Pain, Learning, and Nocebo
Condition: Chronic Pain; Pain Syndrome
MeSH terms: Chronic Pain
Study type: Interventional

Summary: 
      Nocebo effects, negative responses to inert or active treatments which are putatively induced
      by negative outcome expectations, have been shown to play a significant role in pain
      perception. The underlying neurobiological mechanisms of these effects remain largely
      unexplored. The primary objective of this study is to test the role of N-methyl-D-aspartate
      (NMDA) receptor-dependent learning in an experimental model of conditioned nocebo effects on
      self-reported pain. Secondary objectives are to examine the role of the NMDA manipulation and
      related neural correlates during the acquisition and extinction of nocebo effects using
      statistical learning models. This study will utilize a placebo controlled, double-blind
      design with respect to the pharmacological administration of 80 mg D-Cycloserine (DCS), an
      NMDA agonist, or placebo. Validated conditioning and verbal suggestion (VS) paradigms will
      induce nocebo effects on pain in a random sample of 50 healthy adults. The primary endpoint
      of the study is the magnitude of the induced nocebo effect on pain measured as the difference
      between self-reported pain, between the first conditioned and control extinction trials.
      Secondary endpoints include the classification analysis of the Blood Oxygen Level Dependent
      (BOLD) responses of participants into pharmacological groups with multivariate pattern
      analysis. This study will be conducted at Leiden University and the Leiden University Medical
      Center (LUMC), The Netherlands.
    

Detailed description: 
      Main outcome variable:

      - 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 extinction phase.

      A significant difference here is assessed within the mixed model analysis of variance
      (ANOVA), comparing within-subjects differences for control and nocebo trials between DCS and
      placebo groups.

      Time frame: On the day of the experimental session, during the extinction phase

      Secondary outcome variables:

        -  The difference in BOLD response at a series of a priori ROIs between pharmacological
           groups during the acquisition of nocebo effects.

        -  The classification accuracy (into pharmacological groups), indicating that patterns of
           activation in the network of a priori ROIs form a model that can detect differences in
           neural activations during the acquisition of nocebo effects.

        -  The difference in BOLD response at a series of a priori ROIs between pharmacological
           groups during the extinction of nocebo effects.

        -  The classification accuracy (into pharmacological groups), indicating that patterns of
           activation in the network of a priori ROIs form a model that can detect differences in
           neural activations during the first trials of the extinction phase.

        -  The difference in BOLD response at a series of a priori ROIs between pain at baseline
           and nocebo-augmented pain.

        -  The classification accuracy, indicating that patterns of activation in the network of a
           priori ROIs form a model that can detect commonalities and differences in neural
           activations between the experience of pain at baseline and nocebo-augmented pain.

        -  The prediction accuracy, indicating that patterns of activation in the network of a
           priori ROIs form a model that can predict the magnitude of induced nocebo effects based
           on patterns of activations during the acquisition of nocebo effects.

        -  The moderation of the magnitude of induced nocebo effects in the first trials of the
           extinction phase by scores on the psychological questionnaires.

           0. Manipulation checks: Pain intensity responses during the acquisition phase To assess
           the effectiveness of the conditioning paradigm, pain ratings during acquisition will be
           analysed using a 2x1 mixed model ANOVA with group as a between-subjects factor (DCS,
           placebo), and pain intensity scores as a within-subjects, repeated measure with two
           levels (conditioned and unconditioned trials).

      Effect of DCS on learning The Wechsler Memory Scale-Fourth Edition (WMS-IV) subtest Verbal
      Paired Associates will be used to assess whether DCS enhanced learning. A 2x1 mixed model
      ANOVA with group as the between-subjects factor and WMS-IV scores as the within-subjects
      repeated measure with two measurements, before administering DCS or placebo versus at two
      hours post-administration, before the beginning of the conditioning paradigm.

        1. Primary hypothesis:

           The magnitude of the induced nocebo effect on pain is hypothesized to be larger in the
           DCS group relative to the placebo group. The magnitude of the nocebo effect is measured
           as the difference between self-reported pain on a Numeric Rating Scale (NRS) between the
           first conditioned and control extinction phase trials.

