Is Nociceptive Processing Evoked by Heat Homeostatically Regulated: A Contact-heat Evoked Potentials Study

Homeostatic plasticity is a mechanism that stabilizes neuronal activity to prevent excessive nervous system excitability. This mechanism can be investigated in humans by applying two blocks of non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS).

In healthy subjects, homeostatic plasticity induction over the primary motor cortex increases the amplitude of motor-evoked potentials after the first block of excitatory tDCS, which then decreases after the second block of excitatory tDCS. However, this mechanism is impaired in chronic and experimental pain, demonstrated by an increase in excitability instead of a reversal.

The role of homeostatic plasticity mechanisms in pain is yet to be unraveled, but homeostatic plasticity may hold an important role in pain development or persistence.

Thus, the aim of this study is to investigate if the cortical nociceptive response reflected by contact heat stimulation (CHEPs) is regulated by homeostatic mechanisms. For this, homeostatic plasticity will be induced in both the primary motor (M1) and sensory cortices (S1). The first research question will explore if the contact heat evoked potentials are homeostatically regulated and if this regulation is occurring locally or globally in the cortex. Additionally, it will be investigated if and how capsaicin-induced nociception interacts and effects the homeostatic response as reflected by CHEPs.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Other: Homeostatic Plasticity; Drug: Topical alone (Capsaicin 8% Patch); Other: Placebo Patch; Other: Homeostatic Plasticity (Sham)

Detailed Description

Randomized, cross-over study of four sessions

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Gistrup, Denmark, 9260
    • Aalborg University / Center for Neuroplasticity and Pain

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy right-handed men and women aged 18-60 years
• Speak, read, and understand English or Danish

Exclusion Criteria:

• Pregnant, breastfeeding, or women in childbearing age not using contraceptive methods
• Regular use of cannabis, opioids or other drugs (except contraceptives)
• Current or previous neurologic, musculoskeletal, mental, or other illnesses (e.g. brain or spinal cord injuries, degenerative neurological disorders, epilepsy, major depression, cardiovascular disease, chronic lung disease, etc.)
• Current or previous chronic or recurrent pain condition (other than low back pain in patients recruited for sub-project 6, and this item does not apply to sub-project 8)
• Current regular use of analgesic medication or other medication which may affect the trial (including paracetamol and NSAIDs) For subproject 8, chronic low back pain patients may take analgesic medication provided the dosage is stable
• Open wounds, eczema, scars, or tattoos in the area of the heat stimulation (sub-project 1)
• Lack of ability to cooperate
• Recent history of acute pain particularly in the lower limbs (unless related to low back pain in patients included in sub-project 6 or 8)
• Abnormally disrupted sleep in 24 hours preceding experiment
• Any medical or other condition (i.e. musculoskeletal, cardiorespiratory, neurological, etc.)
• Contraindications to TMS application (history of epilepsy, metal implants in head or jaw, etc.)
• Unable to answer to the "Transcranial Magnetic Stimulation Adult Safety Screen" or tDCS screening questionnaire (see Bilag_v1_06092021)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: S1 Homeostatic Plasticity-Pain; Anodal tDCS CP3 1mA FP2 -1mA 4x4 patch on the dorsum of the hand	Other: Homeostatic Plasticity; Anodal tDCS S1/M1; Drug: Topical alone (Capsaicin 8% Patch); 4x4 patch; Other Names: Qutenza Capsaicin (8%)
Placebo Comparator: S1 Homeostatic Plasticity-NoPain; Anodal tDCS C3 1mA FP2 -1mA 4x4 patch on the dorsum of the hand	Other: Homeostatic Plasticity; Anodal tDCS S1/M1; Other: Placebo Patch; 4x4 patch
Sham Comparator: S1 Homeostatic Plasticity-Sham; Sham tDCS C3 FP2 4x4 patch on the dorsum of the hand	Other: Placebo Patch; 4x4 patch; Other: Homeostatic Plasticity (Sham); sham Homeostatic Plasticity protocol over S1
Active Comparator: M1 Homeostatic Plasticity; Anodal tDCS C3 1mA FP2 -1mA 4x4 patch on the dorsum of the hand	Other: Homeostatic Plasticity; Anodal tDCS S1/M1; Other: Placebo Patch; 4x4 patch

