The study consists of two phases. In the first phase, we aim to investigate whether the dopamine receptor D4 (DRD4) genotype confers differential susceptibility to the effects of early life stress on empathy and prosocial behavior more generally in…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
none, the study is not a clinical trial, participants are healthy young adults
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The study parameters of phase 1 are:
- Empathic responses: The participant will play a ball tossing game with three
other (computerized) players. After a period of fair play, one of the fellow
players will be excluded by the other 2 computerized players. We measure the
change in the frequency of throws made by the participant to the excluded
player.
- Prosocial behavior: At the end of the laboratory visit, participants will be
shown a promotional UNICEF video asking them to make a donation (a money box is
positioned next to the screen). We measure the amount of money donated. (All
donations will be transferred to the UNICEF bank account after completion of
the study.)
The study parameters of phase 2 are:
- Resting frontal asymmetry. Participants* resting EEG will be recorded and an
asymmetry index will be computed. We will investigate whether resting frontal
alpha asymmetry can be considered an endophenotype for differential
susceptibility.
- Neural indices of the processing of and attention to infant faces and sounds.
ERP components indicative of processing depth and attention will be computed
from the EEG recorded while participants listen to infant sounds and view
infant faces. EEG asymmetry in response to faces and sounds, as a measure of
approach-withdrawal responses to these stimuli, will also be computed. We will
study effects of L-Dopa on these neural indices, and investigate whether L-Dopa
effects are moderated by the DRD4 genotype and resting frontal asymmetry. In
addition, we will investigate whether changes in neural indices after L-Dopa
administration mediate changes in behavioral measures (sensitivity,
interpretation of infant cues, caregiving attitudes, empathy).
- Cardiac indices of arousal in response to infant faces and sounds. Cardiac
indices indicating sympathetic and parasympathetic activity will be computed
from the ECG and ICG recorded while participants listen to infant sounds and
view infant faces. We will study effects of L-Dopa on these neural indices, and
investigate whether L-Dopa effects are moderated by the DRD4 genotype and
resting frontal asymmetry. In addition, we will investigate whether changes in
cardiac indices after L-Dopa administration mediate changes in behavioral
measures (sensitivity, interpretation of infant cues, caregiving attitudes,
empathy).
-Mirror-neuron activity. Mirror-neuron activity will be studied using measures
derived from the EEG. We will investigate whether potential effects of L-Dopa
on these measures are moderated by the DRD4 genotype and resting frontal
asymmetry. In addition, we will investigate whether changes in mirror-neuron
activity after L-Dopa administration mediate changes in behavioral measures
(sensitivity, interpretation of infant cues, caregiving attitudes, empathy).
- Sensitivity of caregiving behavior. The Leiden Infant Simulator Assessment
will be used to measure participants* sensitivity. We will investigate
investigate whether potential effects of L-Dopa on sensitivity are moderated by
the DRD4 genotype and resting frontal asymmetry.
- Interpretation of infant cues. An infant-face version of the Reading the Mind
in the Eyes Test will be used to measure participants* interpretation of infant
cues. We will study effects of L-Dopa on this measure, and investigate whether
L-Dopa effects are moderated by the DRD4 genotype and resting frontal
asymmetry.
Secondary outcome
- Early life experiences. With respect to differential susceptibility it is
important to take early experiences into account: In order to conclude that the
DRD4 genotype conveys differential susceptibility, those carrying the 7-repeat
allele should not only be more affected by the intervention (L-Dopa
administration), and perform *best* under favorable conditions, but also do
*worst* under unfavorable circumstances. As DRD4 genotype has repeatedly been
observed to moderate effects of parenting experiences (see e.g., 1), we expect
that under placebo conditions carriers of the 7-repeat allele with relatively
unfavorable childhood experiences will do worst (i.e., show the least favorable
scores on caregiving behavior and the least attention and approach responses to
infant stimuli), whereas under DA conditions carriers of the 7-repeat allele
with relatively favorable experiences will do best (i.e., most favorable
caregiving scores, and most attention and approach).
Background summary
The proposed study is a comprehensive micro-trial of dopamine-system mediated
differential susceptibility in the realm of caregiving behavior. We first aim
to investigate whether the dopamine receptor D4 (DRD4) genotype confers
differential susceptibility to the effects of early life stress in a large
sample of adults, in accordance with a meta-analysis that showed similar
effects in children. We then aim to investigate more specifically whether DRD4
genotype confers differential susceptibility to effects of a dopaminergic
pharmacological intervention (L-Dopa administration) on caregiving-related
neurocognitive processes, behaviors, and attitudes. In addition, we examine
whether frontal asymmetry can serve as an endophenotype for differential
susceptibility. Because the analysis (and use) of genetic material is
(relatively) time-consuming and expensive, and surrounded by ethical concerns
and objections, and because multiple genes may be involved in conveying
susceptibility (although a single gene might be an excellent proxy for a
genetic pathway), obtaining an endophenotype for susceptibility would be
worthwhile. Resting frontal asymmetry may be such an endophenotype, and it can
be measured easily and non-invasively, and measures are relatively cheap.
