Neural and Psychological Mechanisms of Pain Perception

• ClinicalTrials.gov Identifier: NCT02446262
• Recruitment Status: Recruiting
• First Posted: May 18, 2015
• Last Update Posted: August 8, 2022
• Sponsor: National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Center for Complementary and Integrative Health (NCCIH) )

Tracking Information

• First Submitted Date: May 14, 2015
• First Posted Date: May 18, 2015
• Last Update Posted Date: August 8, 2022
• Actual Study Start Date: June 11, 2015
• Estimated Primary Completion Date: February 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 24, 2021)

• Physiological responses (heart rate, skin conductance, respiration, pupil dilation, eye gaze position) [ Time Frame: During the study visit in response to painful and non-painful stimuli. ]
  In behavioral and fMRI experiments, we measure autonomic responses in anticipation and response to painful and non-painful stimuli using non-invasive measures.
• Pain perception (pain ratings) [ Time Frame: During the study visit in response to painful stimuli. ]
  Substudies of pain collect pain ratings using a visual analogue scale, either verbally or via computer.
• BOLD response in brain regions of interest measured using fMRI [ Time Frame: During the study visit in response to painful and non-painful stimuli. ]
  FMRI substudies proceed following behavioral substudies. We measure brain responses in anticipation and response to painful and non-painful stimuli.

• Original Primary Outcome Measures (submitted: May 15, 2015): Pain perception (pain ratings) [ Time Frame: 2 years ]

Current Secondary Outcome Measures (submitted: July 24, 2021)

Questionnaire measures (e.g. State-trait anxiety index, Fear of Pain questionnaire, Intolerance of Uncertainty questionnaire, McGill Pain Questionnaire) [ Time Frame: Trait measures are collected during initial screening visit ; State measures are collected on every visit ]

Personality measures that have been linked with pain and emotion will be tested as moderators of effects on the above outcomes.

• Original Secondary Outcome Measures (submitted: May 15, 2015): State-trait anxiety index, Fear of Pain questionnaire, Intolerance of Uncertainty questionnaire, McGill Pain Questionnaire) [ Time Frame: 2 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neural and Psychological Mechanisms of Pain Perception
• Official Title: Neural and Psychological Mechanisms of Pain Perception

Brief Summary

Background:

- Painful stimuli cause changes in a network of brain regions called the Pain Matrix. But most of these regions respond to many other stimuli, not just pain. Researchers want to understand how different factors influence pain. They want to test what happens when people expect different levels of pain and receive treatments that can modify pain. They want to see if these factors influence decisions about pain and how the body responds to it. They also want to compare pain with responses like taste and vision.

Objectives:

- To better understand how pain and emotions are processed and influenced by psychological factors.

Eligibility:

- Healthy volunteers ages 18 50.

Design:

• This study requires 1 to 2 clinic visits that last 1 to 3 hours.
• Participants will be screened with medical history and physical exam.
• Some participants will have one or more magnetic resonance imaging (MRI) scans of their brain. For MRI, participants will lie on a table that slides in and out of a cylinder. The scanner makes loud knocking noises. They will get earplugs.
• Participants heart activity will be recorded with electrocardiogram. Their pulse, sweating, and breathing will be monitored.
• Some participants will take a taste test. Others may perform simple tasks. Others may receive pain in their arm, leg, or hand. The pain will come from heat or electric shocks. Others may judge pain using a topical pain-relieving cream. Some of these tests may be given during MRI.
• Participants will fill out questionnaires.
• The study will last 3 years.

Detailed Description

Objective

Pain is one of the most important signals for an organism s survival. The pathways that transfer noxious input from the periphery to the central nervous system are highly conserved across human and animal models. In humans, the ultimate experience of pain is also highly influenced by psychological factors. For example, the placebo effect leads to robust pain relief and can influence responses to noxious stimuli in the human brain. However, the psychological and neurobiological mechanisms by which psychological

factors influence pain remain largely unknown.