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Contact Heat Evoked Potentials	Baseline (Evoked Potentials after stimulus onset from electroencephalographic channels)	Pre-patch application
Contact Heat Evoked Potentials	Post-Patch (Evoked Potentials after stimulus onset from electroencephalographic channels)	30 minutes after patch application
Contact Heat Evoked Potentials	Post-Priming (Evoked Potentials after stimulus onset from electroencephalographic channels)	During the homeostatic plasticity protocol - 0 minutes after the first block of anodal tDCS
Contact Heat Evoked Potentials	Post-HP (Evoked Potentials after stimulus onset from electroencephalographic channels)	0 minutes after homeostatic plasticity induction
Contact Heat Evoked Potentials	Post-HP+10 minutes (Evoked Potentials after stimulus onset from electroencephalographic channels)	10 minutes after the homeostatic plasticity protocol

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Intensity After Stimulation Blocks (0-10)	Pain intensity measured using an 11-point numeric rating scale where 0= no pain and 10 = worst imaginable pain	0 minutes after the first block of CHEP stimulation
Pain Intensity After Stimulation Blocks (0-10)	Pain intensity measured using an 11-point numeric rating scale where 0= no pain and 10 = worst imaginable pain	0 minutes after the second block of CHEP stimulation
Pain Intensity After Stimulation Blocks	Pain intensity measured using an 11-point numeric rating scale where 0= no pain and 10 = worst imaginable pain	0 minutes after the third block of CHEP stimulation
Pain Intensity After Stimulation Blocks	Pain intensity measured using an 11-point numeric rating scale where 0= no pain and 10 = worst imaginable pain	0 minutes after the fourth block of CHEP stimulation
Pain Intensity After Stimulation Blocks	Pain intensity measured using an 11-point numeric rating scale where 0= no pain and 10 = worst imaginable pain	0 minutes after the fifth block of CHEP stimulation
Presence of Allodynia After Stimulation Blocks	Measured with a calibrated brush for the study of dynamic mechanical allodynia (Brush-05®, Somedic SenseLab AB, Sösdala, Sweden)	0 minutes after the first block of CHEP stimulation
Presence of Allodynia After Stimulation Blocks	Measured with a calibrated brush for the study of dynamic mechanical allodynia (Brush-05®, Somedic SenseLab AB, Sösdala, Sweden)	0 minutes after the second block of CHEP stimulation
Presence of Allodynia After Stimulation Blocks	Measured with a calibrated brush for the study of dynamic mechanical allodynia (Brush-05®, Somedic SenseLab AB, Sösdala, Sweden)	0 minutes after the third block of CHEP stimulation
Presence of Allodynia After Stimulation Blocks	Measured with a calibrated brush for the study of dynamic mechanical allodynia (Brush-05®, Somedic SenseLab AB, Sösdala, Sweden)	0 minutes after the fourth block of CHEP stimulation
Presence of Allodynia After Stimulation Blocks	Measured with a calibrated brush for the study of dynamic mechanical allodynia (Brush-05®, Somedic SenseLab AB, Sösdala, Sweden)	0 minutes after the fifth block of CHEP stimulation
Pittsburg Sleeping Quality Index	The global PSQI score ranges from 0 to 21, calculated by adding seven component scores. A global score above 5 (PSQI > 5) indicates relevant sleep disturbances or poor sleep quality (Buysse et al., 1989).	Pre-intervention and pre-patch application
BECKS Depression Inventory	The questionnaire includes 21 items which are rated on a 4-point scale (0 to 3). The total score is calculated by adding all items. Total score values from 0-13 indicate "normal ups and downs", and scores between 14-19, 20-28, and 29-63, are interpreted as mild, moderate, and severe symptoms (Beck et al., 1996; Goldstein et al., 2013; Wang and Gorenstein, 2013).	Pre-intervention and pre-patch application
Positive and Negative Affective Schedule - Short Form	Scores can range from 10 - 50, with higher scores representing higher levels of positive/negative affect.	Pre-intervention and pre-patch application
State-Trait Anxiety Inventory	A 40-item questionnaire that assesses state and trait anxiety with 20 items each (Skapinakis, 2014; Spielberger et al., 1983). Each subscale (S-Anxiety and T-Anxiety) uses a 4-point Linkert scale ranging from 1 ("not at all" for S- or "almost never" for T-Anxiety) to 4 ("very much so" for S- and "almost always" for T-Anxiety). A higher scole indicates more severe anxiety with a range from 20-80.	Pre-intervention and pre-patch application
Pain Catastrophizing Scale	This questionnaire assesses 13 items describing different thoughts and feelings which may be associated with pain. They are rated on a 5-point scale (0-5) indicating the degree to which these thoughts and feelings are present when having pain. The total score is 0-52, with a higher score indicating a higher pain catastrophizing. (Sullivan M J L, Bishop S, Pivik J. 1995)	Pre-intervention and pre-patch application
Pain intensity (Induced by Capsaicin)	Pain intensity measured using an 11-point numeric rating scale where 0= no pain and 10 = worst imaginable pain	Throughout the experimental session, every 5 minutes and up to 55 minutes after patch application

