Cognitive vs. Emotional Psychopharmacological Manipulations of Fear vs. Anxiety

NCT02153944 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: 14011414-M-0114
• Study Type: interventional
• Target: 142
• Locations: 1 country
• Sites: 1

Brief 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 ...

Conditions

Anxiety Disorder

Keywords

Startle; Induced-Threat; Memory; Stimulant; Cognitive Interference

Outcome Measures

Primary Outcomes (24)

• Magnitude of Startle Reflex During Safe Condition

  The magnitude of the startle reflex during working memory tasks (n-back) while undergoing alternating periods of safety and threat of shock. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. The participant holds each stimulus in short-term memory while new stimuli are presented. For each new item presented, the participant's task is to decide if it is the same as the stimulus presented one time before (1Back), two times before (2Back) or three times before (3Back) by responding "yes" if the stimulus currently presented matches the stimulus presented earlier. Participants responded with a button press. The startle reflex was elicited with a 102 decibel (dB) white noise (40-ms duration) delivered via headphone. The eyeblink component of the startle reflex was recorded binaurally with two silver chloride (AgCl) electrodes placed under one eye.

  20-120 milliseconds following the onset of the startle stimulus

• Magnitude of Startle Reflex During Threat Condition

  The magnitude of the startle reflex during working memory tasks (n-back) while undergoing alternating periods of safety and threat of shock. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. The participant holds each stimulus in short-term memory while new stimuli are presented. For each new item presented, the participant's task is to decide if it is the same as the stimulus presented one time before (1Back), two times before (2Back) or three times before (3Back) by responding "yes" if the stimulus currently presented matches the stimulus presented earlier. Participants responded with a button press. The startle reflex was elicited with a 102 decibel (dB) white noise (40-ms duration) delivered via headphone. The eyeblink component of the startle reflex was recorded binaurally with two silver chloride (AgCl) electrodes placed under one eye.

  20-120 milliseconds following the onset of the startle stimulus

• Proportion of Correct Responses in the Working Memory Task (N-back) - Safe Condition

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one, two, or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. The participant holds each stimulus in short-term memory while new stimuli are presented. For each new item presented, the participant's task is to decide if it is the same as the stimulus presented one time before (1Back), two times before (2Back) or three times before (3Back)" by responding "yes" if the stimulus currently presented matches the stimulus presented earlier. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1Back, 2Back, 3Back) using repeated measures ANOVA.

  Task started 90 minutes post drug admin up to max of 125 mins post drug admin (max total is 35 mins) during a 6-hour single day visit

• Proportion of Correct Responses in the Working Memory Task (N-back) - Threat Condition

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one, two, or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. The participant holds each stimulus in short-term memory while new stimuli are presented. For each new item presented, the participant's task is to decide if it is the same as the stimulus presented one time before (1Back), two times before (2Back) or three times before (3Back)" by responding "yes" if the stimulus currently presented matches the stimulus presented earlier. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1Back, 2Back, 3Back) using repeated measures ANOVA.

  task started 90 minutes post drug admin up to max of 125 mins post drug admin (max total is 35 mins) during a 6-hour single day visit

• Proportion of Correct Responses in the Working Memory Task (N-Back): Safe Condition - 1BACK - Run 1

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe).Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes post drug admin plus zero seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Threat Condition - 1BACK - Run 1

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes plus 90 seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Safe Condition - 1BACK - Run 2

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes plus 180 seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Threat Condition - 1BACK - Run 2

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes plus 260 seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Safe Condition - 3BACK - Run 1

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes post drug admin plus 45 seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Threat Condition - 3BACK - Run 1

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes plus 135 seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Safe Condition - 3BACK - Run 2

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes plus 215 seconds within a 6-hour study visit

• Proportion of Correct Responses in the Working Memory Task (N-back): Threat Condition - 3BACK - Run 2

  Stimuli were presented one at a time on a screen. Participants were instructed to remember (working memory) one or three stimuli back (N-back) from the current stimulus on the screen while undergoing alternating periods of safety and threat of shock i.e. while anticipating unpleasant electric shocks or no shock (safe). Two levels of difficulties were tested: 1- and 3-back. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Participants indicated whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task included 3 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block represented a given level of difficulty, i.e., 1- and 3-back. Performance on working memory task (n-back) accuracy was measured across condition (threat and safe) x Load (1-back, 3-back) using repeated measures ANOVA.

  90 minutes plus 305 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Safe Condition - 1BACK - Run 1

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition( threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes post drug admin plus zero seconds within a 6-hour study visit

• Reaction Time to Stimuli: Threat Condition - 1BACK - Run 1

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes plus 90 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Safe Condition - 1BACK - Run 2

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes plus 180 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Threat Condition - 1BACK - Run 2

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes plus 260 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Safe Condition - 3BACK - Run 1

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes post drug admin plus 45 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Threat Condition - 3BACK - Run 1

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes plus 135 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Safe Condition - 3BACK - Run 2

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes plus 215 seconds within a 6-hour study visit

• Reaction Time to Stimuli: Threat Condition - 3BACK - Run 2

  Reaction time (RT) is the time it takes to respond to stimuli. Participants RTs were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks (threat) or no shock (safe) during the n-back paradigm task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back. The task was organized in 2 runs, 8 blocks per run (4 safe and 4 threat presented alternatively), 18 sequential letters per block. Each block (threat or safe) corresponded to 2 tasks, 1- and 3-back tasks. RT was analyzed using condition (threat, safe) x Load (1Back, 3Back) repeated-measures ANOVA.

  90 minutes plus 305 seconds within a 6-hour study visit

• Measure of BOLD Response in Brain Clusters - Safe Condition - 1BACK

  The blood-oxygen-level dependent (BOLD) responses were measured using an fMRI scanner. The cerebral fMRI BOLD uses magnetic fields to measure localized changes in brain blood flow and blood oxygenation in activated regions-of-interest (ROI). Participants BOLD responses were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks or no shock (safe) during the n-back task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back.

  started 90 minutes post drug administration plus 90 seconds within a 6-hour study visit

• Measure of BOLD Response in Brain Cluster - Threat Condition - 1BACK

  The blood-oxygen-level dependent (BOLD) responses were measured using an fMRI scanner. The cerebral fMRI BOLD uses magnetic fields to measure localized changes in brain blood flow and blood oxygenation in activated regions-of-interest (ROI). Participants BOLD responses were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks or no shock (safe) during the n-back task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back.

  started 90 minutes post drug administration plus up to 360 seconds within a 6-hour study visit

• Measure of BOLD Response in Brain Clusters - Safe Condition - 3BACK

  The blood-oxygen-level dependent (BOLD) responses were measured using an fMRI scanner. The cerebral fMRI BOLD uses magnetic fields to measure localized changes in brain The blood-oxygen-level dependent (BOLD) responses were measured using an fMRI scanner. The cerebral fMRI BOLD uses magnetic fields to measure localized changes in brain blood flow and blood oxygenation in activated regions-of-interest (ROI). Participants BOLD responses were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks or no shock (safe) during the n-back task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back.

  started 90 minutes post drug administration plus up to 270 seconds within a 6-hour study visit

• Measure of BOLD Response in Brain Cluster - Threat Condition - 3BACK

  The blood-oxygen-level dependent (BOLD) responses were measured using an fMRI scanner. The cerebral fMRI BOLD uses magnetic fields to measure localized changes in brain blood flow and blood oxygenation in activated regions-of-interest (ROI). Participants BOLD responses were measured while undergoing alternating periods of safety and shock threat conditions i.e. while anticipating unpleasant electric shocks or no shock (safe) during the n-back task. The n-back is a paradigm used to assess working memory function by presenting sequential stimuli individually. Two levels of difficulties were tested: 1Back and 3Back (n-back). Participants were instructed to indicate whether the letter currently displayed was the same as the letter presented 1 or 3 letters back.

  started 90 minutes post drug administration plus up to 450 seconds within a 6-hour study visit

Secondary Outcomes (4)

• Measure of Level of Anxiety

  20 minutes after arrival for study; 80, 100, & 125 minutes post drug administration

• Measure of Level of Anxiety

  20 minutes after arrival for study; 10 minutes & 145 minutes post drug administration

• Measure of Heart Rate

  20 minutes after arrival for study; 80 minutes & 125 minutes post drug administration

• Measure of Heart Rate

  20 minutes after arrival for study; 10 minutes & 145 minutes post drug administration

Study Arms (5)

Behavioral: Drug challenge with methylphenidate

EXPERIMENTAL

Participant received methylphenidate 20 mg orally during study visit

Drug: Methylphenidate

Behavioral: Drug challenge with placebo

PLACEBO COMPARATOR

Participant received placebo orally during study visit

Drug: Placebo

Behavioral: Drug challenge with propranolol

EXPERIMENTAL

Participants received propranolol 40mg orally during study visit

Drug: Propranolol

fMRI: Drug challenge with methylphenidate

EXPERIMENTAL

Participant received methylphenidate 20 mg orally during study visit

Drug: Methylphenidate

fMRI: Drug challenge with placebo

PLACEBO COMPARATOR

Participant received placebo orally during study visit

Drug: Placebo

Interventions

Propranolol DRUG

Propranolol 40 mg was given orally during study visit

Behavioral: Drug challenge with propranolol

Methylphenidate DRUG

Methylphenidate 20mg was given orally during study visit

Behavioral: Drug challenge with methylphenidate; fMRI: Drug challenge with methylphenidate

Placebo DRUG

Placebo was given orally during study visit

Behavioral: Drug challenge with placebo; fMRI: Drug challenge with placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Ages 18-50
• Males and females
• Subjects give their own consent

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Gaillard C, Lago TR, Gorka AX, Balderston NL, Fuchs BA, Reynolds RC, Grillon C, Ernst M. Methylphenidate modulates interactions of anxiety with cognition. Transl Psychiatry. 2021 Oct 21;11(1):544. doi: 10.1038/s41398-021-01621-2.

  PMID: 34675189 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anxiety Disorders

Interventions

Propranolol; Methylphenidate

Condition Hierarchy (Ancestors)

Mental Disorders

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr Maryland Pao
• Organization: National Institute of Mental Health (NIMH)

paom@mail.nih.gov

301-435-5770

Study Officials

• Monique Ernst, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2014
• First Posted: June 3, 2014
• Study Start: June 16, 2014
• Primary Completion: October 7, 2021
• Study Completion: October 7, 2021
• Last Updated: April 11, 2023
• Results First Posted: April 11, 2023

Record last verified: 2021-10

Locations

US (1)