Exploring Pain Modulation With TMS and Repeated Pain Conditioning in Healthy Individuals

NCT06726018 | Not Yet Recruiting

• 1 other identifier: 2261897-1
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

Conditioned pain modulation (CPM) is the behavioral measure of diffuse noxious inhibitory control (DNIC), an endogenous pain inhibitory pathway in which pain inhibits pain. CPM is less efficient in individuals with chronic pain conditions, and it is a predictor for the development of chronic pain. Continuous stimulation of central/cortical mechanisms through engaging CPM might alter pain processing and improve pain inhibition. Transcranial Magnetic Stimulation (TMS) is a valuable tool for assessing how effectively the brain's central and cortical mechanisms engage in pain inhibition, particularly through pathways like CPM. While alterations in cortical excitability related to analgesic-induced pain inhibition have been documented, the effects of continuous stimulation of central pain pathways, along with the mediating influence of psychosocial factors, remain underexplored. This study aims to investigate the central pain modulatory mechanisms, as assessed by CPM, and cortical excitability, as measured by TMS, in healthy participants. Additionally, the study will evaluate the impact of sociocultural factors, including ethnic identity, optimism, resilience, perceived stress, and marginalization, on the magnitude and efficiency of CPM responses. The successful completion of this research will determine how cortical excitability changes due to training and whether these changes are mediated by psychosocial factors.

Conditions

Healthy Adult

Keywords

Pain; Pain Modulation; Conditioned Pain Modulation; Transcranial Magnetic Stimulation; Chronic Pain Mechanisms

Outcome Measures

Primary Outcomes (3)

• Conditioned Pain Modulation as an assessment

  Participants will receive a testing stimulus of pressure applied per ascending intensity at the web space of the foot until the pain reaches 40 out of 100, then discontinued. After testing the stimulus, Participants will receive a conditioning stimulus contact heat stimulus applied to the thenar of the left hand for 60 s at an intensity of 46.5 ◦C. Subjects will be asked to rate the heat pain during the four 60-second trials. Subjects will be instructed that they may remove their hand at any time if the heat is intolerable. After 60 seconds, the contact heat will be completely removed, and the testing stimulus will be re-applied to the web space of the dominant foot. Conditioned pain modulation will be calculated as the average pain ratings of the second testing stimulus series minus the average pain ratings of the first testing stimulus series. Negative numbers indicate efficient pain modulation

  Two-weeks

• Transcranial Magnetic Stimulation

  Individuals meeting the TMS safety criteria will undergo baseline TMS to determine the resting motor threshold, short-interval intracortical inhibition (SICI) protocols. Both are established, reliable, valid protocols to measure motor cortical excitability and inhibition, respectively. TMS will be delivered using a D702 coil connected to Magstim 2002 magnetic stimulators via a Bistim unit (Magstim, UK). A resting motor threshold, defined as the stimulus intensity required to elicit a 50uV motor evoked potential in 5 out of ten TMS stimuli at the motor hotspot for dominant abductor pollicis brevis (APB) muscle will be determined with the participant seated, both shoulders in neutral, forearm supinated, and palms resting on a pillow in their lap. Twenty pulses of 1mV peak to peak motor evoked potentials will be recorded to assess cortical excitability. SICI will be investigated by applying a subthreshold conditioning stimulus before the test stimulus using a 1ms (SICI1ms) or a 3ms (SICI

  Two-weeks

• Quantitative Sensory Testing

  Slow Ramp Protocol: A computer-controlled TSAII NeuroSensory Analyzer (Medoc, Inc.) will deliver a thermal stimulus to the dominant forearm, starting at 35°C and increasing to 51°C in 1°C increments, each lasting 1 seconds. Participants will report when the sensation changes from warmth to pain (pain threshold) and when it becomes intolerable (pain tolerance). The procedure will be repeated twice with a pseudorandom interval (1 sec/min), and average thresholds and tolerances will be analyzed. Post-Stimulus Ratings: Participants will rate pain every 10 seconds for 60 seconds after the thermode is removed. These ratings primarily reflect C-fiber-mediated responses. Pressure Pain Threshold: Using an algometer with a 1 cm rubber tip, pressure will be applied at 1 kg/s to the first dorsal interosseous muscle of the dominant hand. Participants will report when the sensation changes from pressure to pain (pain threshold). The procedure will be repeated twice. Average will be calculated.

  Two-weeks

Study Arms (3)

High Exposure (HE)

EXPERIMENTAL

Participants will receive five sessions total: four sessions of the Intervention, CPM and TMS as an outcome in every session and questionnaires and QST as an outcome in the first and fifth sessions.

Behavioral: Conditioned Pain Modulation (CPM)

Low Exposure (LE)

ACTIVE COMPARATOR

Participants will receive only two sessions in total: one session of the intervention, questionnaires, quantitative sensory testing, CPM and TMS as an outcome at both sessions.

Behavioral: Conditioned Pain Modulation (CPM)

No Exposure (NE)

NO INTERVENTION

Participants will receive only two sessions in total: questionnaires, quantitative sensory testing, and TMS as an outcome at both sessions.

Interventions

Conditioned Pain Modulation (CPM) BEHAVIORAL

Participants will receive a testing stimulus of pressure applied per ascending intensity at the web space of the foot until the pain reaches 40 out of 100, then discontinued. After testing the stimulus, participants will then receive a conditioning stimulus by immersing the non-dominant hand into the water-cooled by refrigeration unit with a temperature of 6 degree Celsius (males) or 8 degree Celsius (females) for 60 seconds. Subjects will be asked to rate the cold pain during the four 60-second trials. Participants completely removed their hand from the cold pressor for 30 seconds following each of the four 60-second immersions, during which time the testing stimulus will be re-applied per the sequential paradigm to the web space of the foot. Participants complete four 60-second periods of immersion.

