The main objective is to investigate the role of MRs in memory acquisition and recall during stress and non-stress conditions. Specifically, we are interested in two domains of memory, spatial and fear memory. Secondary objectives are to determine…
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Brief title
Condition
- Cognitive and attention disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
At the behavioural level, the main study parameter in the spatial memory task
is accuracy (i.e. how well subjects remember the right location for a given
object learned earlier) and the strategy used (i.e., automatic stimulus
response association or elaborate spatial map strategy). For fear acquisition
we assess how fast and accurate subjects learn the relationship between
specific stimuli and threat using skin conductance responses. At the brain
system level, we seek to investigate whether neural response patterns obtained
by fMRI can reveal the neural mechanism by which MR activation is causing
stress induced changes in spatial memory and fear learning.
Secondary outcome
- Baseline levels of salivary cortisol (the first 3 saliva samples are used to
compute an individual baseline cortisol level per participant)
- Changes in blood pressure and heart rate
- Changes in resting state connectivity due to stress and administration of an
MR blocker
- Personality and life events questionnaires:These questionnaires partly ask
for very private details (such as abuse in early childhood) but are important
as stress, early life experiences and personality traits have substantial
impacts on endocrine measures, brain development and cognitive performance in
adulthood. Thus we aim to use the following questionnaires:
• State-Trait Anxiety Inventory (STAI) (Spielberger, Gorsuch, Lushene,
Vagg, & Jacobs, 1983).
• Life Threatening Events (LTE) (Brugha & Cragg, 1990).
• Shortened Temperament and Character Inventory (TCI; Cloninger, 1994).
• Trier Inventory of Chronic Stress (Trier Inventory of Chronic Stress,
TICS-LE. Unpublished English Version).
• Herinneringen aan de opvoeding, short form (EMBU-s; Arrindell et al.,
1999), a questionnaire on early life parental care.
- Mood state questionnaires:
• Positive Affect Negative Affect (PANAS) (Watson et al., 1988).
• State-Trait Anxiety Inventory (STAI) (Spielberger et al., 1970) to
assess state anxiety.
• Mood rating scale (Bond & Lader, 1974), extended with 8 items to assess
evaluation of the study situation.
Background summary
Stress and stress hormones (e.g. glucocorticoids, GCs) have profound impact on
memory, an effect of fundamental importance for psychological trauma formation.
Specifically, stress causes a switch towards a more automatic in contrast to
elaborate processing as shown in spatial memory tasks. This switch appears
dependent on one type of GCs receptors, the mineralocorticoid receptor (MR) as
assessed in rodents. Stress also impacts on the acquisition of fear memory. It
has been suggested that fear acquisition is also dependent on MR. To explore
this role of MRs for the first time in humans, we will combine sophisticated
behavioral tasks in a functional magnetic resonance imaging (fMRI) setting with
a well-established stress-induction procedure and a pharmacological
manipulation of the MR. This series of human experiments is complemented by
parallel experiments in rodents and slice preparation conducted by
collaborators in Leiden and Utrecht.
Study objective
The main objective is to investigate the role of MRs in memory acquisition and
recall during stress and non-stress conditions. Specifically, we are interested
in two domains of memory, spatial and fear memory. Secondary objectives are to
determine brain regions involved in memory changes under stress and the
influence of Spironolacton on these stress-induced changes in neural activation
patterns during memory formation and recall.
Study design
We plan a double-blind, placebo-controlled, between-subject study using a
full-factorial design with the factors being stress (stress vs. control), and
MR activation (Spironolacton vs. placebo). We will probe the effects of 400mg
Spironolacton on memory formation under stress and non-stress conditions. Thus,
four groups of subjects will be tested: Stress & Spironolacton, Stress &
Placebo, Control & Spironolacton, Control & Placebo. The study will take place
in the afternoon on two consecutive days for a given subject.
Intervention
Half of the subjects will undergo a slightly modified version of the Socially
Evaluated Cold Pressure Task (SECPT; Schwabe, Haddad, & Schachinger, 2008) to
induce stress. The other half will undergo a control condition meant to cause
no stress. Furthermore, half the subjects of the stress- and the non
stress-group will receive a single dose Spironolacton (400mg tablet) 90 minutes
before undergoing fMRI; the other participants will receive placebo.