Finally, rigorous statistical probing will be conducted, including the use of
simulations to test the integrity of the data. Results of these statistical
assessments will be used to correct the data accordingly. These analyses will
help to improve the quality of data-analysis and conclusions, and provide
statistical guidelines for future data-analysis of similar designs.
Study objective
The study consists of two phases. In the first phase, we aim to investigate
whether the dopamine receptor D4 (DRD4) genotype confers differential
susceptibility to the effects of early life stress on empathy and prosocial
behavior more generally in a large sample of adults. The second phase will be a
more thorough test of differential susceptibility in the realm of more specific
empathic and social behavior, i.e. caregiving. In this phase, we aim to
investigate whether DRD4 genotype and resting frontal asymmetry confer
differential susceptibility to effects of a dopaminergic pharmacological
intervention on caregiving-related neurocognitive processes, behaviors, and
attitudes. Rigorous statistical probing will be conducted, including the use of
simulations to test the integrity of the data, and results of these statistical
assessments will be used to correct the data accordingly.
Phase 1 addresses the following questions:
1. What is the relationship between early life experiences, and adult empathy
and prosocial behavior, and does DRD4-genotype moderate this effect?
Phase 2 addresses the questions:
2. What is the effect of L-Dopa administration (a pharmacological intervention
that heightens levels of dopamine) on parenting-related neurocognitive
processes, behaviors, and attitudes?
3. Does the DRD4 genotype moderate the efficacy of the pharmacological
intervention?
We expect effects of L-Dopa administration to be more pronounced in carriers of
the 7-repeat allele.
4. Can resting frontal asymmetry serve as an endophenotype for differential
susceptibility?
5. Does measurement imperfection dilute or mask statistical main effects or
interaction effects of genes and intervention?
6. Can knowledge about dilution or masking of effects be used to correct for it
in order to improve the quality of substantive results?
We expect to produce reference material (e.g. look-up tables) to correct
results from common analyses, using the fact that different types of variables
have rather constant error rates.
Study design
Study design: The first phase of this study will involve recruitment of 600
individuals, who will be asked to provide a DNA sample and will fill out a
questionnaire on common background variables (age, education), as well as early
life experiences (early parenting, neglect, and abuse). To study the role of
genotype and early experience on prosocial behavior and empathy, the
participants will be asked to perform two brief laboratory computer-based
tasks. DNA samples will be collected through a salivary DNA collection kit
Oragene® 110 (DNA Genotek).
The second phase of the study will use a subset of the participants (n=200).
The experimental procedure will be a double-blind, randomized
placebo-controlled trial with a within-subject design. These participants will
participate in two identical laboratory sessions at the Department of Child and
Family studies, separated by approximately 4 weeks. L-Dopa will be administered
orally shortly before one session and a placebo shortly before the other. The
order of administration (L-Dopa first or placebo first) will be counterbalanced
across participants To study the role of the DRD4 receptor in differential
susceptibility to L-Dopa administration, groups of 7-repeat carriers and
non-carriers will be compared. The data collection is expected to take
approximately 12 months.
Intervention
Participants will receive a fixed dose of 100 mg levodopa combined with 25 mg
of carbidopa (Sinemet, Tmax1*445 min, half-time1*41-2 h), or placebo. A PET
study in healthy volunteers demonstrated that a single dose of Sinemet changes
DA levels in the putamen and caudate 1 h after intake.
Study burden and risks
Potential risk related to the study is negligible. A dose of 100 mg levodopa
combined with 25 mg of carbidopa (Sinemet) will be administered orally shortly
before one session and a placebo shortly before the other. Although chronic use
of Sinemet can have considerable side-effects, a single dose of 100 mg levodopa
combined with 25 mg of carbidopa has been used and found safe in several
previous psychological studies. Saliva will be collected once to be used for
genotyping. Collecting saliva is easy and almost effortless (participants just
spit into a tube). The computerized tasks administered during the block of
neurocognitive assessments (lasting about 30 minutes in total) require the
participant to concentrate, but are otherwise simple and require minimum
effort. The measurement of EEG and cardiac data is risk-free and non-invasive.
There will be a 15-minute break after this block to allow the participants to
relax and drink something. The behavioral tasks and questionnaires likewise
require the participant to be alert and active, but are not physically or
emotionally demanding, and participants will hardly notice the video-recording.
Wassenaarseweg 52
Leiden 2333AK
NL
Wassenaarseweg 52
Leiden 2333AK
NL
Listed location countries
Age
Inclusion criteria
healthy, female, 18 years old or older, of caucasian descent
Exclusion criteria
pregnancy, breastfeeding, drug or alcohol abuse, prior psychiatric or neurological disorder,use of medication (except oral contraceptives), existing medical condition
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000206-36-NL |
| CCMO | NL47825.058.14 |