Adolescent neurobiological predictors of developing psychosis

Psychosis is a severe psychiatric condition with a lifetime prevelance of
approximately 3%. The onset of psychosis is often preceded by prodromal signs
and symptoms. This has lead to the development of the clinical- or ultra
high-risk (UHR) approach to psychosis research. This approach identifies
individuals at increased risk of developing psychosis on the basis of prodromal
symptoms, allowing researchers to track them over time, as psychosis develops.
The incidence of psychosis is high in UHR studies and conversion occurs in
relatively close temporal proximity to initial intake (16-35% in 2-2.5 year
follow-up). Such an approach allows for the investigation of changes that
accompany the onset of psychosis, including brain changes, behavioural and
cognitive changes. Such research has the potential to improve our understanding
of how psychosis develops, in particular when it compares psychotic development
to typical developmental trajectories. By investigating the impact of risk
factors, such as brain changes and genetic risk factors, we can improve our
understanding of the role of such risk factors. Studies that elucidate the
neurobiology of psychosis will ultimately facilitate future design of new and
effective ways to treat this disorder. Furthermore, a knowledge of the
underlying biological substrate will improve accurate identification of
individuals at high-risk.
Several research groups have reported premorbid neuro-anatomical and
-functional changes in subjects at clinical high-risk for psychosis in both
grey and white matter areas. Researchers have most often focused on the age
range of 20-25 years, when psychosis typically first occurs. However, on
average the earliest prodromal signs occur up to 5 years before psychosis
onset.
An earlier study by our group investigated brain structure volumes in a
well-defined sample of young adolescents at UHR for psychosis (aged 12-18
years) . Preliminary results from our own data show that adolescents at risk
for psychosis who develop psychosis within two years of the initial MRI-scan
show a greater decrease in cortical thickness, in particular in areas
implicated in psychosis. However, research into such grey matter changes is
very limited and these findings should be considered preliminary and need to be
replicated. Clearly, further research is needed. Also new techniques are now
assessible to investigate white matter integrity and connectivity of resting
state networks.
Furtermore, there is evidence that psychosis is hereditary, with heritability
estimates for psychotic disorders between 82% and 85%. The genes involved are
not known, but some candidates have been identified. The impact of these genes
on brain development and particular on the developmental trajectory to
psychosis has not yet been established. Therefore, we propose to include an
exploratory analysis of candidate risk genes for psychosis in this protocol.

The two primary objectives of this study are:
(1) to explore whether UHR in adolescence is associated with neurobiological
differences at baseline and/or changes in the course of 4-8 year of follow-up
as measured using MR-techniques and compared with typically developing controls.
(2) to assess association and potential predictive value of (changes in)
cortical thickness and resting state brain activation for the development of
subsequent psychosis.

For the second objective we will focus on two hypotheses:
(1) Adolescent cortical thickness as assessed in the course of time (but before
first occurrence of psychosis) is associated with the occurrence of psychosis
within 8 years (duration of earlier study and follow-up in the current
protocol).
(2) Adolescent white matter integrity, as assessed with DTI in the course of
time (but before occurrence of psychosis) is associated with the occurrence of
psychosis within 4 years (duration of follow-up in the current protocol).

Two secondary objectives are to
(1) explore if development of resting state brain activation is associated with
developing psychosis using longitudinal RS-fMRI
(2) explore the association of candidate risk genes for psychosis with the
measures of brain structure that are identified as predictors.
structure. The second is an exploratory analysis of resting state networks, as
assessed with resting state fMRI.

Our study design will be similar to the earlier study. We propose a
longitudinal study, where diagnosis (UHR for psychosis vs control) will be the
between-subject grouping variable. The first cohort will include a maximum of
140 subjects from our earlier study. They will be approached to participate in
two follow-up measurements. The second cohort will consist of participants from
a new recruitment. They will be asked to participate in two measurements (1
follow-up). Follow-up MR-scans will take place approximately 24 months after
the preceding scan.
Participants will receive a set of questionnaires by mail and will be asked to
complete them. Participants that still go to school will also be asked to
approach a teacher for a questionnaire. During the first visit participants
will be asked to particpate in an abbreviated IQ assessment and one or two
interviews (depending on age participant). Parents will (depending on age
participant) be asked to participate in an interview at the same time. In the
last part of the first visit, all subjects will be offered to participate in a
MRI-simulation. In a MRI practice session, subjects will be desensitized to the
scanner environment with the use of a simulator. If a child does not
successfully complete the simulation session, or indicates verbally that he or
she no longer wishes to take part in the study, or if the child, the parent or
the experimenter assesses the child as too anxious, the actual scanning session
will be cancelled. During the second visit, the MRI-scan will be made and DNA
will be collected via venepuncture or by using a spit cup (depending on age
participant).

Participation will consist of questionnaires, interviews, an abbreviated IQ
assessment, an MRI-scan (with the option of an MRI simulation session
beforehand), and the collection of saliva or blood (depending on age). Study
participation will be divided over two days and a visit will never take longer
than 4 hours. There are no known risks associated with MRI acquisition, or any
of the proposed methodologies, and we believe the impact on the subjects will
be minimal. As only a single vial of blood will be collected during
venepuncture, the burden for participating subjects is expected to be minimal.
If veneouncture is not preferred by partcipant or parent(s), they will be asked
if DNA can be collected using a spitcup. Donation of DNA is strictly
voluntarily. Subjects may discontinue study participation at any time, without
giving a reason.