High Exposure (HE); Low Exposure (LE)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• pain-free
• between 18-75 years old.

You may not qualify if:

• Participants will not be excluded based on race or gender but will be excluded if they meet any of the following:
• non-English speaking
• systemic medical condition is known to affect sensation
• regular use of prescription pain medication to manage pain
• current or history of chronic pain condition
• currently using blood thinning medication
• any blood clotting disorder such as hemophilia
• any contraindication to the application of ice or cold packs, such as uncontrolled hypertension, cold urticaria, cryoglobulinemia, paroxysmal cold hemoglobinuria, and circulatory compromise
• involved in vigorous physical activities like heavy lifting, digging, aerobics or fast bicycling
• metal in the head or eyes, pacemakers, shunts, or lines, history of craniotomy, history of focal seizures
• Migraine and persistent headaches.

Sponsors & Collaborators

• Priyanka Rana, PT, MPT, PhD: lead

Study Sites (1)

Department of Physical Therapy and Movement Science, University of Texas at El Paso

El Paso, Texas, 79902, United States

Location

Related Publications (14)

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  PMID: 25267013 BACKGROUND

• Ibancos-Losada MDR, Osuna-Perez MC, Castellote-Caballero MY, Diaz-Fernandez A. Conditioned Pain Modulation Effectiveness: An Experimental Study Comparing Test Paradigms and Analyzing Potential Predictors in a Healthy Population. Brain Sci. 2020 Aug 30;10(9):599. doi: 10.3390/brainsci10090599.

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  PMID: 30487891 BACKGROUND

• Harris KM, Gaffey AE, Schwartz JE, Krantz DS, Burg MM. The Perceived Stress Scale as a Measure of Stress: Decomposing Score Variance in Longitudinal Behavioral Medicine Studies. Ann Behav Med. 2023 Sep 13;57(10):846-854. doi: 10.1093/abm/kaad015.

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• Goubert D, Danneels L, Cagnie B, Van Oosterwijck J, Kolba K, Noyez H, Meeus M. Effect of Pain Induction or Pain Reduction on Conditioned Pain Modulation in Adults: A Systematic Review. Pain Pract. 2015 Nov;15(8):765-77. doi: 10.1111/papr.12241. Epub 2014 Nov 11.

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• Bellei-Rodriguez CE, Colloca L, Lorrain D, Marchand S, Leonard G. Nocebo Effect on Pain Perception and Attention with Children With and Without Attention Deficit And/Or Hyperactivity Disorder. J Dev Behav Pediatr. 2024 Nov-Dec 01;45(6):e537-e544. doi: 10.1097/DBP.0000000000001314. Epub 2024 Nov 11.

  PMID: 39377730 BACKGROUND

• 6. Chowdhury, N. S., Chiang, A. K., Millard, S. K., Skippen, P., Chang, W.-J., Seminowicz, D. A., & Schabrun, S. M. (2023). Alterations in cortical excitability during pain: A combined TMS-EEG Study. BioRxiv : The Preprint Server for Biology. https://doi.org/10.1101/2023.04.20.537735

  BACKGROUND

• Chen R, Del Rosario K, Lockman A, Boehm J, Bousquet Santos K, Siegel E, Berry Mendes W, Kubzansky LD. Effects of Induced Optimism on Subjective States, Physical Activity, and Stress Reactivity. J Posit Psychol. 2023;18(4):592-605. doi: 10.1080/17439760.2022.2070529. Epub 2022 May 8.

  PMID: 37378047 BACKGROUND

• 4. Burke, K. L., Barry Joyner, A., Czech, D. R., & Wilson, M. J. (1989). An Investigation of Concurrent Validity between Two Optimism/Pessimism Questionnaires: The Life Orientation Test-Revised and the Optimisn essimism Scale. Marshall and Lang.

  BACKGROUND

• Brown SD, Unger Hu KA, Mevi AA, Hedderson MM, Shan J, Quesenberry CP, Ferrara A. The multigroup ethnic identity measure-revised: measurement invariance across racial and ethnic groups. J Couns Psychol. 2014 Jan;61(1):154-161. doi: 10.1037/a0034749. Epub 2013 Nov 4.

  PMID: 24188656 BACKGROUND

• 2. Bollwerk, M., Wetzel, E., Schlipphak, B., & Back, M. D. (2024). Who feels marginalized? A latent class analysis of perceived societal marginalization. Group Processes and Intergroup Relations, 27(3), 597-618. https://doi.org/10.1177/13684302231182924

  BACKGROUND

• Bollwerk, M., Schlipphak, B., & Back, M. D. (2022). Development and Validation of the Perceived Societal Marginalization Scale. European Journal of Psychological Assessment, 38(2), 137-149. https://doi.org/10.1027/1015-5759/a000651

  BACKGROUND

MeSH Terms

Conditions

Pain

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Priyanka Rana, PT, MPT, PhD

CONTACT

352-870-2260; prana@utep.edu

Carolina Valencia, PT, PhD

CONTACT

352-256-9945; cvalencia4@utep.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: December 5, 2024
• First Posted: December 10, 2024
• Study Start: January 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): July 1, 2027
• Last Updated: December 10, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)