The resilient brain of preterm born children

Stress leads to long-lasting and widespread alterations in brain structure and
function. Due to the brain*s rapid development and its complex characteristics,
it is not surprising that a preterm brain is extremely vulnerable to both
exogenous and endogenous perturbations. Indeed, extremely preterm (EP) born
children (<28 weeks of gestational age) continue to be at increased risk for
lifelong neuropsychiatric disorders such as Autism Spectrum Disorder (ASD),
anxiety/depression, and attention-deficit/hyperactivity disorder (ADHD), with
an overt expression during adolescence and young adulthood. However, whilst
some develop one or more psychiatric disorders later in life, others are able
to thrive after EP birth. To date, it remains unknown why some individuals show
resilience in the face of stressors. We hypothesize that alterations in an
individuals* stress-sensitivity might underlie these astonishing differences in
outcome.

The primary objective is twofold. First, we aim to investigate how the brain
responds to acute stress and, second, which factors explain variability
underlying brain activity following acute stress. The study population consists
of extremely preterm born children and healthy-term born control at the age of
8-11. Our research can only be performed in children since we believe that the
regulatory capacity of stressors during middle childhood is of great predictive
value for several forms of psychopathology, many of which begin or intensify
during adolescence.

An observational study in extremely preterm born children and healthy term-born
controls at the age of 8-11. Participants will be randomly assigned to a
standardized stress-condition, using the Trier Social Stress Test for Children,
or a non-stress control condition. Participants will be divided into four
groups: (a) healthy term-born children - non-stress condition (n=25), (b)
healthy term-born children - stress condition (n=25), (c) extremely preterm
born children - non-stress condition (n=25), and (d) extremely preterm born
children - stress condition (n=85). The stress condition in extremely preterm
born children is considerably larger as to better delineate the role of stress
in the heterogeneous outcomes after preterm birth.

Participants are randomly assigned to either a stress condition or a control
condition of the Trier Social Stress Test for Children (TSST-C;
Buske-Kirschbaum et al., 1997):
- healthy term-born children-non-stress (n=25)
- healthy term-born children-stress (n=25)
- preterm born children-non-stress (n=25)
- preterm born children-stress (n=85)

The TSST-C comprises three key component that has been deemed as potent
psychological triggers of the HPA-axis, namely: uncontrollability,
unpredictability, and social-evaluation (Dickerson & Kemeny, 2004). First,
children will be asked to prepare a story, which will be judged for its quality
by a committee. The child will be told the story telling should be of better
quality compared to other children of their age. After five minutes, the child
is being escorted to the test room, where two committee members will be seated,
as well as two fully equipped video cameras and a microphone. Children are
asked to tell their story to the committee in an exciting and compelling manner
while they are being videotaped. Following the speech, children will perform a
mental arithmetic task, involving a serial subtraction which they have to
perform as quickly and accurately as possible. The number sequence will be
adapted to the child*s age, and the child is instructed to start over when an
incorrect response is made. Throughout this protocol, the committee members
will remain affectively neutral. At the end of the protocol, the committee will
debrief the participants by saying that they were not truly judged in
comparison with other children, and that they did an excellent job. The evoked
moderate psychosocial stress-response is of comparable intensity to stressful
situations experienced in daily life. Prior studies using the same test did no
show any detrimental effects in children (e.g., Bae et al., 2015).
Additionally, the TSST-C has been successfully administers without any
complications in two separate studies conducted at the UMC Utrecht (METC:
08/271 and 12/224).

The control-TSST is a reliable no-stress control condition consisting of
similar tasks as in the TSST-C but without the social-evaluative threat (i.e.,
jury, video camera), making it less stressful. The goal is to maintain a high
level of research transparency, meaning that they are informed about the two
experimental conditions and the aims of the study prior to task completion. The
control-TSST has been successfully administered in children (see Bernhard et
al., 2018).

Children and their parent(s) are invited to the UMC Utrecht for a 2* hour
lasting testing day, of which ~15 minutes is spend on leisure. The current
project has no direct beneficiary effects for either child or parent. Travel
costs will be compensated and the child receives a small gift (i.e., ~¤2.50).

The visit includes the following tasks: (1) Informed consent procedure (~10
min), (2) MR simulator (~45 min), (3) TSST-C (~20 min), (4) one MRI scan in the
3T scanner (~60 min), and (5) collection of several saliva samples, continuous
electrocardiography, subjective stress, and hair (~20 min). Total duration is
165 minutes, of which 15 minutes is spend on leisure. Prior to the visit, both
child and parent(s) are asked to fill out questionnaires (see 8.3.7 for an
overview). Parents will be given the opportunity to complete the questionnaires
during the testing day on a computer or laptop at the department of Psychiatry
(UMCU).

The risks involved in the present study are considered negligible. During the
stress-induction task (Trier Social Stress Test for Children [TSST-C]), heart
rate will be non-invasively monitored. The evoked moderate psychosocial
stress-response is of comparable intensity to stressful situations experienced
in daily life (e.g., presenting in class). Prior studies using the same test
did not show any detrimental effects in children (e.g., Bae et al., 2015).
Additionally, the TSST-C has been successfully administered without any
complications in two separate studies conducted at the UMC Utrecht (METC:
08/271 and 12/224).

Participants will undergo a MRI session of 60 minutes. During the MRI, children
are asked to perform two tasks. The scan procedure is almost identical to the
one used in the YOUth adolescent cohort (METC: 14/617). Compared to YOUth, the
current study does include a different emotional processing task. The MRI scan
does not require administration of any contrast agent, ionizing radiation or
sedation. The MRI procedure is painless and not uncomfortable, although it does
require the subject to lie still with the head and part of the body in a
tunnel-like device. Children do not view the MRI experience as problematic, as
shown by prior research at the UMC Utrecht (YOUth cohort, METC: 14/617). The
code of conduct related to expressions of objection by minors participating in
medical research, as stated by the CCMO, will be followed. Incidental findings
may be noticed on the MRI scan. If medical treatment for these findings is
indicated, the participants will be notified. If parents do not want to be
informed about these findings, children cannot participate.

The current study aims to investigate stress-sensitivity in middle childhood,
as opposed to adolescence or adulthood. Moreover, we have specifically chosen
childhood as our main focus since a child*s stress-sensitivity might have
persistent effects on behaviour and predisposes individuals to suffer from
psychiatric disorders. In line with developmental cascades (i.e., the *spill
over* or snowballing effect of one domain of competence to another domain of
function), we believe that the regulatory capacity of stressors during middle
childhood holds significance for the future development of several forms of
psychopathology, many of which begin or intensify during adolescence (Masten &
Tellegen, 2012). Hence, researching stress-sensitivity in children contributes
to a greater understanding of the neurodevelopmental aetiology and functional
impact of brain activity following acute stress, and will aid in providing
appropriate lifelong support. It is of utmost importance to identify preterm
born children with maladaptive stress-responses, to facilitate the development
of early intervention and prevention programs.