Collaborators and Investigators

• Sponsor: Aalborg University
• Investigators: Study Director: Thomas Graven-Nielsen, PhD, DMSc, Aalborg University

Publications and helpful links

General Publications

• Thapa T, Graven-Nielsen T, Chipchase LS, Schabrun SM. Disruption of cortical synaptic homeostasis in individuals with chronic low back pain. Clin Neurophysiol. 2018 May;129(5):1090-1096. doi: 10.1016/j.clinph.2018.01.060. Epub 2018 Feb 9.
• Thapa T, Graven-Nielsen T, Schabrun SM. Aberrant plasticity in musculoskeletal pain: a failure of homeostatic control? Exp Brain Res. 2021 Apr;239(4):1317-1326. doi: 10.1007/s00221-021-06062-3. Epub 2021 Feb 26.
• Wittkopf PG, Larsen DB, Gregoret L, Graven-Nielsen T. Prolonged corticomotor homeostatic plasticity - Effects of different protocols and their reliability. Brain Stimul. 2021 Mar-Apr;14(2):327-329. doi: 10.1016/j.brs.2021.01.017. Epub 2021 Jan 24. No abstract available.
• Wittkopf PG, Larsen DB, Graven-Nielsen T. Protocols for inducing homeostatic plasticity reflected in the corticospinal excitability in healthy human participants: A systematic review and meta-analysis. Eur J Neurosci. 2021 Aug;54(4):5444-5461. doi: 10.1111/ejn.15389. Epub 2021 Jul 30.
• Wittkopf PG, Boye Larsen D, Gregoret L, Graven-Nielsen T. Disrupted Cortical Homeostatic Plasticity Due to Prolonged Capsaicin-induced Pain. Neuroscience. 2023 Nov 21;533:1-9. doi: 10.1016/j.neuroscience.2023.09.011. Epub 2023 Sep 27.
• Lejeune N, Petrossova E, Frahm KS, Mouraux A. High-speed heating of the skin using a contact thermode elicits brain responses comparable to CO2 laser-evoked potentials. Clin Neurophysiol. 2023 Feb;146:1-9. doi: 10.1016/j.clinph.2022.11.008. Epub 2022 Nov 24.
• Lenoir C, Algoet M, Mouraux A. Deep continuous theta burst stimulation of the operculo-insular cortex selectively affects Adelta-fibre heat pain. J Physiol. 2018 Oct;596(19):4767-4787. doi: 10.1113/JP276359. Epub 2018 Sep 4.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2023
• Primary Completion (Actual): March 4, 2024
• Study Completion (Actual): March 4, 2024

Study Registration Dates

• First Submitted: November 22, 2023
• First Submitted That Met QC Criteria: December 26, 2023
• First Posted (Actual): January 9, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 15, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Transcranial Direct Current Stimulation; Capsaicin; Homeostatic Plasticity
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Dermatologic Agents; Antipruritics; Capsaicin
• Other Study ID Numbers: CHEPS-DMZ-CNAP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The individual participant data will not be available online, but the data collected can be shared upon reasonable request.

Drug and device information, study documents

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