Neurobehavioral Correlates of Caffeine on Anxiety, Avoidance and Interoception in Healthy Individuals and Panic Disorder.

Study Overview
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Brief Summary
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The current study is a placebo-controlled, double-blind, randomized controlled study using a cross-over design, including Healthy Controls (HC) and participants with Panic Disorder (PD). The primary aim of the study is to investigate the neural correlates and behavioral effects of caffeine (versus placebo), and its impact on emotional reactivity, decision-making, and interoception, and compare the effects in individuals with PD vs HCs. Subjective anxiety and the occurrence of panic attacks will also be measured. Multimodal neuroimaging methods, such as structural and functional MRI, will be used to address the aims of the study. Emotional reactivity, emotional decision-making and interoception will be measured with experimental tasks in a 7 Tesla (7T) magnetic resonance (MR) scanner, jointly with measures of skin conductance, heart rate, respiratory rate, and self-reported ratings of anxiety and interoception. Emotional reactivity will be assessed using emotional and neutral faces. Emotional decision-making will be assessed with an approach-avoidance conflict task. Changes in interoception (bodily sensation, such as pulse and respiration) will be explored using a task in which participants are asked to focus on their breathing or an external stimulus. Caffeine effects on brain resting-state activity will also be assessed. All tasks will be conducted while in the 7T MR scanner. A secondary aim of the study is to examine the impact of genetic variability in the adenosine A2A receptor (ADORA2A) genotype (e.g., rs5751876 T/T) on the effects of caffeine (vs placebo), as ADORA2A genotype has previously been associated with elevated caffeine-induced anxiety.

Detailed Description
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Given the novelty of the intended study and the lack of previous neuroimaging and emotion-related behavioral studies on caffeine effects in HCs and PD, analyses will be exploratory without directed hypotheses. It is intended to conduct between-group analyses (HCs vs PD) in the two conditions (caffeine versus placebo), as well as within-group analyses in HCs and PD separately. Between-group analyses will also be conducted between individuals with different ADORA2A genotypes.

Official Title
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Adenosine Receptors From Genes to Behavior: Neurobehavioral Correlates of Caffeine on Anxiety, Avoidance, Decision-Making and Interoception in Healthy Individuals and Panic Disorder.

Conditions
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Panic Disorder, Healthy

Intervention / Treatment
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* Dietary Supplement: Caffeine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Panic Disorder group (PD): Primary diagnosis of Panic Disorder. Healthy control group (HCs): No current or history of psychiatric disorders. All participants (PD and HCs): Weekly caffeine consumption ≤ 300 mg. Exclusion Criteria: Weekly caffeine consumption ≥ 300 mg. Thoracic or head surgery, or any other surgery or metallic implanted devices not compatible with the safety standards for 7T MR scanner. History of severe psychiatric disorder (e.g., schizophrenia). Somatic or neurological conditions (e.g., hypertension and heart condition). Ongoing treatment with psychotropic medication or treatment with psychotropic medication which has been discontinued within 2 months. Other ongoing treatments that may confound the results. Current drug or alcohol abuse/dependency. Habitual nicotine use. Uncorrected visual or hearing impairment. Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study entails two sessions with a cross-over design. Participants will be randomized to start with either the caffeine condition or the placebo condition. The study includes two arms: (a) participants with Panic Disorder (anticipated n = 50) and (b) Healthy controls (anticipated n = 50). Both arms (Panic Disorder and Healthy controls) will complete both conditions with the two sessions (caffeine and placebo condition) in randomized order.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Panic Disorder<br>Participants will be randomized to start with either the caffeine condition or the placebo condition. Participants will complete session 2 with the other condition (condition not allocated to in session 1). | Dietary Supplement: Caffeine<br>* Caffeine capsule 250 mg, oral intake<br>Drug: Placebo<br>* Placebo capsule, oral intake<br>|
| Other: Healthy controls<br>Participants will be randomized to start with either the caffeine condition or the placebo condition. Participants will complete session 2 with the other condition (condition not allocated to in session 1). | Dietary Supplement: Caffeine<br>* Caffeine capsule 250 mg, oral intake<br>Drug: Placebo<br>* Placebo capsule, oral intake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Task-related BOLD fMRI signal | Task-related BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging) signal will be collected through a 7T MR scanner, starting approximately 30 minutes after oral intake of caffeine or placebo pill. Tasks: Emotional reactivity, Approach-Avoidance Conflict Task, Interoception, Resting-state fMRI. | Session 1 (day 1) | 
| Task-related BOLD fMRI signal | Task-related BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging) signal will be collected through a 7T MR scanner, starting approximately 30 minutes after oral intake of caffeine or placebo pill. Tasks: Emotional reactivity, Approach-Avoidance Conflict Task, Interoception, Resting-state fMRI. | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Self-reported anxiety | Anxiety will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task measured with self-reported ratings, on a scale from 0-100 (0= no anxiety - 100= extreme anxiety). | Session 1 (day 1) | 
| Self-reported anxiety | Anxiety will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task measured with self-reported ratings, on a scale from 0-100 (0= no anxiety - 100= extreme anxiety). | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Self-reported interoceptive awareness | Interoceptive awareness will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task in the MR scanner, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no awareness - 100= extreme awareness). | Session 1 (day 1) | 
| Self-reported interoceptive awareness | Interoceptive awareness will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task in the MR scanner, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no awareness - 100= extreme awareness). | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Self-reported interoceptive functional impairment | Interoceptive functional impairment will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no impairment - 100= extreme impairment). | Session 1 (day 1) | 
| Self-reported interoceptive functional impairment | Interoceptive functional impairment will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no impairment - 100= extreme impairment). | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Skin conductance responses (SCR) | Skin conductance responses will be used to assess emotional reactivity at the physiological level to emotional stimuli vs neutral stimuli (faces). | Session 1 (day 1) | 
| Skin conductance responses (SCR) | Skin conductance responses will be used to assess emotional reactivity at the physiological level to emotional stimuli vs neutral stimuli (faces). | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Occurrence of panic attacks | The occurrence of panic attacks will be assessed according to the Diagnostic Statistical Manual (DSM-5) criteria for panic attacks and will be coded dichotomous as present or not present. | Session 1 (day 1) | 
| Occurrence of panic attacks | The occurrence of panic attacks will be assessed according to the Diagnostic Statistical Manual (DSM-5) criteria for panic attacks and will be coded dichotomous as present or not present. | Session 2 (day 2; minimum of 36 hours after session/day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structural brain data, T1-w sMRI | Structural brain changes will be analyzed through T1-weighted sMRI (structural magnetic resonance imaging). | Session 1 (day 1) | 
| Structural brain data, T1-w sMRI | Structural brain changes will be analyzed through T1-weighted sMRI (structural magnetic resonance imaging). | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Heart rate variability | Heart rate variability (HRV) will be assessed by using a 7T MR-compatible heart rate band, during the whole MR scanner time. | Session 1 (day 1) | 
| Heart rate variability | Heart rate variability (HRV) will be assessed by using a 7T MR-compatible heart rate band, during the whole MR scanner time. | Session 2 (day 2; minimum of 36 hours after session/day 1) | 
| Respiratory rate | Respiratory or breathing rates will be assessed during the whole MR scanner time. | Session 1 (day 1) | 
| Respiratory rate | Respiratory or breathing rates will be assessed during the whole MR scanner time. | Session 2 (day 2; minimum of 36 hours after session/day 1) |