Personality Trait Predictors of Placebo Analgesia and Neurobiological Correlates

Supplemental Information

SUPPLEMENTARY METHODS

1.Subjects

Fifty right-handed, non-smoking subjects were recruited via advertisement. Results on 20 of the 50 subjects in the current sample were part of a previous manuscript (Scott et al, 2008). In addition to completing physical and neurological examinations, study participants underwent screening using the non-patient version of the Structured Clinical Interview for DSM-IV. Participants had no history of or current medical, neurological, or psychiatric illnesses, including substance abuse, or dependence, and had alcohol intake of less than 5 drinks per week. Women had regular menstrual cycles of 26 to 32 days’ duration and had not used hormonal birth control for at least 1 year. The women were studied during the follicular phase of the menstrual cycle. This was determined by menstrual diaries and confirmed by plasma levels of progesterone immediately before scanning (progesterone levels, <3 ng/mL [to convert progesterone to nanomoles per liter, multiply by 3.18]).

2. Quantitative Analyses

Description of the Partial Least Square (PLS) Technique and x-score.

Assume X is a n×p matrix and Y is a n×q matrix, where n is the number of subjects (n=47), p is the number of predictors (n=25) and q is the number of dependent variables (n=1=∆ in VAS from pain to pain+placebo). The PLS technique works by successively extracting factors from both X and Y such that covariance between the extracted factors is maximized. For our purpose we will assume that we have a single response (∆ in VAS) variable i.e., Y is n×1 and X is n×p, as before.

PLS technique tries to find a linear decomposition of X and Y such that X =TPT + E and

Y=UQT + F, where

  • T n×r = X-scores U n×r = Y-scores
  • P p×r= X-loadings Q 1×r = Y-loadings
  • E n×p = X-residualsF n×1 = Y-residuals

Decomposition is finalized so as to maximize covariance between T and U and an iterative process is used to extract the X-scores and Y-scores.

The factors or scores for X and Y are extracted successively and the number of factors extracted (r) depends on the rank of X and Y. In our case, Y is a vector and all possible X factors will be extracted.

Eigen Value Decomposition Algorithm.

Each extracted x-score are linear combinations of X. For example, the first extracted x-score t of X is of the form t=Xw, where w is the eigen vector corresponding to the first eigen value of XTYYTX. Similarly the first y-score is u=Yc, where c is the eigen vector corresponding to the first eigen value of YTXXTY. Note that XTY denotes the covariance of X and Y.

Once the first factors have been extracted we deflate the original values of X and Y as,

X1=X – ttTX and Y1=Y- ttTY.

The above process is now repeated to extract the second PLS factors.

The process continues until we have extracted all possible latent factors t and u, i.e., when X is reduced to a null matrix. The number of latent factors extracted depends on the rank of X.

3. Experimental design

Subjects were placed in the scanner gantry with needles (25G11/2) in both masseter muscles approximately 30 minutes before radiotracer administration. Each scanning session, with and without placebo administration, consisted of a control condition (0.9% isotonic saline, 5-25 min after start of scanning) and a painful condition (5% hypertonic saline, 45-65 min after start of scanning), infused in the masseter muscle. Volunteers were told that these two conditions would take place, but not the order in which they would take place, allowing for expectation of pain during the control condition.

In the pain condition, a steady state of moderate muscle pain was maintained for 20 min after radiotracer administration by a computer-controlled delivery system through the infusion of medication-grade hypertonic saline solution (5%) into the left masseter muscle. In this model of sustained deep somatic pain, the intensity of the painful stimulus is standardized across subjects (Stohler and Kowalski, 1999; Zhang et al, 1993). Briefly, volunteers are asked to rate pain intensity every 15 seconds from 0 (no pain) to 100 (most intense pain imaginable) using an electronic 0 to 100 visual analog scale (VAS) placed in front of the scanner gantry during both control and pain conditions. Initially, the subject-specific settings of the closed-loop system for maintaining muscle pain were established. This consisted of measuring each subject’s response to a standard 0.15-mL bolus of 5% sodium chloride injected over a 15-second period as an impulsive input while recording the subject’s pain intensity response every 15 seconds. A suitable infusion rate for the maintenance of pain over time was then estimated by comparing the subject’s response to the mean response of 65 subjects of the same age range exposed to the same bolus. From that point on, the adaptive controller depended on feedback from subjects. The subject ratings of pain intensity every 15 seconds were fed back to the computer via an analog-digital board, which then changed the infusion rate to maintain pain at similar levels over time. The same individual infusion profiles generated during the pain challenges were used for the studies with placebo administration. (Scott et al, 2008).

