In order to set up paradigms for pharmaco-MRI studies for development of novel psychotropic medications. The present study will investigate the effect of: - low-dose benzodiazepine on brain activation and test performance on a testbed of well…
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Health condition
neurosciences
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Outcome measures
Primary outcome
A generally diminished subject performance is expected in the presence of the
medication. The study design is such that it will be possible to numerically
quantify the effects. Specifically: the working memory task should reveal an
increased difficulty in successfully complete the n-back test, possibly due to
interference in the underlying mechanism of constant update of the target
letter; the episodic memory should reveal an increased difficulty in
retrieving a reliable information, and that difficulty should be detectable
both as a variation in the answers variance and in their accuracy; finally, the
divided attention task could shed light on possible interference effects caused
by the medication in successful coping with two different activities. The
placebo sessions will provide a reference in order to attempt to disentangle
the physical and the psychological components of the effects generated by the
assumption of benzodiazepine.
These informations may concur in paving the way towards a better understanding
of the interaction mechanisms between neuronal activity at a network level and
medications, specifically concerning the localization of areas specifically
affected by the benzodiazepine, thus setting parameters for future studies of
the same kind and for development of novel psychoactive substances targeted at
specific regions/functions.
Secondary outcome
n.a.
Background summary
A staggering volume of papers using fMRI explore the localization and/or
cognitive anatomy associated with some cognitive task, however only a minority
study the effect of drugs.
Most investigations contrast the changes is the blood-oxygen-level-dependent
(BOLD) signal at baseline and following task administration. Task-dependent
activation of the brain results in transient increases in cerebral blood flow
and glucose utilization with little or no increase in oxygen consumption. Thus,
a relative oxygen surplus exists during active states which is the basis for
the BOLD signal. Combining BOLD fMRI, recording of local field potentials
(LFPs) and single- and multiunit spiking activity from the visual cortex of
Macaque monkeys, Logothetis et al demonstrated that the BOLD signal correlates
with LFPs and hence that the BOLD contrast method reflects the input and
intracortical processing of a given area rather than its spiking output.
Local cortical information processing which is measured with BOLD fMRI is
supported by modules consisting of a mesh work of glutamate- and
gamma-aminobutyric acid (GABA)-containing projection neurons and interneurons,
respectively, that receive extensive projections from subcortical modulatory
systems. Psychotropic drugs affect the function of these modules directly by
acting on locally expressed neurotransmitter receptors and transporters,
(catabolic) enzymes and/or ion channels and hence drug effects can be
meaningfully investigated with BOLD fMRI as has been demonstrated for a variety
of drug classes.
Functional MRI is an especially useful tool to investigate drug effects on
uniquely human brain functions. Nevertheless, the potential of BOLD fMRI for
novel central nervous system (CNS) drug development has not yet been fully
realized. One of the reasons may be that limited information is available on
the stability of the signal across sessions. Although in theory this may be
overcome by always testing subjects in a parallel-group design, the MRI
scanning procedure itself may influence brain function and/or performance for
example because of high noise level in the scanner. Pre-exposure may help to
accommodate the subject to the testing environment and thereby diminish
potential effects of the procedure on the study results.
Study objective
In order to set up paradigms for pharmaco-MRI studies for development of novel
psychotropic medications.
The present study will investigate the effect of:
- low-dose benzodiazepine on brain activation and test performance on a testbed
of well studied standard tasks. The testbed of standard tasks will be
constituted by: a working memory task; an episodic memory task; a dual task
combining a motor with an oddball paradigm, resulting in divided attention;
- first exposure to the MR scanner and test environment on brain activation and
test performance during a second and third exposure following administration of
the above-mentioned tasks;
- benzodiazepine on the resting state fMRI signal and the stability of this
signal.
Study design
The proposed study will be a double-blind, 4-way crossover study in young
healthy male, right-handed subjects between 18-25 y.o.a. . At least 20
volunteers will be recruited. For the statistical analysis it is obligatory to
have twenty completed sessions.
