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

Aalborg University, Aalborg, Denmark

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).

Study Overview

• Status: Completed
• Conditions: Prolonged Pain, EEG, Resting State Functional Connectivity
• Intervention / Treatment: Other: 8% Capsaicin patch; Other: placebo patch

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9220
    • Aalborg University, Department of Health Sciences and technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 44 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Healthy men and women, age 19-44, right-handed (assessed using the Edinburgh Handedness Inventory, speak and understand English.

Exclusion Criteria:

1. Chili allergies
2. History of chronic pain or current acute pain
3. 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.
4. Present or previous musculoskeletal disorders such muscle/tendon strain, ligament sprain tension,tendonitis, degenerative disc disease, mechanical back syndrome, and ruptured/herniated disc.
5. Present or previous mental illnesses such as depression, bipolar disorder, and schizophrenia.
6. Pregnancy
7. Current use of medications that may affect the trial (e.g. pain relieving medication and anti-inflammatory medication)
8. Using hair products that may interfere with EEG conductance such as gel, except for shampoo, prior to the trial.
9. Drug addiction defined as the use of cannabis, opioids or other drugs
10. Consumption of alcohol, caffeine, or tobacco 6 hours before the experimental onset
11. Lack of ability to cooperate -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Capsaicin; 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; 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.
Placebo Comparator: Placebo; Placebo condition: participants received no pain.	Other: placebo patch; A transparent patch with no formulation or effect but the same size of the capsaicin patch was applied to the same location.

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).

Collaborators and Investigators

• Sponsor: Aalborg University
• Collaborators: European Commission; Danish National Research Foundation
• Investigators: Study Director: Thomas Graven-Nielsen, DMSc, PhD, Aalborg University

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2021
• Primary Completion (Actual): November 6, 2021
• Study Completion (Actual): November 6, 2021

Study Registration Dates

• First Submitted: December 13, 2021
• First Submitted That Met QC Criteria: December 13, 2021
• First Posted (Actual): December 15, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Dermatologic Agents; Antipruritics; Capsaicin
• Other Study ID Numbers: N-20190057

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: No personal data will be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No