        2. Secondary hypotheses:

           2.1. The magnitude of the conditioned nocebo effects still present after extinction is
           measured as the change from the average nocebo effect reported in the first trials of
           the extinction phase (after acquisition) and the average nocebo effect reported in last
           trials of the extinction phase (after extinction).

           2.2. DCS and placebo groups will be characterized by divergent neural activity across a
           set of a priori regions of interest (ROIs) during acquisition. ROI analysis of
           differences in BOLD responses will be performed on periaqueductal grey, (PAG),
           ventrolateral prefrontal cortex, (vlPFC), and dorsolateral prefrontal cortex (dlPFC),
           amygdala, anterior cingulate cortex (aCC), hippocampus, rostral ventromedial medulla
           (RVM), thalamus, insula.

           2.3 Multivariate pattern analysis (i.e., machine learning methods) will be used to
           investigate differences in BOLD responses during the acquisition of nocebo effects and
           thereby classify participants into pharmacological treatment groups (1) DCS, or 2)
           placebo) based on neural activity in the following ROIs: PAG, vlPFC, dlPFC, aCC, RVM,
           amygdala, thalamus, insula.

           2.4. DCS and placebo groups will be characterized by divergent BOLD responses across a
           set of a priori ROIs during extinction. ROI analysis for differences in BOLD responses
           between DCS and placebo groups will be performed on the following ROIs: PAG, vlPFC,
           dlPFC, aCC, RVM, amygdala, thalamus, insula.

           2.5 Multivariate pattern analysis will be used to investigate differences in BOLD
           responses during the extinction of nocebo effects and thereby classify participants into
           pharmacological treatment groups (1) DCS, or 2) placebo) based on neural activity in the
           following ROIs: PAG, vlPFC, dlPFC, aCC, RVM, amygdala, thalamus, insula.

           2.6. Pain and baseline, and nocebo augmented pain of a similar intensity will be
           characterized by divergent neural activations. Within the placebo group, ROI analysis
           for differences in BOLD responses between nocebo experiences and sensory experiences of
           pain based on BOLD responses in the following ROIs: PAG, vlPFC, dlPFC, aCC, RVM,
           amygdala, thalamus, insula.

           2.7. Pain and baseline, and nocebo augmented pain of a similar intensity will be
           characterized by divergent neural activations. Within the placebo group, multivariate
           pattern analysis will be used to investigate the differences in BOLD responses between
           nocebo experiences and sensory experiences of pain based on neural activity in the
           following ROIs: PAG, vlPFC, dlPFC, aCC, RVM, amygdala, thalamus, insula.

           . 2.8. Patterns of BOLD responses measured during the acquisition of nocebo effects in
           all pharmacological groups (1) DCS, or 2) placebo) at the previously listed ROIs, will
           predict the magnitude of nocebo effects on pain during extinction.

        3. Questionnaires To assess the influence of psychological traits, questionnaires will also
           be included. These will include the Pain Catastrophizing Scale (PSC), Spielberger State
           Trait Anxiety Inventory (STAI), and the Body Vigilance Scale (BVS).
    

Intervention name(s): D-cycloserine; Conditioning; Extinction; fMRI; Placebo
Intervention type(s): Drug; Behavioral; Behavioral; Other; Drug
Intervention description(s): Antibiotic medication that augments the function of NMDA-receptors; During nocebo acquisition trials, the conditioned stimulus (i.e., activation of a sham electrode that can increase pain sensitivity, is paired to unconditioned high-pain stimuli (nocebo trials). During control trials of the acquisition phase, moderate-pain stimuli are paired to no sham electrode activation.; During nocebo extinction, moderate pain stimulations are administered both after the administration of the conditioned stimulus (i.e., activation of the sham electrode) and the control stimulus (no activation of the sham electrode), in order to evoke nocebo responses to the sham hyperalgesic procedure.; In both arms of the study, BOLD response data will be collected with fMRI during the acquisition and extinction of nocebo effects on pain.; Placebo control in oral form
Other intervention name(s): DCS
Intervention MeSH terms: Cycloserine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Nocebo; Pain; BOLD; fMRI; Conditioning