stress and functional connectivity in bipolar disorder

Bipolar I disorder (BP1) is characterized by recurrent manic and depressive
episodes. Stress increases the risk for these symptoms. It is currently unknown
how stress causes these detrimental effects and what the underlying biological
mechanisms are. Multiple neuroimaging studies have established impairments of
both structural and functional connectivity within emotional networks in
patients with bipolar disorder. The overall aim of this study is to
investigate how stress affects the brain of euthymic BP1 patients by examining
functional connectivity. This provides a unique opportunity to investigate how
acute stress affects connectivity in the diseased brain in which connectome
abnormalities are already present.

Repeatedly measuring brain activity with functional MRI (fMRI) allows the
assessment of both the spatial and temporal characteristics of stress on
neuronal connectivity. This is relevant as the effects of stress follow a
distinct temporal pattern. Immediately after stress, catecholamines and fast
(non-genomic) effects of corticosteroids promote instrumental and short-term
behavior. In contrast, in the aftermath of stress, behavior is aimed at
restoring higher cortical functions with more flexible behavior. Examining the
temporal effects of stress on the brain by repeatedly measuring functional
connectivity patterns can provide a dynamic readout of stress vulnerability in
BD1 patients.

Primary objective: Investigate the effects of a stress task on resting state
and task-induced functional connectivity in patients with bipolar I disorder.
Secondary objective:
- Correlate the endocrine response to mental challenge to resting state and
task-induced functional connectivity
- Investigate the association between (epi)genetic variation in genes involved
in emotional control and functional connectivity in the brain during rest and
task.

A small monocenter intervention study in healthy individuals (N=40) and BP1
patients (N=40). Participants will be randomized to either the stress condition
(Trier Social Stress Test, TSST) or a validated control condition, resulting in
the following 4 groups:
- healthy individuals * control test (N=20)
- healthy individuals * stress test (N=20)
- BP1 patients * control test (N=20)
- BP1 patients * stress test (N=20)

All participants will be subjected to either the stress or control condition of
the Trier Social Stress Test, a validated and standardized test to induce a
psychosocial challenge in laboratory settings.

Risks for participants are minimal. Participants are invited to the UMCU two
times with a duration of approximately 4 hours and sufficient time for breaks.
No direct benefits are present for participants. All participants will be given
a reimbursement of ¤60,- for their cooperation and time. An additional
reimbursement of ¤15,- will be received after the reward task. Also potential
travel costs will be reimbursed.

The visit includes:
- Inclusion, collect a blood sample, complete several questionnaires
- Three MRI scans in the 3T scanner before and after the Trier Social Stress
Test (TSST)
Total duration: 265 min (of which 60 min in the 3T scanner).


Regarding a risk analysis, a negligible risk for participants is estimated. The
stress test involves a speech test and/or a short arithmetic test that does not
lead to extreme perceived stress levels. The stress test has often been applied
without any known lasting disadvantageous effects as reviewed in literature
(Dickerson & Kemeny, 2004). This includes previous studies from our group (the
CHOICE study [METC 11-222) and Epistress [METC 11-259] and COLUMBUS [METC
12-563]) and an ongoing stress study measuring functional connectivity in
siblings of schizophrenia patients, which show no detrimental effects and the
feasibility of repeated scans in the MRI scanner.