Cognitive vs. Emotional Psychopharmacological Manipulations of Fear vs. Anxiety
Status:
Completed
Trial end date:
2021-10-07
Target enrollment:
Participant gender:
Summary
Objective:
The overall aim of this protocol is to examine the effect of pharmacological manipulations of
affective and cognitive processes on anxiety and task performance. Ultimately, the goal is 1)
to provide insight into the relative influence of cognitive and affective states on anxiety,
2) generate theoretical models that can be applied to a better understanding of the
interaction between cognition and emotion, 3) develop a better screening approach to
candidate anxiolytics, and 4) help formulate novel therapeutic interventions for clinical
anxiety.
Excessive or inappropriately sustained anxiety and fear lead to the most common group of
psychiatric disorders. A number of theoretical models have been proposed to understand the
mechanisms engaged in these maladaptive behaviors. Most recent emphasis has focused on the
synergistic contribution of cognitive and emotional processes. Our laboratory has been
instrumental in delineating aspects of behavioral and neural processes that are associated
with fear and anxiety, using psychophysiological and neuroimaging measures of fear and
anxiety. Evidence shows that levels of anxiety modulate cognitive performance, such as
working memory or perceptual discrimination, and that, conversely, cognitive engagement
influences severity of experimentally induced anxiety. The exact contribution of emotional
processes vs. cognitive processes to the experience of anxiety is not clear, similarly to the
neural mechanisms underlying these interactions.
In this protocol, we propose to manipulate pharmacologically separately cognitive and
emotional processes to dissociate their contribution to fear/anxiety, while using
state-of-the-art measures of anxiety derived from translational work. Indeed, we already
developed integrative experimental models of fear and anxiety via the manipulation of
predictable and unpredictable shock, respectively. We already employed successfully these
models to measure anxiolytic and anxiogenic effects of various compounds such as alprazolam,
citalopram, hydrocortisone, and oxytocin in healthy participants.
We propose in a first step (step-1) to start with a simple proof-of-concept study, using two
pharmacological compounds in a double-blind randomized parallel design, each preferentially
acting respectively on the cognitive (methylphenidate) or affective (propranolol) domain, and
using a single cognitive process (working memory). In a second step (step-2), we propose to
extend this work to the fMRI to examine the cognitive correlates of the effects seen in the
step-1 behavioral study, specifically with methylphenidate. Whereas the comparison among
three drugs is planned for the electrophysiology study, we plan to study only the drug that
improves cognition in the fMRI. The reason we will focus on methylphenidate in step 2 is that
our overall goal is to study the effect of improving cognitive functions on anxiety using
neuroimaging. To reach this goal, we plan to use different approaches to boost cognitive
functions in the coming years, including psychopharmacology, direct current stimulation,
mindfulness. Methylphenidate is our first psychopharmacological study towards this objective.
Future work will also expand to other compounds and cognitive processes, as well as vary the
strategy to induce anxiety. Presently, anxiety will be induced using the threat of shock,
while participants perform the task. We will examine in step-1 whether 1) the reduction of
induced-anxiety with propranolol improves cognitive performance, and 2) the facilitation of
cognitive performance with methylphenidate reduces induced-anxiety. In step-2, we will
identify the neural mechanisms underlying the effects of methylphenidate, the drug having
beneficial effects on cognitive function.
Study population:
Medically and psychiatrically healthy adult males and females, aged 18 to 50 years.
Design:
The study is a double-blind design. For step-1, three groups of healthy participants will
come for one experimental session. During this session, they will be asked to perform a
working memory task under the threat of shock, i.e., while anticipating unpleasant electric
shocks. Each group will receive one drug challenge, either placebo, propranolol (40 g) or
methylphenidate (20 mg). For step-2, the study tasks will be conducted in a 3T fMRI scanner.
In this step, only methylphenidate and placebo will be compared. Two groups will come for one
experimental session, one will receive placebo and the other one will receive methylphenidate
(20 mg). In a follow-up study for the step-2 fMRI the two groups will come for one
experimental fMRI session one will receive methylphenidate (60 mg).
Outcome measures:
In step-1, the primary outcome measures are the startle reflex and performance on the working
memory task. In step-2, the primary outcome measures are the startle reflex and the cerebral
fMRI blood-oxygen-level ...