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A Functional Neuroimaging Study of Expectancy Effects on Pain Response in Patients With Knee Osteoarthritis

  • Randy L. Gollub
    Correspondence
    Address reprint requests to Randy L. Gollub, MD, PhD, 120 2nd Ave, Room 101D, Charlestown, MA 02129.
    Affiliations
    Psychiatric Neuroimaging, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts
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  • Irving Kirsch
    Affiliations
    Program in Placebo Studies and Therapeutic Encounter, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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  • Nasim Maleki
    Affiliations
    Psychiatric Neuroimaging, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Ajay D. Wasan
    Affiliations
    Departments of Anesthesiology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Robert R. Edwards
    Affiliations
    Pain Management Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts
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  • Yiheng Tu
    Affiliations
    Psychiatric Neuroimaging, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Ted J. Kaptchuk
    Affiliations
    Program in Placebo Studies and Therapeutic Encounter, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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  • Jian Kong
    Affiliations
    Psychiatric Neuroimaging, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts
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Open AccessPublished:January 08, 2018DOI:https://doi.org/10.1016/j.jpain.2017.12.260

      Highlights

      • We used fMRI to explore the effect of acupuncture in older patients with osteoarthritis of the knee.
      • Pain decreased after both real and sham acupuncture when patients expected relief.
      • fMRI activity associated with pain relief differed for real and sham acupuncture.
      • Expectancy may work by distinct mechanisms when coupled with different treatments.

      Abstract

      Placebo treatments and healing rituals share much in common, such as the effects of expectancy, and have been used since the beginning of human history to treat pain. Previous mechanistic neuroimaging studies investigating the effects of expectancy on placebo analgesia have used young, healthy volunteers. Using functional magnetic resonance imaging (fMRI), we aimed to investigate the neural mechanisms by which expectancy evokes analgesia in older adults living with a chronic pain disorder and determine whether there are interactions with active treatment. In this fMRI study, we investigated the brain networks underlying expectancy in participants with chronic pain due to knee osteoarthritis (OA) after verum (genuine) and sham electroacupuncture treatment before and after experiencing calibrated experimental heat pain using a well tested expectancy manipulation model. We found that expectancy significantly and similarly modulates the pain experience in knee OA patients in both verum (n = 21, 11 female; mean ± SD age 57 ± 7 years) and sham (n = 22, 15 female; mean ± SD age 59 ± 7 years) acupuncture treatment groups. However, there were different patterns of changes in fMRI indices of brain activity associated with verum and sham treatment modalities specifically in the lateral prefrontal cortex. We also found that continuous electroacupuncture in knee OA patients can evoke significant regional coherence decreases in pain associated brain regions. Our results suggest that expectancy modulates the experience of pain in knee OA patients but may work through different pathways depending on the treatment modality and, we speculate, on pathophysiological states of the participants.

      Perspective

      To investigate the neural mechanisms underlying pain modulation, we used an expectancy manipulation model and fMRI to study response to heat pain stimuli before and after verum or sham acupuncture treatment in chronic pain patients. Both relieve pain and each is each associated with a distinct pattern of brain activation.

      Key words

      Placebo treatments and healing rituals have been used since the beginning of human history. Although it is well known that expectation of treatment benefit can significantly influence health outcomes,
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      Getting the pain you expect: Mechanisms of placebo, nocebo and reappraisal effects in humans.
      the systematic study of placebo effects, including expectancy, in patient populations is just beginning.
      Of all expectancy effects, analgesia evoked by manipulation of expectation for pain relief is the most thoroughly studied. Neuroimaging studies reveal that activation in complex networks of brain regions is associated with placebo analgesia and the pattern of activation depends on the aspect of the experience being investigated (eg, during anticipation, pain administration, or poststimulus pain rating)
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      and may also depend on the type of stimulus and the method and site of its administration. Most of these studies have been performed on young healthy volunteers; only a few studies
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      have examined patients with a chronic pain disorder.
      Accumulating evidence suggests that expectancy-mediated placebo analgesia may work through different brain mechanisms in healthy subjects and patient populations.
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      For instance, one prevailing hypothesis of expectancy-evoked analgesia is that it works through activating the descending pain modulatory system that could subsequently lead to increase in the endogenous opioids that would suppress pain.
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      who are reported to have significant structural changes in key brain regions, such as dorsal lateral prefrontal cortex (LPFC), and brainstem nuclei,
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      These findings suggest that different mechanisms may mediate expectancy analgesia in people with and without chronic pain disorders.
      Much of the research on analgesic expectancy effects investigates only inert treatments such as placebo creams or sham acupuncture. This contrasts with the situation in clinical practice, where expectancy effects interact with an active treatment. Few neuroimaging studies
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      The effect of treatment expectation on drug efficacy: Imaging the analgesic benefit of the opioid remifentanil.
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      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      • Schenk L.A.
      • Sprenger C.
      • Geuter S.
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      Expectation requires treatment to boost pain relief: An fMRI study.
      have investigated expectancy of active analgesic treatments; even fewer studies
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      • Schenk L.A.
      • Sprenger C.
      • Geuter S.
      • Buchel C.
      Expectation requires treatment to boost pain relief: An fMRI study.
      have directly compared the brain networks associated with expectancy effects when inert treatments are given to the brain networks associated with expectancy effects when active treatments are given. Because the underlying networks associated with expectancy effects linked with active treatment may differ from those associated with expectancy effects combined with inert treatment, it is imperative to directly investigate the interaction between “pure” expectancy-mediated analgesia and treatment-mediated analgesia.
      Acupuncture is known to produce analgesic effects
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      that are mediated, at least in part, through the descending pain modulatory system.
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      It is also clear that the nonspecific effects in acupuncture treatment of chronic pain are robust.
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      • Linde K.
      Acupuncture for chronic pain: Individual patient data meta-analysis.
      Thus, acupuncture treatment in patients with knee osteoarthritis (OA) provides a unique model for investigating the neurobiology of expectancy effects of verum (genuine) as well as sham treatments in people living with chronic pain.
      In this study, we used multiple analytic methods applied to functional magnetic resonance imaging (fMRI) data to explore the central brain mechanisms by which expectation modulates the analgesic effects of verum and sham acupuncture treatment in chronic pain patients with knee OA. We hypothesize that different mechanisms underlie expectancy modulation in real versus sham acupuncture in knee OA patients.

      Methods

       Participants

      All participants were initially screened using a detailed telephone questionnaire administered by an experienced research assistant who collected self-report information about current and past medical history, medications, and treatments. All potential participants who passed this initial screen were required to provide written documentation of a recent knee x-ray including the radiology report. The screening information was reviewed by one of our board-certified pain medicine clinicians (A.D.W. or R.R.E.), who contacted the participant directly to verify or clarify any inconclusive information. Participants (n = 67) were enrolled in the study if they met all inclusion criteria and no exclusion criteria.
      Inclusion criteria were: ongoing painful knee symptoms in 1 or both knees, an average daily pain score of at least 3 of 10 during at least half of the past month, and a grade 2 or 3 on the Kellgren-Lawrence Scale, a radiographic scale suggested by the American College of Rheumatology
      • Beattie K.A.
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      • Boulos P.
      • Webber C.E.
      • Eckstein F.
      • Adachi J.D.
      Minimum joint space width and tibial cartilage morphology in the knees of healthy individuals: A cross-sectional study.
      • Gossec L.
      • Hawker G.
      • Davis A.M.
      • Maillefert J.F.
      • Lohmander L.S.
      • Altman R.
      • Cibere J.
      • Conaghan P.G.
      • Hochberg M.C.
      • Jordan J.M.
      • Katz J.N.
      • March L.
      • Mahomed N.
      • Pavelka K.
      • Roos E.M.
      • Suarez-Almazor M.E.
      • Zanoli G.
      • Dougados M.
      OMERACT/OARSI initiative to define states of severity and indication for joint replacement in hip and knee osteoarthritis.
      • Kellgren J.H.
      • Lawrence J.S.
      Radiological assessment of osteo-arthrosis.
      • Kellgren J.H.
      • Lawrence J.S.
      Radiological assessment of rheumatoid arthritis.
      for quantifying knee OA severity.
      Exclusion criteria were: interventional procedure for knee pain within 6 months, including corticosteroid injections to the knee; intent to undergo surgery during the time of involvement in the study; presence of cardiovascular, neurological, or psychiatric disorder that would interfere with conduct of the study; presence of additional pain disorder (including postoperative pain) with severity greater than knee OA pain; pregnancy; positive urine screening test for drugs of abuse; difficulties in reading, speaking, or understanding English; or contraindications to magnetic resonance imaging (MRI) scanning. Further, during the analysis stage, the participants were excluded if they did not complete all of the study sessions, showed excessive head movement during MRI scanning, or had a brain abnormality discovered during the MRI scan.
      All participants were naïve to acupuncture at the time of enrollment so that they could not guess if they were receiving real or sham acupuncture and to also avoid confounds due to previous experience or conditioning effects. The participants were told that this study was an investigation of acupuncture analgesia. Experiments were conducted with approval from the Massachusetts General Hospital institutional review board and written, informed consent of each participant (ClinicalTrials.gov identifier: NCT01040754). Participants were debriefed about the true nature of the study after completion of all procedures. All participants agreed to allow their data to be analyzed.

      Experimental Procedures

      In a previous article we reported on the feasibility of using pretest resting state fMRI data from this experiment to predict treatment response to verum and sham electroacupuncture (EA).
      • Hashmi J.A.
      • Kong J.
      • Spaeth R.
      • Khan S.
      • Kaptchuk T.J.
      • Gollub R.L.
      Functional network architecture predicts psychologically mediated analgesia related to treatment in chronic knee pain patients.
      The present study focuses on analyses of fMRI scans which have not been previously reported. The experimental design was nearly identical to our previous studies
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      conducted in healthy subjects. Each patient participated in 2 behavioral testing sessions the first of which included neuropsychological assessments including the Beck Depression Inventory (BDI)
      • Geisser M.E.
      • Roth R.S.
      • Robinson M.E.
      Assessing depression among persons with chronic pain using the center for epidemiological studies depression scale and the beck depression inventory: A comparative analysis.
      and Spielberger State-Trait Anxiety Inventory (STAI),
      • Spielberger C.D.
      • Gorsuch R.L.
      • Lushene R.E.
      Manual for the State-Trait Anxiety Inventory.
      and 1 fMRI scanning session. Each session was separated by a minimum of 3 days from the other sessions with no more than 10 days of separation between consecutive sessions.
      Calibrated thermal pain stimuli were delivered to the right medial aspect of the forearm using a TSA-2001 Thermal Sensory Analyzer with a 3 cm × 3 cm probe (Medoc Advanced Medical Systems, Rimat Yishai, Israel) running computerized visual analog scale software. All stimuli were initiated from a baseline resting temperature of 32°C and increased to a target temperature determined according to each participant's sensory and affective ratings for nociceptive stimulation. Each stimulus was presented for 12 seconds, including a 2.5-second ramp up and ramp down, and the interstimulus interval ranged from 24 to 30 seconds.
      Gracely Sensory and Affective scales
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      • Wallace M.S.
      • Funk S.D.
      • Rutledge T.R.
      • Wetherell J.L.
      • Matthews S.C.
      • Zisook S.
      • Garfin S.R.
      A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component.
      • Gendreau M.
      • Hufford M.R.
      • Stone A.A.
      Measuring clinical pain in chronic widespread pain: Selected methodological issues.
      • Gracely R.H.
      • Dubner R.
      • McGrath P.A.
      Narcotic analgesia: Fentanyl reduces the intensity but not the unpleasantness of painful tooth pulp sensations.
      • Gracely R.H.
      • Kwilosz D.M.
      The Descriptor Differential Scale: Applying psychophysical principles to clinical pain assessment.
      • Gracely R.H.
      • McGrath P.A.
      • Dubner R.
      Ratio scales of sensory and affective verbal pain descriptors.
      • Gracely R.H.
      • McGrath P.A.
      • Dubner R.
      Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: Manipulation of affect by diazepam.
      • Lenz F.A.
      • Seike M.
      • Richardson R.T.
      • Lin Y.C.
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      • Khoja I.
      • Jaeger C.J.
      • Gracely R.H.
      Thermal and pain sensations evoked by microstimulation in the area of human ventrocaudal nucleus.
      were used to measure subjective pain ratings. To ensure consistent pain administration, a 2 × 3 grid was drawn with marker along the palmar side of the forearm, with 3 boxes each on the radial and ulnar sides. We placed the thermal probe in 1 box of the grid for each stimulus sequence (Fig 1).
      Figure 1
      Figure 1Study design and experimental approach. Enrolled participants are trained to rate calibrated, exogenous heat pain stimuli in session 1. In session 2, participants that rate the session 1 training stimuli consistently across these 2 sessions proceed in the study. They are randomized to either sham or verum treatment and to be treated on either the radial or ulnar side of their right forearm. The expectancy manipulation consists of verbal suggestion that acupuncture will diminish heat pain paired with a conditioning procedure only on the “treated” side. The conditioning consists of administration of RS and IS of noxious heat stimuli to each of the 3 regions on each side of their right forearm (PRE), applying either sham or verum EA to their right hand at LI3 and LI4 acupoints, and then repeating the IS of noxious heat stimuli (POST) with temperatures surreptitiously lowered on the HE side (dIS in green) to create the unmistakable experience of pain relief. The neuroimaging experiment is conducted in session 3. Participants are told that the session 2 procedures will be repeated during fMRI scans. To further boost expectation of pain relief, the first series of noxious heat stimuli on the treated side are again delivered at a lower temperature. The fMRI scans collected during 4 series of identical noxious stimuli to the “treated” and control sides of the forearm are the outcome measures.

       Session 1

      We used the first session to determine appropriate heat stimulus intensities for each participant, to minimize anticipatory anxiety, to control for rating strategy and learning effects, and to teach the participants to rate noxious heat stimuli using the Gracely Sensory Box and Affective Box scales.
      • Gracely R.H.
      • McGrath P.A.
      • Dubner R.
      Ratio scales of sensory and affective verbal pain descriptors.
      The Box Scales are ratio scales used to rate perception of the sensory and affective components of pain sensations that are particularly sensitive to determining change within an experimental session.
      Suprathreshold heat pain stimuli were delivered to the right medial forearm. The thermode was placed over 1 of the 6 regions and left in place for each sequence of stimuli. Two temperatures, one that elicited low ratings (5–7 on the Gracely Scale; mild to moderate) and one that elicited high ratings (14–17; strong to intense) were selected for each participant.

       Session 2

      The pain stimulation during this session consisted of 4 phases. 1) Administration of a random sequence (RS) consisting of 8 randomized high and low temperature stimuli. This RS was administered twice (ie, once to each of the bottom 2 boxes on the grid). 2) Administration of an identical sequence (IS) consisting of 6 repetitions of the same high-intensity stimulus 4 times (ie, once to each of the top 4 boxes of the grid). 3) Treatment with either verum or sham EA. 4) Post-treatment expectancy manipulation as described in the next section (Fig 1).
      Participants had to consistently rate high pain stimuli as more painful than low pain stimuli during the RS administration, report approximately equivalent pain intensity ratings to the IS on the radial and ulnar sides of their arm, and also be consistent in their ratings to these 2 sequences from session 1 to session 2. If so, they were randomized into one of the treatment groups and continued in the study; otherwise they were dropped.

       Expectancy Manipulation

      We manipulated the participants' expectancy of acupuncture analgesia using the same method as in our previous studies in healthy subjects
      • Kong J.
      • Gollub R.L.
      • Rosman I.S.
      • Webb J.M.
      • Vangel M.G.
      • Kirsch I.
      • Kaptchuk T.J.
      Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging.
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      as modified from earlier studies using placebo creams.
      • Wager T.D.
      • Rilling J.K.
      • Smith E.E.
      • Sokolik A.
      • Casey K.L.
      • Davidson R.J.
      • Kosslyn S.M.
      • Rose R.M.
      • Cohen J.D.
      Placebo-induced changes in FMRI in the anticipation and experience of pain.
      At the beginning of session 2 participants were given a scripted explanation that a person's responses to acupuncture can be positive or neutral, and that this response tends to remain consistent over time. Participants then viewed a traditional Chinese medicine meridian diagram and were told that acupuncture could only produce analgesia on the side of the arm through which the meridian passed (the “treated” side, where the needles would be placed) but not on the other side of the arm (the “untreated” side). Neither of these statements is in fact true. This verbal suggestion is one component of the manipulation to enhance expectancy for analgesia on the treated side. To balance the design, half the participants were shown accurate diagrams of the large intestine meridian passing through the radial side of the arm, whereas the other half viewed a modified diagram showing the meridian passing through the ulnar side of the arm. The conditioning aspect of the expectancy manipulation consisted of telling participants that they would receive identical heat pain stimuli before and after treatment, but in reality, after treatment we surreptitiously lowered temperatures on the “treated side” (high expectancy [HE] side) of the arm sufficiently to reduce their rating to “faint to weak” and hence give participants an unmistakable experience of profound analgesia. On the “untreated” (control) side, the temperatures remained at pre-treatment high levels to enhance the “good effect” of acupuncture treatment.

       Acupuncture Administration

      Verum or sham acupuncture was performed at large intestine 3 and 4 on the right hand by a licensed acupuncturist. For verum EA, needles were adjusted until deqi, a unique sensation that indicates efficacious acupuncture,
      • Kong J.
      • Gollub R.
      • Huang T.
      • Polich G.
      • Napadow V.
      • Hui K.
      • Vangel M.
      • Rosen B.
      • Kaptchuk T.J.
      Acupuncture de qi, from qualitative history to quantitative measurement.
      but no sharp pain, was evoked. Needles were then connected to an electroacupuncture device passing a continuous 2-Hz current (IC-1107; OMS Medical Supplies, Weymouth, MA).
      • Kong J.
      • Fufa D.T.
      • Gerber A.J.
      • Rosman I.S.
      • Vangel M.G.
      • Gracely R.H.
      • Gollub R.L.
      Psychophysical outcomes from a randomized pilot study of manual, electro, and sham acupuncture treatment on experimentally induced thermal pain.
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      For sham EA, validated Streiberger sham acupuncture needles were placed on the surface of the skin and connected to a deactivated EA device.
      • Kong J.
      • Gollub R.L.
      • Rosman I.S.
      • Webb J.M.
      • Vangel M.G.
      • Kirsch I.
      • Kaptchuk T.J.
      Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging.
      • Streitberger K.
      • Kleinhenz J.
      Introducing a placebo needle into acupuncture research.
      • Zhu D.
      • Gao Y.
      • Chang J.
      • Kong J.
      Placebo acupuncture devices: Considerations for acupuncture research.
      These placebo needles retract into the barrel when pressed on the skin, similar to the action of a retractable stage dagger. Verum or sham EA treatment lasted approximately 25 minutes.

       Session 3

      Session 3 was performed in a 3T MRI scanner. Participants were told we would repeat the same procedures as in session 2. Participants received same verum or sham EA on the same “treated” side as they had in session 2. After treatment, participants were told that we would again present the identical pain stimuli. As in session 2, we decreased the post-treatment stimulus temperature to low intensity on the “treated,” HE side, but only on the first sequence to further reinforce or boost their expectancy for reduced pain on the “treated” side. Then, we measured the participants' expectancy to the analgesic effect of the acupuncture treatment using a 0 to 10 scale (0 does not work at all, 10 completely relieves pain). Finally, the original high-intensity IS was delivered to each of the remaining 4 boxes. Blood oxygen level-dependent (BOLD) fMRI sequences were run during all applications of pain stimuli as well as during the verum or sham EA treatment. Fig 1 shows a diagram of the experimental design and schematic of the procedures in each session.

       fMRI Data Acquisition and Data Analysis

      Whole-brain imaging during delivery of each of the RS and IS of pain stimuli as well as during verum or sham EA treatment was performed with a 12-channel head coil in a 3T Siemens TIM Trio MRI System (Siemens AG, Munich, Germany). BOLD images were collected with 30 axial slices (4 mm thick with 1-mm skip) parallel to the anterior and posterior commissure, 2,000 ms TR, 40 ms TE, 90° flip angle, and 3.13 × 3.13 mm in-plane spatial resolution. A 3-D magnetization prepared rapid gradient echo sequence was used for high-resolution anatomical data acquisition.
      Data were analyzed with SPM8 software (Wellcome Trust Centre for Neuroimaging at UCL, London, UK). Motion correction, co-registration, normalization, and smoothing (8 mm) were implemented in SPM8. Outliers in the fMRI time series that were potentially due to participants' motion were identified using the ART software (https://www.nitrc.org/projects/artifact_detect).
      • Benjamin C.
      • Lieberman D.A.
      • Chang M.
      • Ofen N.
      • Whitfield-Gabrieli S.
      • Gabrieli J.D.
      • Gaab N.
      The influence of rest period instructions on the default mode network.
      • Whitfield-Gabrieli S.
      • Moran J.M.
      • Nieto-Castanon A.
      • Triantafyllou C.
      • Saxe R.
      • Gabrieli J.D.
      Associations and dissociations between default and self-reference networks in the human brain.
      Images with mean signal intensity 3 SDs or more beyond the mean and with head movement exceeding .5 mm or .015 radians for translational and rotational movement, respectively (relative to the previous scan), were identified and regressed out in the statistical analysis.
      For each individual, the fMRI signal difference between high pain and low pain conditions during the 2 RS scans, and the fMRI signal difference between identical high pain stimuli pre- and post-treatment during the 2 IS scans on the HE side and on the control side were calculated for each participant using a general linear model. Group analysis was performed using a random effects model. For this and all other fMRI analyses, we included age as a covariate of no interest. The contrast of all pre-treatment high pain with all low pain stimuli on HE as well as control sides from the RSs
      • Kong J.
      • Gollub R.L.
      • Rosman I.S.
      • Webb J.M.
      • Vangel M.G.
      • Kirsch I.
      • Kaptchuk T.J.
      Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging.
      • Wager T.D.
      • Rilling J.K.
      • Smith E.E.
      • Sokolik A.
      • Casey K.L.
      • Davidson R.J.
      • Kosslyn S.M.
      • Rose R.M.
      • Cohen J.D.
      Placebo-induced changes in FMRI in the anticipation and experience of pain.
      was used to generate a mask of pain intensity encoding brain regions with which we could test for the treatment mode and expectancy effects in the subsequent analyses. A voxel-wise threshold of P < .005 with P < .05 cluster level false discovery rate (FDR) correction was applied.
      To investigate the effects produced by treatment mode and expectancy, we performed the following analyses: 1) compared pre- and post-fMRI signal change differences between the HE and control sides within each of the verum and sham acupuncture groups using a paired t-test, 2) compared treatment modes (verum and sham) indicated by pre- minus post-treatment differences in the HE and control sides separately using a 2-sample t-test, and 3) estimated the interaction between treatment modes (verum versus sham). This interaction was calculated by comparing fMRI signal changes during pain administration between verum acupuncture on the HE side and sham acupuncture on the control side, and verum acupuncture on the control side and sham acupuncture on the HE side (verum ([HE (pre–post) − control (pre–post)] − sham ([HE (pre–post) − control (pre–post)]). On the basis of our and others' previous imaging studies of pain, placebo analgesia, and pain modulation,
      • Atlas L.Y.
      • Bolger N.
      • Lindquist M.A.
      • Wager T.D.
      Brain mediators of predictive cue effects on perceived pain.
      • Atlas L.Y.
      • Whittington R.A.
      • Lindquist M.A.
      • Wielgosz J.
      • Sonty N.
      • Wager T.D.
      Dissociable influences of opiates and expectations on pain.
      • Eippert F.
      • Bingel U.
      • Schoell E.D.
      • Yacubian J.
      • Klinger R.
      • Lorenz J.
      • Buchel C.
      Activation of the opioidergic descending pain control system underlies placebo analgesia.
      • Kong J.
      • Gollub R.L.
      • Rosman I.S.
      • Webb J.M.
      • Vangel M.G.
      • Kirsch I.
      • Kaptchuk T.J.
      Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Gollub R.L.
      Placebo analgesia: Findings from brain imaging studies and emerging hypotheses.
      • Schenk L.A.
      • Sprenger C.
      • Geuter S.
      • Buchel C.
      Expectation requires treatment to boost pain relief: An fMRI study.
      • Wager T.D.
      • Rilling J.K.
      • Smith E.E.
      • Sokolik A.
      • Casey K.L.
      • Davidson R.J.
      • Kosslyn S.M.
      • Rose R.M.
      • Cohen J.D.
      Placebo-induced changes in FMRI in the anticipation and experience of pain.
      our a priori regions of interest included: 1) pain intensity-encoding brain regions from the RS mask obtained from the contrast of high pain to low pain stimuli, and 2) pain modulation network (ie, brain regions reported to be involved in pain modulation and cognition) including the orbital prefrontal cortex (OPFC), medial prefrontal cortex (MPFC)/anterior cingulate cortex (ACC), and LPFC defined on the basis of Anatomical Automatic Labeling (http://www.fil.ion.ucl.ac.uk/spm/ext/#AAL). An initial threshold of P < .005 was used in all data analysis. To correct for multiple comparisons, Monte Carlo simulations using the 3dFWHMx and 3dClustSim (as part of the Analysis of Functional NeuroImages program [https://afni.nimh.nih.gov] released in July 2017) were applied for the regions of interest (ie, pain encoding and modulation regions listed previously, where for each region, the minimum voxel size required for P < .05 cluster level P value correction will be indicated as k value in the results of the regional functional connectivity analysis presented in the next section). For the rest of the brain, a voxelwise threshold of P < .005 with P < .05 cluster level FDR-corrected was applied.

       Regional Functional Connectivity Analysis

      To acquire further insights into the local changes in the brain connectivity associated with different treatment modalities, we used a data-driven, resting state functional connectivity analysis of the regional homogeneity (ReHo),
      • Jensen K.
      • Srinivasan P.
      • Spaeth R.
      • Tan Y.
      • Kosek E.
      • Petzke F.
      • Carville S.
      • Fransson P.
      • Marcus H.
      • Williams S.C.
      • Choy E.
      • Vitton O.
      • Gracely R.
      • Ingvar M.
      • Kong J.
      Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia.
      • Yu R.
      • Gollub R.L.
      • Vangel M.
      • Kaptchuk T.
      • Smoller J.W.
      • Kong J.
      Placebo analgesia and reward processing: Integrating genetics, personality, and intrinsic brain activity.
      • Zang Y.
      • Jiang T.
      • Lu Y.
      • He Y.
      • Tian L.
      Regional homogeneity approach to fMRI data analysis.
      to investigate regional coherence differences between verum and sham EA in the fMRI data acquired during treatment. ReHo uses Kendall coefficient of concordance to measure the similarity of time courses of voxels within a given cluster. The method assumes that the within a functional cluster, time courses of the fMRI signal from the individual voxels within the cluster are similar to each other, reflecting the temporal synchrony of the regional BOLD signal.
      All preprocessing steps and the ReHo analysis were performed using Data Processing Assistant for Resting State fMRI Advanced edition on the basis of SPM8.
      • Chao-Gan Y.
      • Yu-Feng Z.
      DPARSF: A MATLAB toolbox for “pipeline” data analysis of resting-state fMRI.
      Preprocessing included: removing the first 10 time points, slice timing correction using the middle slice as a reference, realignment (motion correction), normalization into Montreal Neurological Institute space, linear trend removal, and filtering results to those in the range of .01 to .08 Hz. Next, the ReHo was calculated using a 27-voxel cluster. At a given voxel, ReHo was defined as the Kendall coefficient of concordance of the time series of this voxel with those of its 26 nearest neighbors. The resulting map of ReHo values at each voxel was then divided by the global mean value within the whole-brain mask. This result was then smoothed with a 6-mm kernel. Finally, a t-test was performed in SPM8 to compare the difference in ReHo values at each voxel between groups receiving verum and sham EA treatment. A voxelwise threshold of P < .005 with P < .05 cluster level FDR correction was applied.

      Results

      Of the 67 participants who participated in the study, 45 (26 female, average age = 58.7 ± 7.4, 22 in the EA group) completed the study. Three participants were dropped for failing the drug abuse screen in the first session, 8 for inconsistent pain ratings in the second session, and 1 because of a previously unknown, pre-existing brain abnormality. One participant withdrew after a power outage in the scanner halfway through the experiment interrupted the study, 1 because she found the acupuncture sensations to be too uncomfortable, and 4 because they did not feel comfortable enough in the MRI machine to complete the study procedures. Four participants did not continue after the first session because of scheduling difficulties.
      Of the 45 participants who completed the study, fMRI data from an additional 2 participants were dropped, 1 because of excessive head movement during scan, another because of a pre-existing brain abnormality that was not discovered during the scan visit. Thus, a total of 43 participants, n = 21 verum EA (11 female), average age 57 ± 7 years and n = 22 sham EA (15 female), average age 59 ± 7 years were included in the final data analysis. No significant differences in age or gender distribution were found between the 2 groups. The average temperature used for the low pain stimuli was 45.7 ± 1.7°C for the verum group and 45.6 ±1.0°C for the sham group. For the high-pain stimuli, the average temperature used was 48.1 ± 1.4°C in the verum group and 48.0 ± .8°C in the sham group.
      We did not find evidence of major psychiatric disorders in any participants. BDI and STAI scores were within normal range (BDI 5.2 ± 6.7; STAI 25.2 ± 5.9). None of these assessments differed between the 2 groups (verum and sham) or were significantly correlated with the expectancy mediated analgesic effect.

       Subjective Ratings of Pain and Expectancy

      Pain reduction after verum or sham EA was calculated by subtracting the pain rating for each postmanipulation trial from the pain rating for each premanipulation trial and averaging across trials in the sequences. Means and SDs of pain ratings to sequences of identical heat pain stimuli are shown in Table 1. These data were analyzed using a 2 × 2 (told by received) mixed model analysis of variance (ANOVA), in which what participants were told (HE vs control side) was a within subject factor, and what they received (verum or sham EA) was a between subject factor.
      Table 1Subjective Pain Ratings (mean ± SD) to Sequences of IS in Verum and Sham EA Groups
      Verum EASham EA
      Pre-treatmentPost-treatmentPre-treatmentPost-treatment
      HE side12.5 ± 2.211.4 ± 2.213.4 ± 2.412.2 ± 3.3
      Control side12.4 ± 2.013.0 ± 2.313.5 ± 2.414.0 ± 2.4
      The ANOVA revealed a significant main effect on what participants were told (ie, the effect of manipulation of expectancy), F1,41 = 18.417, P < .001 in verum as well as sham groups. Participants reported greater pain reduction on the HE side than on the control side of their forearm (Table 1, Fig 2). There were no other significant main effects or interactions. Treatment modality effect (verum vs sham EA) was not significant (F1,41 = .558, P = .459), nor did the interaction between modality and what participants were told approached significance (F1,41 = .010, P = .920). Within subject t-tests revealed that verum as well as sham EA decreased pain significantly on the HE side of the forearm (P < .001), and further that participants experienced increased pain on the control side (P < .001).
      Figure 2
      Figure 2Scatter plot showing change in each individual participant's pain rating on the 0 to 20 Gracely Scale from pre- to post-treatment on the HE and control sides of their forearm for the verum as well as sham groups. Each rating shown is the average of 12 identical moderate heat pain stimuli. ANOVA revealed a significant main effect on what participants were told (ie, the effect of manipulation of expectancy; F1,41 = 18.417, P < .001 in verum as well as sham groups). Treatment modality effect (verum vs sham EA) was not significant (F1,41 = .558, P = .459), nor did the interaction between modality and what participants were told approach significance (F1,41 = .010, P = .920). Verum as well as sham EA decreased pain significantly on the HE side of the forearm (P < .001), and participants experienced increased pain on the control side (P < .001).
      To put into perspective the behavioral expression of placebo effects in the older chronic pain population of this study (average age = 58.7 ± 7.4) compared with younger healthy subjects (average age = 26.4 ± 4.9), we also directly compared the results of this study with our previous study.
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      We added type of participants to the ANOVA, resulting in a 2 × 2 × 2 (participant status by told by received) mixed model ANOVA, in which what participants were told (HE vs control side) was a within subject factor, and what they received (verum or sham EA) and participant status (healthy or chronic pain) were between subject factors. This ANOVA revealed a significant main effect on what participants were told (F1,63 = 32.693, P < .001) with participants reporting greater pain reduction on the HE side than on the control side. There were no other significant main effects or interactions, suggesting the magnitude and direction of expectancy effects as indicated by subjective pain rating changes in older chronic pain patients are comparable with that observed in young healthy subjects. We note that age could not be added as a covariate in this analysis, because it is perfectly correlated with group. Had we obtained a group difference, this confound would have posed an interpretive problem. However, because we did not, our results make it clear that neither age nor patient status make a difference in the conditioning effect we obtained.
      In this study, expectation of pain relief measured before the application of post-treatment IS sequence was 7.6 ± 1.3 for the verum EA group and 7.5 ± 1.5 for the sham EA group, indicating that all participants had a strong belief that treatment would be effective in reducing their pain and no difference in expectation of pain relief between the verum and sham EA groups. We performed additional analyses to investigate relations between pain scores at baseline, expectancy ratings at baseline as well as during the scan, and pre–post ratings on the HE side of the arm. We found no significant correlations between measures of knee pain at time of scanning and expectancy effects in either the verum or sham acupuncture groups.
      At the conclusion of the study, all participants completed a final questionnaire using a scripted assessment on a computer program inquiring about whether they thought a needle was inserted into their skin in each session, whether they thought any of the sessions were a placebo treatment, and their certainty of their answers. Consistent with previous studies using the Streitberger needles for sham acupuncture, 19 of the 21 participants in the sham cohort reported with great confidence that they thought real needles were inserted, as did all the participants in the verum cohort. Six of the 21 participants in the sham group believed that at some point in the study they received a placebo treatment, whereas only 2 of the 22 who received verum acupuncture thought that.

      fMRI Results

       Evoked Pain

      The contrast between all pre-treatment high and low pain stimuli during the RS sequence yielded significant activations in the entire predicted network of pain intensity sensitive regions, including bilateral insula, dorsal ACC/MPFC, secondary somatosensory cortex (S2), thalamus, putamen, periaqueductal gray, cerebellum, precuneus, and left (contralateral) primary sensory and motor cortex (S1/M1) (Fig 3).
      • Atlas L.Y.
      • Bolger N.
      • Lindquist M.A.
      • Wager T.D.
      Brain mediators of predictive cue effects on perceived pain.
      • Atlas L.Y.
      • Whittington R.A.
      • Lindquist M.A.
      • Wielgosz J.
      • Sonty N.
      • Wager T.D.
      Dissociable influences of opiates and expectations on pain.
      • Kong J.
      • Gollub R.L.
      • Polich G.
      • Kirsch I.
      • Laviolette P.
      • Vangel M.
      • Rosen B.
      • Kaptchuk T.J.
      A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect.
      • Kong J.
      • Gollub R.L.
      • Rosman I.S.
      • Webb J.M.
      • Vangel M.G.
      • Kirsch I.
      • Kaptchuk T.J.
      Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging.
      • Kong J.
      • Loggia M.L.
      • Zyloney C.
      • Tu P.
      • Laviolette P.
      • Gollub R.L.
      Exploring the brain in pain: Activations, deactivations and their relation.
      • Kong J.
      • White N.S.
      • Kwong K.K.
      • Vangel M.G.
      • Rosman I.S.
      • Gracely R.H.
      • Gollub R.L.
      Using fMRI to dissociate sensory encoding from cognitive evaluation of heat pain intensity.
      Figure 3
      Figure 3Evoked pain activation maps. The group average statistical map of the fMRI signal change difference evoked by high versus low heat pain intensity stimuli during the initial RS are presented. The group average across all participants of the study is shown in the first row. This pain network activation map was used as the mask for subsequent analysis. Abbreviations: dACC, dorsal ACC; PAG, periaqueductal gray.

       Effect of Expectancy (Within Group Comparisons)

      The results of the within group HE versus control side comparisons (HE side (pre-treatment minus post-treatment) versus control side (pre-treatment minus post-treatment) are shown in Table 2 and Fig 4. In the verum EA group (Fig 4A), identical noxious stimuli delivered to the HE side produced greater signal increases after treatment than those delivered to the control side (HE side minus control side) in left (contralateral to pain stimuli) LPFC (k = 32), right lateral OPFC (k = 32), and right insula/putamen (k = 83). There was no brain region that showed a significant difference for the opposite comparison.
      Table 2Comparison Results of fMRI Signal Change Differences (Pre-treatment Pain > Post-treatment Pain) Between HE and Control Sides of the Forearm in Response to IS, and Regression Analysis Between the Subjective Pain Rating Change and Corresponding fMRI Signal Changes in Verum and Sham EA Treatment Groups
      ComparisonsBrain RegionZ ScoreNumber of Voxels in ClusterPeak Coordinate (x y z)
      Expectancy effect with verum EAHE > controlNo region above threshold
      Control > HERight lateral OPFC3.44162−52 40 −4
      Left LPFC3.1711352 12 14
      Right insula/putamen3.20145−32 8 2
      Expectancy effect with sham EAHE > controlNo region above the threshold
      Control > HEBilateral sACC/MPFC3.731002 44 −16
      Right lateral orbital prefrontal gyrus3.71116−36 46 −12
      Regression analysis in verum EA groupPositiveNo region above threshold
      NegativeNo region above the threshold
      Regression analysis in sham EA groupPositiveLeft posterior MPFC3.616214 42 36
      Left occipital cortex3.4376114 −78 6
      Right occipital cortex3.56971−20 −74 34
      NegativeNo region above threshold
      Figure 4
      Figure 4Effect of expectancy on brain activation in verum versus sham EA. The results of the within group HE versus control side comparisons (HE [pre-treatment minus post-treatment] minus control side [pre-treatment minus post-treatment]) are shown in this illustration. The brain networks involved in expectancy effect in the group treated with verum EA (A), in the group treated with sham EA (B), and the difference between the two (C) are shown. The activation identified in the insula/putamen region (A) and (C) is found within the pain-intensity encoding mask generated by the high–low pain contrast in the RS scans (shown in ). The other regions of activation found in the LPFC, OPFC, and sACC/MPFC (A) and (B) are found within the mask of the pain modulation network derived from the literature.
      • Atlas L.Y.
      • Bolger N.
      • Lindquist M.A.
      • Wager T.D.
      Brain mediators of predictive cue effects on perceived pain.
      • Atlas L.Y.
      • Whittington R.A.
      • Lindquist M.A.
      • Wielgosz J.
      • Sonty N.
      • Wager T.D.
      Dissociable influences of opiates and expectations on pain.
      • Eippert F.
      • Bingel U.
      • Schoell E.D.
      • Yacubian J.
      • Klinger R.
      • Lorenz J.
      • Buchel C.
      Activation of the opioidergic descending pain control system underlies placebo analgesia.
      • Kong J.
      • Gollub R.L.
      • Rosman I.S.
      • Webb J.M.
      • Vangel M.G.
      • Kirsch I.
      • Kaptchuk T.J.
      Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Gollub R.L.
      Placebo analgesia: Findings from brain imaging studies and emerging hypotheses.
      • Schenk L.A.
      • Sprenger C.
      • Geuter S.
      • Buchel C.
      Expectation requires treatment to boost pain relief: An fMRI study.
      • Wager T.D.
      • Rilling J.K.
      • Smith E.E.
      • Sokolik A.
      • Casey K.L.
      • Davidson R.J.
      • Kosslyn S.M.
      • Rose R.M.
      • Cohen J.D.
      Placebo-induced changes in FMRI in the anticipation and experience of pain.
      Abbreviation: L, left side.
      In the sham EA group, identical noxious stimuli delivered to the HE side produced more signal increases after treatment than those delivered to the control side in bilateral subgenual ACC (sACC)/MPFC (k = 75), and right OPFC (k = 32; Table 2 and Fig 4B). There was no brain region that showed a significant difference for the opposite comparison.

       Differences in the Effect of Expectancy Between Verum and Sham Groups

      To directly compare the effect of expectation in the verum and sham EA groups, we performed a 2-sample t-test restricted to the 5 regions (bilateral sACC/MPFC, left LPFC, right OPFC, insula/putamen) that showed a significant pre–post treatment difference between the HE and control sides in either of the 2 groups. We found no significant differences between the 2 groups at the threshold we set; however, we did find a significant difference in the right insula/putamen (peak coordinate [x, y, z]: −28, 10, −4, 109 voxels, k = 84) with a threshold of voxelwise P < .05 uncorrected and a corrected threshold of P < .05 at the cluster level on the basis of Monte Carlo simulations with the 3dFWHMx and 3dClustSim (see the Methods section; Table 2 and Fig 4C). There was no brain region that showed a significant difference when we applied a whole-brain correction.

       Effect of Verum Versus Sham EA Treatment

      To investigate the effects of acupuncture treatment, we compared pre- and post-treatment fMRI signal differences during pain stimulation between verum and sham EA on HE and control sides separately. We found no significant difference between verum and sham. To explore the relation between brain activity change and subjective pain rating change, we also performed a regression analysis (Table 2). A significant positive association was observed in the right MPFC (k = 89), and bilateral occipital cortex in the sham EA group. No region was significant in the verum EA group.

       Regional Functional Connectivity Difference in Verum Versus Sham EA

      Regional coherence, measured according to the ReHo analysis, increased in left postcentral and precentral gyrus in an area corresponding to the right hand where the EA was applied in the verum group more than the sham group (Table 3, Fig 5). Conversely, compared with sham EA, during verum EA, the regional coherence significantly decreased in bilateral dorsal ACC/MPFC, right S2, supramarginal gyrus/superior temporal gyrus, inferior parietal lobule, and left insula/operculum.
      Table 3ReHo Difference Between Verum and Sham EA
      ComparisonBrain RegionPeak Coordinate (x y z)Z ScoreNumber of Voxels in Cluster
      Verum > shamLeft postcentral/precentral gyrus52 −19 563.86265
      Sham > verumBilateral dorsal ACC/MPFC7 16 283.98483
      Left insula/operculum36 −10 43.87275
      Right supramarginal gyrus/superior temporal gyrus−49 −57 284.29233
      Right S2−43 −32 243.65
      Right inferior parietal lobule−37 −47 523.23
      Figure 5
      Figure 5Regional coherence difference between EA and sham EA in knee OA patients. Brain regions that showed a significant regional coherence increase during verum EA compared with sham EA are shown in (A). Brain regions that showed significant regional coherence decrease during verum EA compared with sham EA are shown in (B). Abbreviations: G, ; dACC, dorsal ACC; L, left side.
      To further explore the different brain response during EA in patients and healthy control participants, we also reanalyzed our data set in the younger healthy cohort that used a similar paradigm.
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Kong J.
      • Kaptchuk T.J.
      • Polich G.
      • Kirsch I.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.L.
      An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment.
      We found no significant difference between verum and sham at the statistical threshold we set. At a less conservative threshold of P < .05 uncorrected with 20 continuous voxels, we found that compared with sham EA, verum EA produced significant regional coherence increases in bilateral precentral and postcentral gyrus, and left insula.

