(Grand)parenting, oxytocin, and the oxytocin receptor gene: an fMRI and observational study

With the proposed study we aim to gain insight into the effects of oxytocin
(OT) on both parents* and grandparents* sensitive, empathic, and protective
responses to their (grand)children, and in the neural origins of these
responses.
In humans, as well as other mammals, OT is profoundly involved in
parturition and lactation, mother-infant bonding, the formation of romantic
partner relationships, and parental behavior (Bakermans-Kranenburg & Van
IJzendoorn, 2008; Campbell, 2008; Carter, 2003; Feldman et al., 2007; Galbally
et al., 2011; Insel, 1992; Naber et al., 2010; Parker et al., 2005). Research
into the role of OT in human parent-child relationships has remained largely
limited to (positive) effects of OT on adequate, empathic and
sensitive-responsive parental behaviors (see e.g., Bakermans-Kranenburg & Van
IJzendoorn, 2008; Feldman et al., 2007). In addition, the focus of human OT
research more generally has been on OT*s capacity to promote prosocial
behaviors, such as generosity (e.g., Kosfeld et al., 2005) and charitable
donating (e.g., Barraza et al. 2011; Van IJzendoorn et al., 2011). However,
there is also some evidence that OT can, under some circumstances, promote
aggressive behavior, aimed at protecting one*s offspring (Bosch et al., 2005)
or in-group members (De Dreu et al., 2010) from external threat or danger. With
the proposed study we intend to study not just empathic and sensitive, but also
protective responses of (grand)parents toward their (grand)children.
Given the considerable amount of evidence detailing the involvement of
OT in human as well as animal parenting, and considering that many grandparents
maintain (close) relationships with their grandchildren (e.g., Mueller et al.,
2002), it is surprising that studies focusing on the potential role of OT in
grandparent-grandchild relationships are currently lacking. As OT has been
shown to be involved in parenting of infants and (young) children, and in
bonding throughout life, as well as in human social behavior toward non-kin
(e.g., Heinrichs et al., 2009; Van IJzendoorn & Bakermans-Kranenburg, 2011), it
seems highly likely that OT plays a role in facilitating grandparenting and
grandparent-grandchild relationships as well. However, various factors limit
the generalizability of findings obtained from younger adults to ageing
individuals (Huffmeijer et al., 2012c). Studies of older adults, grandparents
in this case, comparing their responses to those of younger adults (parents)
are thus urgently needed.
Results of a growing number of neuroimaging experiments, investigating
the neural origins of OT*s behavioral effects, suggest that oxytocin modulates
amygdala activity in response to salient social stimuli, including facial
expressions (Domes et al., 2007) an infant cries (Riem et al., 2011), which is
relevant with respect to effects of OT on attention, social stress and anxiety
(e.g., Baumgartner et al., 2008; Kirsch et al., 2005). In addition, because the
amygdala is involved in fear, anger, and aggression (e.g., Derntl et al.,
2009), modulation of amygdala activity may be important for (potential) effects
of OT on protective responses and protective aggression. Effects of OT on other
brain regions involved in social cognition, theory of mind, and empathy (e.g.,
superior temporal cortex, inferior frontal gyrus, fusiform gyrus; Domes et al.,
2010) have also been observed. In the current study, we may thus expect effects
of OT on (grand)parents* sensitive, empathic, and protective responses toward
their own (grand)children to be related to both modulation of amygdala activity
and changes (increases) in activity in areas involved in social cognition and
reward processing.
In most neuroimaging studies a direct link between effects of OT on
neural activation and those on behavior is missing. In the proposed study we
aim to remedy this by combining measures of neural and behavioral effects of OT
in a single study, and by recording brain activation during a virtual
interaction with the (grand)child. Brain activity will be recorded using fMRI
during two tasks: a priming task, designed to elicit protective responses by
showing the participants pictures of their own and an unfamiliar (grand)child
preceded by a subliminally presented picture with neutral or mildly threatening
content, and a cyberball game, a virtual ball tossing game that the participant
plays with her own (grand)child and an unfamiliar (grand)mother-(grand)child
pair (computerized players in reality) designed to elicit empathic responses
and behavior when a child is excluded from the game by the remaining two
participants.
Finally, all action of oxytocin is necessarily dependent on the
oxytocin receptor (OXTR). In several studies associations have been found
between social behavior, including mothers* sensitive responsiveness, and
variations in the OXTR genotype that cause variations in OT transmission (e.g.,
Bakermans-Kranenburg & Van IJzendoorn, 2008). However, in OT administration
studies the role of the OXTR has largely been ignored. In the proposed study we
aim to investigate the interactive effects of administered oxytocin and the
OXTR genotype on (grand)parents neural activity and behavior toward their
(grand)children.

