Measuring and Modulating Changes in EEG Resting State Functional Connectivity During Short-term and Long-term Pain

Study Overview
=================
Brief Summary
-----------------
Background and aims: Experimental prolonged pain models can shed more light on the cortical mechanisms involved in the transition from acute to chronic pain including changes in resting state functional connectivity (rsFC). This experiment aimed at examining the effect of 24-hour-capsaicin application on the rsFC of the default mode network (DMN), a prominent network in the dynamic pain connectome. Methods: Electroencephalographic (EEG) rsFC measured by Granger causality was acquired at baseline, 1-hour, and 24-hour following the initial patch application (placebo or capsaicin). After 24 hours, the patch was cooled down then heated up to assess rsFC changes in response to pain relief and facilitation. Pain was induced using a topical capsaicin patch (or placebo as control) on the right forearm and assessed on a 0-10 numerical rating scale (NRS).

Official Title
-----------------
Aalborg University, Aalborg, Denmark

Conditions
-----------------
Prolonged Pain, EEG, Resting State Functional Connectivity

Intervention / Treatment
-----------------
* Other: 8% Capsaicin patch
* Other: placebo patch


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy men and women, age 19-44, right-handed (assessed using the Edinburgh Handedness Inventory, speak and understand English. Exclusion Criteria: Chili allergies History of chronic pain or current acute pain Present or previous neurologic such as epilepsy, Alzheimer disease, dementia, stroke, migraine and other headache disorders, multiple sclerosis, Parkinson's disease, neuroinfections, brain tumours and head trauma. Present or previous musculoskeletal disorders such muscle/tendon strain, ligament sprain tension,tendonitis, degenerative disc disease, mechanical back syndrome, and ruptured/herniated disc. Present or previous mental illnesses such as depression, bipolar disorder, and schizophrenia. Pregnancy Current use of medications that may affect the trial (e.g. pain relieving medication and anti-inflammatory medication) Using hair products that may interfere with EEG conductance such as gel, except for shampoo, prior to the trial. Drug addiction defined as the use of cannabis, opioids or other drugs Consumption of alcohol, caffeine, or tobacco 6 hours before the experimental onset Lack of ability to cooperate -

