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Neural and Psychological Mechanisms of Pain Perception

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02446262
Recruitment Status : Recruiting
First Posted : May 18, 2015
Last Update Posted : August 8, 2022
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  ICMJE May 14, 2015
First Posted Date  ICMJE May 18, 2015
Last Update Posted Date August 8, 2022
Actual Study Start Date  ICMJE June 11, 2015
Estimated Primary Completion Date February 15, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (submitted: May 15, 2015)
Pain perception (pain ratings) [ Time Frame: 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Neural and Psychological Mechanisms of Pain Perception
Official Title  ICMJE Neural and Psychological Mechanisms of Pain Perception
Brief Summary


- 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.


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


- Healthy volunteers ages 18 50.


  • 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


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.


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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Other
Condition  ICMJE
  • Pain
  • Normal Physiology
  • Healthy Volunteers
Intervention  ICMJE
  • 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  ICMJE
  • 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
    • 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
    • Behavioral: Attention
    • Behavioral: Placebo instructions
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 9, 2018)
Original Estimated Enrollment  ICMJE
 (submitted: May 15, 2015)
Estimated Study Completion Date  ICMJE June 15, 2023
Estimated Primary Completion Date February 15, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.


  • 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Adebisi O Ayodele, C.R.N.P. (301) 827-0415
Contact: Lauren Y Atlas, Ph.D. (301) 827-0214
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02446262
Other Study ID Numbers  ICMJE 150132
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  ICMJE
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  ICMJE National Center for Complementary and Integrative Health (NCCIH)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP