The neurochemical basis of goal-directed behavior

The aim of the current project is to enrich research on neurochemistry and
goal-directed behavior conducted at the FSW and LUMC using neuro positron
emission tomography (PET), and in doing so fill a pervasive gap in the
literature on this behavior. Excellent goal-directed behavior is often
considered a hallmark of human achievement over other animal species, leading a
vast body of literature to examine why some of us are better or worse at
certain aspects of this behavior, as well as how and why this behavior fails in
the case of clinical disorders. While the neurobiology underlying goal-directed
behavior is often speculated upon, it is notably ill-investigated as the
majority of research relies on indirect measurement of this neurobiology, for
example by using proxy measures such as genetics, or even foregoing such
measurement entirely in favor of making only behavioral assessments. As a
result, existing literature on neurochemistry and goal-directed behavior is
burdened by pervasive use of indirect markers of neurobiological constructs,
leading conclusions to be based on assumptions that are scarcely validated.
However, PET enables relatively direct measurement of specific neurotransmitter
systems, and therefore allows us to correlate neurotransmitter function with
behavioral-physiological assessments and validate their presumed associations.
This contributes knowledge to several major fields of interest of Leiden
University, such as neurochemical (dys)function in psychiatric and
neurodegenerative disorders and healthy aging, and in particular the role of
neurochemistry in the human potential for cognitive performance and well-being
over the lifespan.

In the present study we aim to test how individual differences in the
catecholamines, i.e., highly influential neurotransmitters, dopamine (DA) and
noradrenaline (NA) function are related to individual differences in
goal-directed behavior in healthy individuals. To do so, we propose the
following objectives:
The first main objective of this study is 1a. to examine whether striatal
[18F]DOPA influx (Ki) values in healthy individuals are correlated with
performance on tasks tapping into goal-directed behavior, such as
task-switching and working memory paradigms. Secondary to this aim is 1b. to
investigate whether regional [18F]DOPA influx (Ki) values predict brain
functional and structural connectivity on the other hand, measured using 3
Tesla MRI scanning. Furthermore, the aim 1c. is to validate the relationship
between DA and NA activity, indexed by regional [18F]DOPA influx (Ki) values,
and presumed indirect makers of these neurotransmitters, such as spontaneous
eye blink rate and pupil dilation. In addition, there are many inter-individual
characteristics that are known to predict cognitive performance, such as heart
rate variability, reward sensitivity and subclinical traits of psychosis and
autism. This study aims to explore the neurochemical basis underlying these
characteristics by determining whether they are correlated with individual
differences in DA and NA function.
The other main objective of this study is to validate the effects of
transcutaneous (through the skin) vagus nerve stimulation (tVNS), a safe,
non-invasive and mild method of stimulation that transiently enhances NA
activity in the brain. Behavioral studies are consistent with enhancement of
NA-related performance during tVNS, but these studies lack any direct
measurement of NA activity in relation to tVNS efficacy. As a concrete test of
its mechanism-of-action, this study will examine whether behavioral response to
tVNS, measured on cognitive computer tasks, is predicted by baseline NA
activity, indexed by [18F]DOPA influx (Ki) values in the locus coeruleus.

Cross-sectional

Participants will be assessed on four separate occasions: (1) Screening,
behavioral measurements (computer tasks, questionnaires), (2) tVNS and
psychophysiological-behavioral measurements, (3) (f)MRI scan, and (4) PET/CT
scan.
Regarding PET/CT scanning, the radiation dose of this study is 3.3 mSv and
falls within category IIb (minor to intermediate). Nataf et al. (2006)
performed 170 [18F]DOPA PET examinations for the detection of neuroendocrine
tumors. A few of those patients reported a single, minor adverse effect. They
experienced a light and transient burning sensation at the injection site. This
was probably caused by the acidity of the radiopharmaceutical. To our
knowledge, no other side effects have been reported.
Regarding (f)MRI scanning, there are no known risks associated with
participating in an fMRI study. Numerous human subjects have undergone (f)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.
Regarding tVNS, the stimulation frequency, intensity and duration are within
safety limits established from prior work in humans (Kreuzer et al., 2012).
Previous studies have used comparable or higher tVNS stimulation frequency,
intensity and duration without reporting adverse side-effects (Dietrich et al.,
2008; Kraus, Kiess, Schanze, Kornhuber, & Forster, 2007). The stimulation is
not painful, only a typical short-lasting skin sensation (i.e., itching and/or
tingling) is experienced.
Benefits of the study: The results of this study will contribute greatly to our
understanding of the neurobiology of goal-directed behavior. By looking
directly at the individual synthesis capacity of catecholamines, we will better
understand how and why individual differences in goal-directed behavior occur
in the healthy population, which will also inform us of how disturbances in
this neurobiology can explain failure of goal-directed behavior in patients
with clinical disorders or even only subclinical symptoms. Furthermore, the
results from this study serve as a critical and unprecedented validation of
indirect markers of catecholamine function, such as blink rate and pupil
dilation. These markers are pervasively used in studies of both healthy and
clinical populations alike to predict behavioral assessments, and have been
used as predictive factors for efficacy of cognitive enhancement techniques and
as indicators for clinical diagnoses and treatment responsivity. However,
large-scale, well-powered research validating the nature of these markers is
extremely scarce if not non-existent, which severely undermines the
interpretability of the existing literature. By validating these markers, this
study will serve as a crucial reference for research that wishes to use these
non-invasive and cost-efficient markers in studies of clinical and healthy
populations. In doing so, our results are an important step toward creating
treatments and cognitive enhancement interventions tailored to individual
needs, which is of particular interest in an increasingly individualistic
society that places high value and expectations on optimizing personal
achievement. Although we only examine healthy individuals in this study, the
knowledge derived from this study is not restricted to the healthy population.
It will also help us understand and predict how and why this behavior can fail
in clinical disorders, which features (e.g. blink rate, pupil dilation) can
predict self-reported, subclinical symptoms, which paves the way for
establishing predictors of sensitivity to specific, targeted treatments. For
example, if blink rate indeed positively predicts striatal dopamine activity,
then depressive patients with a high blink rate might not benefit and instead
even suffer from treatments targeted at enhancing striatal dopamine.