum (Cools & D*Esposito, 2011). The
importance of DA to everyday cognitive-behavioral functioning is illustrated by
cases in which the DA system is severely dysregulated, for example in
Parkinson*s disease (Dauer & Przedborski, 2003) and schizophrenia (Howes,
McCutcheon, & Stone, 2015).

~Genetic variation in DA function~
Many studies have shown a crucial role for inter-individual differences in DA
function. Such differences have been found to affect both cognition and the
interplay between the PFC and striatum. So far, progress has been made in
identifying genetic markers that can account, in part, for these differences.
In particular, the enzyme catechol O-methyltransferase is responsible for
degradation of DA in the PFC (Karoum, Chrapusta, & Egan, 1994), whereas the DA
transporter (DAT) is responsible for DA reuptake in the striatum (Sesack,
Hawrylak, Matus, Guido & Levey, 1998). Variations in the COMT and DAT genes are
known to affect prefrontal and striatal DA levels, respectively, and have
received increasing attention as possible modulators of cognitive control
functions (Cools & D*Esposito, 2010). Common variations in the DAT gene are 9
and 10-repeat alleles, which are associated with higher and lower striatal DA
level, respectively. On the other hand, common variations in the COMT gene are
a substitution of a Met for a Val allele, with Met carriers having higher
prefrontal DA levels than Val carriers. In light of this information it is
interesting to note that Bertolino et al. ( 2006) showed that these
polymorphisms, while targeting one specific area, can modulate the function of
both the PFC and striatum. Their findings indicated that brain-activation
patterns of individuals with putatively low striatal DA (10-repeat carriers of
DAT) resembled that seen in subjects with putatively high prefrontal DA levels
(Met carriers of COMT).
In the present study we wish to extend these findings by investigating
the effects of DA-related gene polymorphisms (COMT, DAT) not only on structural
connectivity in the brain but functional connectivity as well. Structural
connectivity is assessed using diffusion tensor imaging (DTI), which quantifies
the density of white matter tracts. In light of the aforementioned findings by
Bertolino et al. (2006), we expect that carriers of the 9-repeat allele of the
DAT gene, who have higher striatal DA, will have increased white matter
connectivity in the striatum, relative to 10-repeat allele carriers and Met
carriers of COMT. Further, we will assess functional connectivity using
resting-state brain-activation patterns, and we expect that individuals with a
genetic predisposition towards higher striatal activation will concurrently
have lower PFC activation.

To investigate the effect of dopamine-related genetic polymorphisms on
resting-state fMRI measures of network functional and structural connectivity.

~Design~
The proposed study will use a between-subjects design, with genotype as
between-subjects factor.

~General procedure~
The proposed study will consist of one session of fMRI data collection. The
study is carried out in the fMRI room on the first floor. Upon arrival buccal
swabs are used to collect genetic material. fMRI data collection will take
approximately 30 minutes per session, during which both functional and
structural connectivity is assessed.

~Session time line~

Session 1
-20 min. Arrival 5 min.
-15 min. Collect DNA via buccal swabs 5 min.
-10 min. Transfer to fMRI room / change into MRI clothes 10 min.
0 min. MRI: T1 and resting state 30 min.
30 min. Subject leaves scanner 5 min.
35 min. Debriefing 5 min.
40 min. End of experiment

60 min. total duration

There are no known risks associated with participating in an fMRI study.
Numerous human subjects have undergone MRI without apparent harmful
consequences. Radiofrequency power levels and gradient switching times used in
these studies are within the FDA-approved ranges. Some people become
claustrophobic while inside the scanner and in these cases the study will be
terminated immediately at the subject's request.