Pain can be modulated by explicit beliefs about treatments, prior experience and learning, interpersonal processes that support the patient-provider relationship, and contextual factors related to the treatment environment. In the proposed series of experiments, we will systematically investigate the neural and psychological mechanisms that mediate the effects of these factors on acute pain. We will focus on expectations, attention, emotion, conditioning/associative learning, and social factors. These experiments will principally use functional magnetic resonance imaging (fMRI) and psychophysiological measurements, as well as behavioral assays and self-reports. We will examine the effects of different types of pain-related expectations on decisions about pain as well as responses in the brain and periphery. We will also compare acute pain with other hedonic and perceptual processes. This will allow us to distinguish processes

that are unique to pain perception from those that are not specific to pain, such as processes involved in perception and decision-making across domains.

Together, the proposed series of experiments aim to elucidate the psychological, neurobiological, and physiological mechanisms that modulate pain. This, in turn, can identify targets for pain treatment and inform mechanistic studies of altered pain processing in clinical populations.

Study Population

We plan to recruit 400 healthy volunteers between age 18 and 50.

Design

The aim of the proposed series of experiments is to understand how expectations, attention, and emotion influence acute pain. We will manipulate expectations about noxious stimuli using associative learning and verbal instructions, in both within-subjects and between-groups designs. We will measure decisions about pain experience (self- report) as well as neural and physiological responses to noxious stimuli that cause pain. We will combine computational modeling with advanced neuroimaging analyses to isolate the neural and psychological mechanisms that mediate the effects of expectations, attention, and emotion on subjective pain. To determine the specificity of these mechanisms, we will compare acute pain modalities (e.g., thermal pain versus shock- induced pain), and we will contrast pain with other hedonic and perceptual domains (e.g., taste).

Outcome measures

Dependent variables for all experiments will include decisions about pain and/or other percepts (e.g., sweetness of a taste) measured with visual analogue scales, reaction time, physiological responses (e.g., skin conductance, pupil dilation), and/or BOLD activation in regions of interest. We are specifically interested in processes within the network of regions known to be involved in pain processing (pain-processing network, PPN), as well as responses in the prefrontal cortex (PFC), ventral striatum (VS), and amygdala. We hypothesize that nociceptive stimuli and pain ratings will be associated with unique patterns of activation within the PPN, whereas responses in regions associated with value, executive function, and decision-making will be common across outcomes.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Other

Condition

• Pain
• Normal Physiology
• Healthy Volunteers

Intervention

• Behavioral: Instructions
  In sub-study 1, half the participants are instructed about outcomes, half learn through experience.
• Behavioral: Attention
  In sub-study 4, participants learn about outcomes and we manipulate attention toward or away from the pain.
• Behavioral: Thermal Pain
  In sub-studies 2 and 3, participants are exposed to thermal stimuli and/or tastants (sugar water, salt water, neutral rinse) and we are measuring how learning varies based on the type of outcome.
• Behavioral: Placebo instructions
  In sub-study 5, we test whether placebo effects and expectancy cues modulate pain through similar mechanisms.
• Behavioral: Liquid tastants
  MR-compatible, pneumatic-pressurized tastant-delivery system to deliver tastants that are sweet, neutral, or unpleasant.

Study Arms

• Substudy 1: Instructed subjects
  Participants are instructed about outcomes
  Intervention: Behavioral: Instructions
• Substudy 1: Uninstructed subjects
  Participants learn through experience
  Intervention: Behavioral: Instructions
• Substudy 2: heat group
  Participants learn about heat outcomes through conditioning
  Intervention: Behavioral: Thermal Pain
• Substudy 2: salt group
  Participants learn about salt outcomes through conditioning
  Intervention: Behavioral: Liquid tastants
• Substudy 2: sugar group
  Participants learn about sugar outcomes through conditioning
  Intervention: Behavioral: Liquid tastants
• Substudy 3: healthy volunteers
  All participants experience all outcomes, within subjects designs
  Interventions:

  • Behavioral: Thermal Pain
  • Behavioral: Liquid tastants
• Substudy 4: healthy volunteers
  Participants are instructed to attend toward or away from the stimulus
  Intervention: Behavioral: Attention
• Substudy 5: healthy volunteers
  Participants experience both placebo and cue-based expectations within subjects
  Interventions:

  • Behavioral: Attention
  • Behavioral: Placebo instructions

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 9, 2018): 400
• Original Estimated Enrollment (submitted: May 15, 2015): 260
• Estimated Study Completion Date: June 15, 2023
• Estimated Primary Completion Date: February 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:
• Healthy
• Between 18 and 50 years old
• Fluent in English
• Able to provide written informed consent.

EXCLUSION CRITERIA (all sub-studies):

• Unable to comply with study procedures or follow-up visits.
• Has a major medical condition or medical history that in a clinician's assessment could affect heat sensitivity, pain thresholds, or ability to comply with study procedures. This may include cardiovascular, autonomic, neurological or psychiatric conditions (including stroke and blindness or deafness, a history of brain damage, substance or alcohol dependence or abuse or psychosis) or a chronic systemic disease (e.g., diabetes).
• Has a medical condition that in a clinician's assessment might affect somatosensation (e.g., Raynaud s disease, peripheral neuropathy, or circulatory disorder).
• Has a current chronic pain condition or has had chronic pain in the past (painful condition lasting more than six months).
• Has a dermatological condition such as scars or burns, or has had a tattoo in the testing region within the previous 4 weeks that might influence cutaneous sensibility.
• Regular use of prescription medication that has a significant effect on pain or heat perception. Excluded medications include central-acting agents such as opiates (morphine, tramadol), antidepressants (amitriptyline, duloxetine, milnacipran), anticonvulsants (gabapentin, pregabalin), anxiolytics (barbituates, benzodiazepines), hypnotics (zolpidem, sodium oxybate), antipsychotics (valproate, lithium, olanzapine), antimigraine agents (sumatriptan, ergotamine), and muscle relaxants (cyclobenzaprine, carisoprodol). Use of analgesic medications, such as non-steroidal anti-inflammatories, salicylates, and acetaminophen, taken on an "as needed" basis is acceptable as long as the last dose taken was within 5 half-lives of testing.
• Is pregnant.
• NCCIH and NIMH employees.

EXCLUSION CRITERIA (fMRI sub-studies):

• Individuals with conditions that could pose a risk relating to the safety of the fMRI procedure or pain stimulation will be excluded from the MRI portion of the protocol, but may participate in the non-fMRI sessions (with the exception of pregnant women). Such conditions include:

  • Those with ferromagnetic metal in the cranial cavity or eye, e.g.. aneurysm clip, implanted neural stimulator, cochlear implant, ocular foreign body.
  • Those with an abnormality on a structural MRI.
  • Those with an implanted cardiac pacemaker or auto-defibrillator.
  • Those with an insulin pump.
  • Those with an irremovable body piercing.
  • Pregnant women (based on urine test completed within 24 hours prior to scan).
• Individuals who are left-handed (based on self-report or score on handedness questionnaire) will be excluded from fMRI substudies.

EXCLUSION CRITERIA (placebo analgesia sub-studies):

-Participation in an NIH study of analgesia, as gleaned from CRIS

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Adebisi O Ayodele, C.R.N.P.; (301) 827-0415; bisi.ayodele@nih.gov

Contact: Lauren Y Atlas, Ph.D.; (301) 827-0214; lauren.atlas@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02446262
• Other Study ID Numbers: 150132; 15-AT-0132
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: .We will share deidentified data only as per language in the protocol.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Center for Complementary and Integrative Health (NCCIH) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Center for Complementary and Integrative Health (NCCIH)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Lauren Y Atlas, Ph.D.; National Center for Complementary and Integrative Health (NCCIH)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: August 2, 2022