Cognitive vs. Emotional Psychopharmacological Manipulations of Fear vs. Anxiety

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 ...

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 dependent (BOLD) responses. For both step-1 and step-2, secondary measures include skin conductance, heart rate, and subjective measures of anxiety.

Eligibility Criteria:
* INCLUSION CRITERIA:
* Ages 18-50
* Males and females
* Subjects give their own consent

EXCLUSION CRITERIA:

* Clinically significant prior exposure to medications, that based on the investigator s judgment, may impact the study, such as Ritalin (MPH).
* Any significant medical or neurological problems (e.g. cardiovascular illness, respiratory illness, neurologic illness, seizure, etc.)
* Raynaud syndrome
* IQ \< 80
* Sinus bradycardia (P\<45), or tachycardia (P\>90)
* Significant ECG abnormality (i.e., greater than first-degree block etc.) as determined by investigators judgement
* High or low blood pressure (SBP\>140 or SBP\<90; SDP\<50 or SDP\>90)
* A first-degree family history of mania, schizophrenia, or other psychoses based on verbal reports
* Significant past psychopathology (e.g., hospitalization for psychiatric disorders, recurrent depression, suicide attempt, psychoses)
* Current psychiatric disorders according to Diagnostic and Statistical Manual (DSM)-V
* Current alcohol or substance use disorder
* Current use of psychotropic medication
* Impaired hearing (clinic study only)
* Pregnancy or positive pregnancy test
* Neurological syndrome of the wrist (e.g., carpal tunnel syndrome) for shocks to be delivered on affected arm.
* Breastfeeding
* Significant lab abnormalities (i.e., complete blood count (CBC) with differential, acute care and mineral panel, hepatic panel, TSH)
* Positive urine toxicology screen
* You have been in another study with an experimental medication within the previous month
* For physiological/clinic participants: small startle reactivity (a change in EMG activity that is less than 3 times the baseline EMG activity)
* Current daily use of anti-acid -medication or within 5 half-lives of study visit if taken on pro re nata (PRN) basis
* Employee of National Institute of Mental Health (NIMH) or an immediate family member who is a NIMH employee.
* For functional magnetic resonance imaging (fMRI) participants: Any medical condition that increases risk for fMRI:

  * Any metal implants (clips, screws, plates, pins, etc.) that are not safe for MRI or metal fragments cause by injuries or metal working. Metal implants that are deemed MRI safe are allowable (i.e. certain screws).
  * Any sort of medical implants that are not safe for the MRI (aneurysm clips, pacemaker, insulin pump, Hickman line, etc.). Medical implants that are MRI safe (Nexplanon implant, certain intrauterine device (IUDs), etc.) are allowable.
  * Permanent eye liner and tattoos above the neck
  * Patients who have difficulty lying flat on their back for up to 90 min in the scanner
  * Participants who are uncomfortable in small closed spaces (have claustrophobia) and would feel uncomfortable in the MRI machine