Study burden and risks
Considering the application of a classical, widely used drug, strict exclusion
criteria, the screening procedure, continuous monitoring of the subjects and
the experiences of colleagues in Amsterdam and Hamburg with applicating
Spironolacton in young, healthy subjects, we do not expect SAE or any other
side effects. For more information we refer to the Summary of Product
Characteristics (SPC) of Spironolacton.
MRI measurements themselves do not pose any risk, if appropriate precautions
are made. However, the noise and the relative confined space of the MRI scanner
may cause discomfort to some subjects.
The stress induction procedure will most likely cause distress in the
participants. This can hardly be avoided in a study investigating the
mechanisms underlying the effects of stress on human memory. To minimize
discomfort as much as possible, we will use a safe, often applied and very
short stress-induction procedure (3 minutes) compared to other paradigms
frequently used.
Further discomfort might be caused by procedures such as providing a blood
sample for screening, filling out questionnaires about adverse early-life
experiences or chronic stress, and the time spend on the study. Furthermore, in
order to evoke a fear response, participants will be subjected to mild electric
stimuli (e.g. "shocks"). This procedure has been widely used in humans in
classical aversive conditioning paradigms, also in our previous studies (CMO
protocol number 2010/257). The strength of the electric stimuli is set
individually for each subject using a staircase procedure so that the actual
stimulation is uncomfortable but not painful. The 'common knowledge' sensation
most closely mimicking the sensation of the electric stimuli is hitting one*s
funny bone (medial epicondyle of the humerus). These settings are necessary to
be able to study fear learning.
The consent discussion starts sufficiently in advance of the initiation of
study-related procedures to allow potential subjects time to reflect on the
potential benefits and risks and possible discomforts. Participants are
informed about the study when they are screened (usually days before inclusion)
and the risk associated with participation in this study in total can be
regarded as minimal. The results of this study will provide us with better
insight into the mechanisms underlying memory changes under stress. This might
in turn help for better under-standing of how traumatic memories are built and
finally provide deeper insight into phenomena like posttraumatic stress
disorder which pose an enormous burden on individuals, their families and the
society at large.
P.O.Box 9101
6500 HB Nijmegen
NL
P.O.Box 9101
6500 HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
- Male, healthy volunteers
- Age 18 - 35 years
- Normal or corrected-to-normal vision
- Normal uncorrected hearing
- Body mass index between 18.5 and 30
- Willingness and ability to give written informed consent and willingness and ability to understand the nature and content, to participate and to comply with the study requirements
Exclusion criteria
- Anuria,
- Acute or history of renal insufficiency / impairment of renal excretory function (or creatinine levels > 1.1 mg/dl at screening)
- Hyperkalemia (or potassium levels of > 5.0 mEq/L at screening)
- History of psychiatric treatment /current psychiatric treatment
- History of neurological treatment /current neurological treatment
- History of endocrine treatment /current endocrine treatment
- History of autonomic failure (e.g., vasovagal reflex syncope)
- History of psychotropic medication (e.g. antidepressants)
- History of hepatic impairments
- History of cardiovascular diseases
- Hypotension (< 90 / 60 mmHG)
- Bradycardia / Tachycardia (heart rate < 50 or > 100 at rest)
- Use of any medication on a regular basis
- Metal objects in or around the body
- Irregular sleep/wake rhythm (e.g., regular nightshifts or cross timeline travel)
- Claustrophobia
- Use of recreational drugs weekly or more often
- Smoking of more than 5 cigarettes per day
- Average use of more than 3 alcoholic beverages daily and self-reported inability or un-ease to cease drinking alcohol for 24 hours prior to testing.
- Caffeine consumption 3 hours before testing
- Professional sports or participation in competitions (as Spironolacton can lead to a positive doping test)
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-003493-85-NL |
| CCMO | NL37819.091.11 |
| OMON | NL-OMON19893 |