Neural and Psychological Mechanisms of Pain Perception

Study Overview
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Brief Summary
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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
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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 500 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.

Official Title
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Neural and Psychological Mechanisms of Pain Perception

Conditions
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Pain, Normal Physiology, Healthy Volunteers

Intervention / Treatment
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* Behavioral: Instructions
* Behavioral: Attention
* Behavioral: Thermal Pain
* Behavioral: Placebo instructions


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Substudy 1: Instructed subjects<br>Participants are instructed about outcomes | Behavioral: Instructions<br>* In sub-study 1, half the participants are instructed about outcomes, half learn through experience.<br>|
| Other: Substudy 1: Uninstructed subjects<br>Participants learn through experience | Behavioral: Instructions<br>* In sub-study 1, half the participants are instructed about outcomes, half learn through experience.<br>|
| Other: Substudy 2: heat group<br>Participants learn about heat outcomes through conditioning | Behavioral: Thermal Pain<br>* 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.<br>|
| Other: Substudy 2: salt group<br>Participants learn about salt outcomes through conditioning | Behavioral: Thermal Pain<br>* 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.<br>|
| Other: Substudy 2: sugar group<br>Participants learn about sugar outcomes through conditioning | Behavioral: Thermal Pain<br>* 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.<br>|
| No Intervention: Substudy 3: healthy volunteers<br>All participants experience all outcomes, within subjects designs | |
| Other: Substudy 4: healthy volunteers<br>Participants are instructed to attend toward or away from the stimulus | Behavioral: Attention<br>* In sub-study 4, participants learn about outcomes and we manipulate attention toward or away from the pain.<br>|
| Other: Substudy 5: healthy volunteers<br>Participants experience both placebo and cue-based expectations within subjects | Behavioral: Placebo instructions<br>* In sub-study 5, we test whether placebo effects and expectancy cues modulate pain through similar mechanisms.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Questionnaire measures (e.g. State-trait anxiety index, Fear of Pain questionnaire, Intolerance of Uncertainty questionnaire, McGill Pain Questionnaire) | Personality measures that have been linked with pain and emotion will be tested as moderators of effects on the above outcomes. | Trait measures are collected during initial screening visit ; State measures are collected on every visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Visual Analogue Pain Scale, Placebo, Affective Neuroscience, Functional Magnetic Resonance Imaging (fMRI)