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 44 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants experienced both experimental (capsaicin) condition and placebo conditions. Due to the long-lasting effects of capsaicin after 24 hours of application, placebo condition always preceded the capsaicin condition.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capsaicin<br>Capsaicin condition: in this condition participants received pain using a (5x10 cm) 8% topical capsaicin patch on the volar part of the dominant right forearm. | Other: 8% Capsaicin patch<br>* Cutaneous pain was induced using a (5x10 cm) 8% topical capsaicin patch (transdermal patch, 'Qutenza', Astellas) on the volar part of the dominant right forearm (5 cm from the wrist) of each participant.<br>|
| Placebo Comparator: Placebo<br>Placebo condition: participants received no pain. | Other: placebo patch<br>* A transparent patch with no formulation or effect but the same size of the capsaicin patch was applied to the same location.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in resting state functional connectivity | resting state functional connectivity is assessed using Granger causality. It can take on any value starting with 0 representing no connectivity. Higher granger causality scores indicate higher connectivity. | Granger causality is assessed at 5 time points for each condition (capsaicin or placebo): baseline, 1 hour, 24 hours, 24 hours, cooling at 24hours, and heating at 24 hours. | 
| Change in Subjective pain intensity | Intensity rated by the participants on a numerical rating scale anchoring from 0 no pain to 10 the worst imaginable pain . Higher numerical rating scores indicate higher pain intensity. | Intensity is assessed at 5 time points for each condition (capsaicin or placebo): baseline, 1 hour, 24 hours, cooling at 24hours, and heating at 24 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain sensitivity (Warmth detection threshold) | Warmth detection threshold is assessed using a thermal stimulator probe (3 × 3 cm, Pathway Medoc Ltd, Israel). Higher threshold scores indicate less sensitivity. . | Warmth detection threshold is assessed at 3 time points for each condition (capsaicin or placebo): baseline, 1 hour, and 24 hours. | 
| Change in Pain sensitivity ( Cold detection threshold). | Cold detection threshold is assessed using a thermal stimulator probe (3 × 3 cm, Pathway Medoc Ltd, Israel). Higher threshold scores indicate less sensitivity. | Warmth detection threshold is assessed at 3 time points for each condition (capsaicin or placebo): baseline, 1 hour, and 24 hours. | 
| Change in Pain sensitivity ( Heat pain threshold). | Heat detection threshold is assessed using a thermal stimulator probe (3 × 3 cm, Pathway Medoc Ltd, Israel). Higher threshold scores indicate less sensitivity. | Heat pain threshold is assessed at 3 time points for each condition (capsaicin or placebo): baseline, 1 hour, and 24 hours. | 
| Change in Pain sensitivity ( Cold pain thresholds). | Cold pain threshold is assessed using a thermal stimulator probe (3 × 3 cm, Pathway Medoc Ltd, Israel). Higher threshold scores indicate less sensitivity. | Cold pain threshold is assessed at 3 time points for each condition (capsaicin or placebo): baseline, 1 hour, and 24 hours. | 
| Change in Pain sensitivity ( Mechanical pain thresholds). | Mechanical pain thresholds was assessed using a set of seven weighted pinprick stimulators consisting of steel tubes ending with a tip contact area of 0.25 mm diameter and excreting forces of 0.8, 1.6, 3.2, 6.4, 12.8, 25.6, and 51.2 g. Higher threshold scores indicate less sensitivity. | Mechanical pain threshold is assessed at 3 time points for each condition (capsaicin or placebo): baseline, 1 hour, and 24 hours. | 
| Pain vigilance | Pain Vigilance and Awareness Questionnaire (PVAQ). This questionnaire consists of 16 items evaluating preoccupation and attention to one's pain over the past two weeks, rated between 0 = never and 5 = always, with a maximum score of 80. The higher the scores, the higher the preoccupation with pain. | It is assessed at baseline and after 24 hours for each condition (capsaicin or placebo). | 
| Pain Catastrophizing | Scale (PCS). This questionnaire comprises 13 items assessed on a 5-point scale ranging from 0 = not at all to 4 = all the time, with a maximum score of 52. It evaluates three scales of catastrophizing: rumination, magnification, and helplessness. Ratings reflect the degree to which specific thoughts and feelings are present when experiencing pain over the last three months. Higher scores indicate a higher degree of pain catastrophizing. | It is assessed at baseline and after 24 hours for each condition (capsaicin or placebo). | 
| Sleep quality assessment | Pittsburgh Sleep Quality Index (PSQI). This questionnaire determines sleep quality and sleep patterns across seven areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction over the last month. These areas are evaluated on a scale ranging from 0 = no difficulty to 3 = severe difficulty, with a maximum score of 21. Higher scores reflect poor sleep quality. | It is assessed at baseline and after 24 hours for each condition (capsaicin or placebo). | 
| Fatigue assessment | Modified Fatigue Impact Scale (MFIS). The MFIS evaluates the degree to which fatigue influences overall perceived function over the last 4 weeks. It assesses three subscales: cognitive (9 items), physical (10 items), and psychosocial (2 items) functioning. Items are measured on a scale from 0 = no problem to 4 = extreme problem, with a maximum score of 120. Higher scores indicate higher levels of fatigue. | It is assessed at baseline and after 24 hours for each condition (capsaicin or placebo). | 
| Positive and negative affect | Positive and Negative Affect Scale (PANAS). This scale consists of 20 items assessing two groups of emotions: negative and positive (10 items each). Subjects rate the intensity of a specific emotion they are experiencing at the moment on a scale (1 = very slightly or not at all to 5 = Extremely). for each emotion group with a maximum of 50. Higher scores indicate more intense emotions. The positive affect items were interested, excited, strong, enthusiastic, proud, alert, inspired, determined, attentive, and active. The negative affect items were distressed, upset, guilty, scared, hostile, irritable, ashamed, nervous, jittery, and afraid. | They are assessed at baseline and after 24 hours for each condition (capsaicin or placebo). | 
| Depression scores | Beck Depression Inventory (BDI-II). The BDI determines the severity of depressive mood states and consists of 21 questions assessing hopelessness, guilt, fatigue, and other physical symptoms, rated between 0 = no symptom impact and 3 = maximum symptom impact with a maximum score of 63. Higher scores indicate severe depressive symptoms. To obtain measures of trait depression, subjects in this study are instructed to rate the items in relation to how they generally feel. | They are assessed at baseline and after 24 hours for each condition (capsaicin or placebo). |