Electrophysiological Correlates of Nocebo Effects on Pain
Condition: Chronic Pain Syndrome; Chronic Pain, Psychogenic; Chronic Pain; Hyperalgesia
MeSH terms: Hyperalgesia; Chronic Pain
Study type: Interventional

Summary: 
      Pain is a nociceptive somatosensory process that can arise as a debilitating and chronic
      symptom in various diseases or following an injury. How pain is experienced can vary widely
      within and across individuals, and can be shaped by cognitive processes such as learning.
      Nocebo effects, negative changes in symptom severity attributed to learned
      outcome-expectations, demonstrate how learning processes can be detrimental for the
      experience of pain. Research to date has produced inconclusive findings regarding the
      electrophysiological correlates on nocebo effects. The few studies that have applied
      electroencephalography (EEG) in this field have pointed towards a potential involvement of
      alpha-band activity, but the direction of this involvement remains unclear. For example, an
      EEG study of conditioned nocebo hyperalgesia found a pre to post increase in resting state
      alpha band power that was correlated with pain catastrophizing scores and not with the
      magnitude of the nocebo effect. Later, other studies also found pre to post changes in alpha
      band power, however, these changes were correlated with the magnitude of nocebo effects and
      not pain catastrophizing. Given the discrepancy in findings, in this study the investigators
      plan to primarily investigate whether EEG components predict the magnitude of nocebo
      responses to thermal-pain stimuli. The investigators will also explore electrophysiological
      correlates during pain anticipation and whether nocebo responses would be significantly
      related to spectral and temporal EEG biomarkers. This study will utilize a validated model of
      instructional and associative learning methods (i.e., negative suggestions and classical
      conditioning, respectively) to experimentally induce nocebo effects on heat-evoked pain.
      Developing objective, brain-derived markers for nocebo responses, or the detection of
      individuals most susceptible to nocebo hyperalgesia, will aid in the comprehensive management
      of pain. This study is conducted at Leiden University.
    

Detailed description: 
      Main outcome variable for nocebo responses:

      - The magnitude of induced nocebo hyperalgesia is defined as the difference in pain ratings
      for the first nocebo trial compared to the first control trial of the evocation phase.

      Note: A significant difference will be assessed using a Repeated Measures ANOVA as a
      manipulation check. Then, calculated difference scores represent the magnitude of induced
      nocebo hyperalgesia and will be used for the primary and first and second secondary
      hypotheses.

      Definitions of other outcome variables:

      - The magnitude of nocebo responses (and nocebo-augmented pain) during the evocation phase is
      defined in the specific nocebo evocation trials that show heightened pain relative to the
      preceding control trials, for each subject. For EEG analyses, all trials that show the
      experience of heightened pain in nocebo trials relative to the preceding control trials,
      during the evocation phase will be used.

      Note: Calculated difference scores between the specific nocebo evocation trials that show
      heightened pain relative to control trials will be used in further analyses of EEG data.
      While the entirety of the evocation data will be reported and analyzed, the main EEG analyses
      will include a selection of evocation trials where nocebo responses were reported. It is
      necessary to use EEG data for trials that show a nocebo response in order to explore
      electrophysiological correlates of nocebo effects.

      0. Manipulation checks: Induction of nocebo hyperalgesia First, the investigators will
      examine whether significant nocebo hyperalgesia was induced. A Repeated-Measures Analysis of
      Variance (RM ANOVA) will be performed for nocebo responses (on the pain Numeric Rating
      Scale), with trial type as the within-subjects factor with two levels (first nocebo evocation
      trial, first control evocation trial). First evocation trial pairs were chosen based on the
      clearest effects being observed during piloting and in previous nocebo studies.

        1. Primary hypothesis:

           Pre-induction to post-induction decreases in resting-state alpha band power will
           positively correlate with the magnitude of induced nocebo hyperalgesia.

        2. Secondary hypotheses:

           2.1. The magnitude of induced nocebo hyperalgesia in all nocebo-response evocation
           trials, will be related to temporal (e.g., Detrended Fluctuation Analysis) and spectral
           (e.g., Absolute Power, Relative Power and Central Frequency) biomarker values of alpha,
           beta, and gamma oscillations.

           2.2. The experience of nocebo-augmented pain in nocebo trials and pain during control
           trials of the evocation phase will be characterized by divergent alpha, beta, and gamma
           oscillation power and peak frequencies.

           2.3. The experience of nocebo-augmented pain in nocebo evocation trials and baseline
           high-pain stimulations, will be characterized by divergent alpha oscillation power and
           peak frequencies.

           2.4. The experience of control and nocebo trials during the induction phase, will be
           characterized by divergent alpha, beta, and gamma oscillation power and peak
           frequencies.

           2.5. Nocebo induction trials will be characterized by increased gamma band coherence
           relative to control induction trials during anticipation.

        3. Questionnaires To assess the influence of psychological and personality traits,
           questionnaires will also be included. These will include the Pain Catastrophizing Scale
           (PSC), the Fear of Pain Questionnaire-III (FPQ-III), the Experience of Cognitive
           Intrusion of Pain (ECIP) scale, and the Amsterdam Resting State Questionnaire (ARSQ
           2.0).

      3.1. Correlation analyses will be performed between scores on the questionnaires and the
      magnitude of the nocebo effect.

      3.2. Correlation analyses will be performed between scores on the questionnaires and measures
      of EEG, as well as pre-to post resting-state differences, in alpha, beta, and gamma frequency
      bands.
    

Intervention name(s): Baseline pain stimulations; Conditioning; Evocation; Electroencephalography (EEG)
Intervention type(s): Behavioral; Behavioral; Behavioral; Other
Intervention description(s): During baseline pain stimulations, a comparison block will include 6 high- and 2 moderate-pain stimulations.; During nocebo induction trials, the conditioned stimulus (i.e., a sham medical gel that can increase pain sensitivity, named "TDA" and contained in either a brown or a blue jar) is paired to unconditioned high-pain stimuli (nocebo trials). Lower 'baseline' pain is paired with no gel application (control trials).; During nocebo evocation, lower pain stimulations are administered both after the administration of the conditioned stimulus (i.e., a sham medical gel "TDA") and the control stimulus (no medical gel), in order to evoke nocebo responses to the sham hyperalgesic medication.; In the single group of participants, EEG recordings will be conducted during baseline, during a first resting-state of 5-minutes, during induction/evocation of nocebo responses, and during a second resting-state of 5-minutes.
Other intervention name(s): Nocebo Induction phase; Nocebo testing phase
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Pain; Nocebo; Hyperalgesia; Electroencephalography; EEG; Conditioning; Learning; Negative suggestions