During the pain+placebo scanning session, subjects were given the following instructions before administration of the placebo: “We are studying the effect of a pain relief medication. This medication is thought to have analgesic effects through the activation of natural brain systems that suppress pain.” The placebo condition consisted of the introduction of 1mL of 0.9% isotonic saline into 1 of the intravenous ports every 4 minutes starting 2 minutes before the pain anticipation and pain challenges, and lasting for 15 seconds each time. Subjects were aware that the study drug was to be administered because they were alerted by a computer-generated human voice recording, followed by a second-by-second count of the infusion timing (15 seconds).

Each subject underwent 4 pain challenges, 2 of them with placebo administration, as previously described (Scott et al, 2008), and the order of each pair of pain and pain + placebo studies was randomized, but only the results of 2 of the sets are reported here, those associated with [11C]carfentanil PET scanning.

4. Neuroimaging methods

As previously described in detail (Scott et al, 2008), two 90-minute [11C]carfentanil PET studies per subject were acquired during the experimental pain challenge with and without placebo administration (Figure 3). Scans were acquired in a Siemens (Knoxville, TN) HR+ scanner in three-dimensional mode (reconstructed full-width half maximum –FWHM- resolution 5.5 mm in-plane and 5.0 mm axially), with septa retracted and scatter correction. Participants were positioned in the PET scanner gantry, and two intravenous (antecubital) lines were placed. A light forehead restraint was used to eliminate intrascan head movement. Radiotracer administrations of 15  1 mCi with a maximum cols mass of 0.03µg/kg were separated by at least 2 hours to allow for radiotracer decay. Fifty percent of the radiotracer doses were administered as an initial bolus, and the remaining 50% by continuous infusion for the remainder of the study. This procedure compensates for the metabolism of the radiotracer, leading to constant plasma concentrations over time and more rapid equilibration between kinetic compartments. For each study, 21 sets of scans (frames) were acquired over 90 minutes with an increasing duration (30 seconds frames x 4, 1 min x 3, 2.5 min x 2, 5 min x 8, 10 min x 4). Reconstruction, coregistration and warping methods were identical to those described in Scott et al. (2008). Anatomical MRI scans were acquired prior to PET scanning on a 3 Tesla scanner (General Electric, Milwaukee, WI). Acquisition sequences were axial SPGR Inverse Recovery-Prepared MR [echo time (TE) = 3.4 ms, repetition time (TR) = 10.5 ms, inversion time (TI) = 200 ms, flip angle = 25o, number of excitations (NEX) = 1, using 124 contiguous images, 1.5 mm-thickness). Reductions in the in vivo availability of receptors after the acute challenge (i.e., placebo administration during an experimental pain challenge) were used to reflect competition between radiotracer and endogenous ligand, associated with neurotransmitter release (Narendran and Martinez, 2008).

SUPPLEMENTARY BIBLIOGRAPHY

Narendran R, Martinez D (2008). Cocaine abuse and sensitization of striatal dopamine transmission: a critical review of the preclinical and clinical imaging literature. Synapse 62(11): 851-869.

Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2008). Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 65(2): 220-231.

Stohler CS, Kowalski CJ (1999). Spatial and temporal summation of sensory and affective dimensions of deep somatic pain. Pain 79(2-3): 165-173.

Zhang X, Ashton-Miller JA, Stohler CS (1993). A closed-loop system for maintaining constant experimental muscle pain in man. IEEE Trans Biomed Eng 40(4): 344-352.

SUPPLEMENTARY TABLES

Table S1. Simple linear regression.

(EWB, PWB, SWB: Emotional, Psychological and Social Well-Being, respectively; SWLS: Satisfaction With Life Scale; BAS_RR, BAS_Drive: Behavioral Activation Scale Reward-Responsiveness, Drive; BIS: Behavioral Inhibition Scale; STAI Trait: Speilberger Trait Anxiety).

Table S2. Correlations between selected traits and regional µ-opioid system activation during placebo administration.

Data show Pearson correlation values (r). Significant correlations are marked with one (p<0.05) or two asterisk (P<0.01).