With the proposed study we aim to gain insight into the effects of oxytocin
(OT) on both parents* and grandparents* sensitive, empathic, and protective
responses to their (grand)children, and in the neural origins of these
responses.

The primary objectives of the proposed study are to investigate effects of
oxytocin on mothers* and grandmothers* neural activity (measured using fMRI)
related to empathic and protective responding to their (grand)children. We
expect that oxytocin will decrease activity in brain areas associated with
hyperarousal and fearfulness (notably the amygdala) thereby promoting adaptive
(protective) responding, increase activity in brain regions associated with
social cognition and empathy (e.g., superior temporal cortex, inferior frontal
gyrus, insula, fusiform gyrus), and facilitate empathic responses. In addition
we expect changes in brain activity to be related to increases in empathic
behavior, with larger changes in brain activity associated with enhanced
facilitation of empathic behavior. We will also examine the role of the
oxytocin receptor gene in mediating effects of administered oxytocin. We expect
effects of oxytocin to be more pronounced in individuals carrying those alleles
associated with more efficient oxytocin transmission.
Second, we will examine effects of oxytocin on mothers* and grandmothers*
sensitive responsiveness toward their (grand)children and on grandmother-mother
interactions. Third, the potential relations between the (grand)child*s
rejection sensitivity and both mother*s and grandmother*s empathic responding
to the child, and the potential relations between the grandmother*s, mother*s,
and child*s level of empathic behavior will be examined.

We will employ a randomized, double-blind, placebo-controlled design: 50 trios
of grandmother, mother, and child will come to the LUMC for two identical
experimental sessions, separated by 4 weeks. Both mother and grandmother will
receive 24 IU of oxytocin via nasal spray during one session and a nasal spray
containing placebo during the other. The order of administration (oxytocin
during the first or during the second session) will be counterbalanced across
grandmother-mother pairs, but grandmother and mother within each pair will
receive the same treatment. Children do not receive nasal spray. The data
collection is expected to take approximately 9 months. The study will be
conducted at the fMRI facilities at the Leiden University Medical Center.

Trios of grandmother, mother, and child will come to the LUMC for two
experimental sessions, separated by four weeks. Three types of measurements
will be conducted during each session: A) fMRI (mother and grandmother), B)
behavioral observations, and C) a computer task performed by the child. Both
mother and grandmother will receive 24 IU of oxytocin via nasal spray during
one session and a nasal spray containing placebo during the other. The order of
administration (oxytocin during the first or during the second session) will be
counterbalanced across grandmother-mother pairs, but grandmother and mother in
each pair will receive the same treatment. Children do not receive nasal spray.

There are no risks associated with the assessments used in this study. Possible
side effects of oxytocin are negligible. No adverse effects have been reported
in participants/patients undergoing MRI at the currently available field
strengths. The parenting context in which a child is raised is of profound
importance for the child*s cognitive and emotional development. Studies
focusing on the (neural) processes affecting the way grandparents, parents, and
(grand)children interact are thus also important for our understanding of the
processes leading to children*s successful or aberrant development. Although
oxytocin has been shown to mediate positive parenting behaviors, there are no
studies into the role of oxytocin in promoting defensive and protective
behaviors in threatening contexts in parents. In addition, the neural
mechanisms underlying parental sensitivity, empathy, and protective behaviors
are currently poorly understood. Finally, the rapidly growing interest in
oxytocin as a method of therapeutic intervention makes it vital to thoroughly
examine the full scope of psychological functioning that intranasal oxytocin
administration may affect.
Participants will be protected against any procedural risks via a thorough
pre-screening process. Structural MRI scans will be inspected by a radiologist,
and in case of visible abnormalities the participant, participant*s physician,
and researcher will be notified. Participants* data will be handled strictly
confidentially, except as required by law. Data will be stored in a
confidential manner both through the use of a numbering system (a number 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. There will be no
personal identification of participants in scientific communications.