After an initial training session (ca. 1 hour), each subject will be tested on
4 occasions which will be separated by approximately 1 week. Subjects will
receive no study medication or a placebo for period 1; periods 2 and 3 will be
randomized to receive 2mg lorazepam (Temesta) or placebo. Period 4 will consist
of a placebo. All doses will be administered ca.30 minutes prior to the start
of the testing procedures.
Each period, images will be acquired at rest and when performing a simple motor
task or tests for working and episodic memory, and attention. Blood flow
measurements will be made using arterial spin labeling (ASL) immediately prior
to and following the test procedures. Tests will be performed in blocks. The
encoding- and recall phases of the episodic memory task will be separated by
the acquisition of a structural MR of the brain for alignment of the activation
parameters and will be treated as 1 block (block A). Block order (block A, plus
working memory = block B; plus divided attention + motor function = block C)
will be randomized for each subject and the block order remains fixed all 4
periods.
Between blocks, subjects will focus for ca. 5 minutes on a neutral fixation
point and a resting state MRI will be obtained. Each block will approximately
last 15 - 20 minutes. The total scanning time will be approximately 90 minutes.
For the working memory a predefined sequence of stimuli (pictures, letters,
sounds) will be presented to the subject, whose task is to decide if the
current stimulus matches the one which was administered n steps back.
The episodic memory, the memory of unique events in time and place, will be
tested using the software package Presentation and a set of pictures selected
from the International Affective Picture System (IAPS)
During the dual task(Attention & motor), two effects are integrated. The
attention part will consist of a Choice Reaction Task (CRT), i.e., an auditory
oddball paradigm. The subject is presented with two stimuli occurring at
different frequencies and it is asked to discriminate them. For the motor part
the subject is requested to produce a constant force by abducting the index
finger of the left hand.
Intervention
Each subject will be tested at 4 different periods, each period will be
separated by ca. 1 week.
The first time the subjects will not receive medication or a placebo.
During the 2nd and 3rd visit the subjects will be given a placebo or once-only
2 mg lorazepam (Temesta).
During the 4th visit the subject will receive placebo medication.
All doses will be taken ca. 30 minutes prior to the start of the tests
Study burden and risks
Participants will thoroughly be examined before they will be included in the
study. Therefore, the experiment will not entail more than minimal risk to the
participants. The study is not intended to benefit the subjects directly
However, the data collected during this study will give the possibility to set
up paradigms for the development or of new psychotropic medication.
The burden associated with cognitive tests is minimal as is the effect of the
benzodiazepine (lorazepam) that will be employed for this study. Lorazepam is
characterized by a medium duration of action (0.4 to 3 hours). After each
visit, a companion or a taxi will take the subjects home.
Ant. Deusinglaan 2
9713 AW Groningen
NL
Ant. Deusinglaan 2
9713 AW Groningen
NL
Listed location countries
Age
Inclusion criteria
Healthy, right-handed male individuals between 18-25 year -o.
Exclusion criteria
•Female sex.
•Previous participation in a study with MRI.
•Clinically significant history of drug allergies (benzodiazepines).
•Recent history (within previous 6 months) of alcohol or drug abuse.
• History of or current significant medical illness including cardiac arrhythmias or other cardiac disease, hematological disease, bronchospastic respiratory disease, dyspnea, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, infection, or any other illness that the investigator considers clinically significant.
• History of or current psychiatric or neurological illness.
• Smoking cigarettes (or equivalent) or the use of nicotine based products, within 3 months prior to study drug administration
• Positive urine screen for drugs of abuse at screening or admission.
• Use of any prescription or over-the-counter psychotropic medication (including herbal medications) within 2 weeks of dosing with the study drug.
• Visual disorder that cannot be corrected through the use of corrective lenses
• Claustrophobia and/or a panic disorder
• Those suffering from phobiae of physical restraint, specifically concerning the head and the hand/finger complex
• Participants who do not fulfill the criteria for participating in an fMRI assessment (e.g. people who have metal implants (pacemaker, heartvalves, vascular clips, eye-implants or red tattoos, piercing)
• Psychological and/or emotional problems, which limit the ability of the subject to comply with the study requirements.
• Any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-010894-19-NL |
| CCMO | NL27170.042.09 |