      Discussion

      We investigated the effects of verum electroacupuncture and sham acupuncture on heat pain ratings and associated BOLD responses in patients with chronic pain due to knee OA. We also used a well studied expectancy manipulation model that combines conditioning and verbal suggestion to try to enhance the treatment-induced analgesia. We found that increased expectation of pain relief by our manipulation significantly decreased subjective reports of heat pain intensity in response to calibrated experimental noxious stimulation after either verum or sham EA in knee OA patients. This matched expectancy effect was associated with different brain activity patterns, measured using fMRI, after verum and sham EA. Our results reflect greater activity after treatment in specific brain regions when responding to identical noxious stimuli applied to areas of skin on the arm where subjects expect to feel less pain (HE side) compared with the control side due to expectation manipulation. The specific brain regions that showed this greater activity differed for the groups treated with verum and sham acupuncture. Within the verum EA group, stronger activation was observed in LPFC, OPFC, and insula/putamen at the time of identical noxious stimulation when there was a high expectation of analgesia. The same contrast in the sham EA treatment group revealed increased activation in sACC/MPFC, and OPFC. In addition, brain activity change in the MPFC and occipital cortex in the sham EA group, but not in the verum EA group, was positively associated with subjective pain rating changes. These results suggest that expectancy effects may be modulated by distinct mechanisms when coupled with different modalities of treatment.
      Previous placebo imaging studies, all in healthy subjects, investigating how expectancy can modulate the analgesic effect of active treatments have yielded inconsistent behavioral results. Using a conditioning-like expectancy manipulation similar to that used in our study, Bingel and colleagues
      • Bingel U.
      • Wanigasekera V.
      • Wiech K.
      • Mhuircheartaigh R.N.
      • Lee M.C.
      • Ploner M.
      • Tracey I.
      The effect of treatment expectation on drug efficacy: Imaging the analgesic benefit of the opioid remifentanil.
      reported that positive expectancy can significantly enhance the analgesic effect of remifentanil, whereas negative expectancy can antagonize its analgesic effect. In another study, Atlas and colleagues
      • Atlas L.Y.
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      using a verbal suggestion balanced placebo paradigm reported that expectancy as well as remifentanil can reduce pain, with no significant interaction between these 2 factors. In a more recent verbal suggestion balanced placebo study using a topical analgesic treatment, Schenk and colleagues
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      investigated the interaction between lidocaine and expectancy using a clinical pain related model (capsaicin-pretreated skin). They reported that lidocaine significantly reduced pain compared with placebo treatment, whereas the main expectancy effect (open administration compared with hidden administration) was not significant. However, unlike Atlas et al,
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      they reported a significant interaction between treatment and expectancy. Open administration of lidocaine reduced pain rating significantly more than hidden, whereas there was no significant difference between open and hidden administration of placebo.
      The inconsistency in how expectation of pain relief affects an active treatment in these experimental settings may be due to a number of factors including differences in expectancy manipulation (verbal suggestion alone vs a more powerful conditioning-like procedure
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      ) and differences in treatment modality (remifentanil, lidocaine, and acupuncture). Taken together, these results suggest that the effect of expectancy on treatment outcome may depend on the specific details of the expectancy manipulation as well as the treatment modality. Because of the experimental design of this study, it is not possible to investigate within subject differences in how expectancy interacts with sham and verum acupuncture.
      Our experimental design, which studied the neural activity associated with placebo effects in older patients with a chronic pain disorder, revealed significant fMRI signal increases in brain regions including bilateral sACC and right lateral OPFC after sham EA treatment on the HE side compared with the control side. Using fMRI and a within subject design, Schmid and colleagues showed that in the setting of comparable expectations of pain relief and comparable placebo analgesia, patients with chronic pain due to irritable bowel syndrome (IBS) activate a similar region of the cingulate cortex in the placebo as well as control conditions, whereas patients with ulcerative colitis in remission and age- and sex- matched healthy control participants have placebo-related reductions in cingulate cortical activation.
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      However, Price and colleagues showed a large placebo response in the form of reduction of brain activity in the ACC in IBS patients as well as in the thalamus, somatosensory cortices, and insula.
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      in IBS patients, which reported increased activity in lateral OPFC associated with placebo analgesia. It is known that the ACC is a component of the descending pain modulation system.
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      leaving open the possible interpretation that modulation of the descending pain modulation system is critical for placebo analgesia.
      Direct comparison between the verum and sham EA groups for differences in expectancy effects showed significant differences in the right insula/putamen. This result is consistent with the interpretation that there are common as well as distinct components of the brain networks that underlie expectancy effects when combined with verum or sham EA. In the verum EA group significant pain-evoked fMRI signal increases were observed in right insula/putamen, lateral OPFC, and left LPFC compared with the control side versus the HE side whereas in the sham group the effect of expectancy was observed in the sACC/MPFC and OPFC. Although not overlapping, the areas of increased activation in the right lateral OPFC observed in verum and sham EA groups are adjacent to each other, suggesting that the right lateral OPFC is involved in expectancy effect across physiological and pathological states, which supports a crucial role of the LPFC in top-down modulatory mechanisms of analgesia.
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      Functional connectivity analysis showed that regional coherence in the insula, operculum, S2, and dorsal ACC was significantly reduced during verum EA compared with during sham EA, indicating that the pain network was significantly modulated during EA stimulation. This result was not observed in a cohort of healthy subjects studied in a very similar paradigm.
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      • Polich G.
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      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      • Zyloney C.E.
      • Jensen K.
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      • Cheetham A.
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      These results suggest that the whole brain response to verum acupuncture treatment is significantly different in people with chronic pain compared with healthy controls, which we speculate may be in part responsible for the different expectancy-evoked neural networks.
      The finding of modulation of the pain network in verum compared with sham in patients with knee OA may be the key to interpreting the difference in expectancy between these 2 treatment modes. As shown in Fig 4C, the difference in expectancy effect between the verum versus sham is limited to the putamen/striatum. On the basis of our ReHo findings, it is likely that the difference of expectancy effect may be driven by the activation of the pain network. The observed activation in the putamen/striatum suggests that the modulation of pain network by verum acupuncture treatment may involve alterations in dopaminergic and opioidergic activity and involve the reward circuits.
      • Chen X.
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      • Retzepi K.
      • Ott D.
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      Acupuncture modulates cortical thickness and functional connectivity in knee osteoarthritis patients.
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      • Scott D.J.
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      • Gracely R.H.
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      Decreased central mu-opioid receptor availability in fibromyalgia.
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      Reward and motivation in pain and pain relief.
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      • Lilien D.L.
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      This may be due to adaptive changes in the brain as a consequence of ongoing nociceptive input in knee OA.
      • Rodriguez-Raecke R.
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      • Ihle K.
      • Ruether W.
      • May A.
      Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.
      • Seminowicz D.A.
      • Wideman T.H.
      • Naso L.
      • Hatami-Khoroushahi Z.
      • Fallatah S.
      • Ware M.A.
      • Jarzem P.
      • Bushnell M.C.
      • Shir Y.
      • Ouellet J.A.
      • Stone L.S.
      Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function.
      Further, this difference in response during EA may explain why we did not find any significant fMRI signal decreases in the present study of knee OA patients when we compared verum with sham EA as we did in our previous study in healthy subjects.
      • Kong J.
      • Kaptachuk T.J.
      • Polich G.
      • Kirsch I.V.
      • Vangel M.
      • Zyloney C.
      • Rosen B.
      • Gollub R.
      Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia.
      The patients who participated in this study were significantly older compared with participants in reported studies on healthy subjects. Although aging is associated with substantial functional and structural changes in areas of the brain known to be involved in placebo responses,
      • Farrell M.J.
      Age-related changes in the structure and function of brain regions involved in pain processing.
      a recent study investigating age-related changes has shown preservation of the placebo response in elderly individuals using a paradigm similar to the one used in this study.
      • Wrobel N.
      • Fadai T.
      • Brassen S.
      • Bingel U.
      Preserved capacity for placebo analgesia in the elderly.
      Benedetti and colleagues
      • Benedetti F.
      • Arduino C.
      • Costa S.
      • Vighetti S.
      • Tarenzi L.
      • Rainero I.
      • Asteggiano G.
      Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective.
      reported that Alzheimer disease patients showed reduced placebo analgesia 1 year after the first test. Interestingly, they also reported that healthy elderly volunteers had robust placebo analgesic responses, further supporting the finding that psychobiological mechanisms underlying the efficacy of placebo effects are present in cognitively intact older people. Although our results support these results and further suggest that these mechanisms remain intact even in the presence of chronic pain due to knee OA, additional work will need to be done regarding generalization to other chronic pain disorders.

      Conclusions

      Our study suggests that expectancy may work through different pathways on the basis of the treatment modality and pathophysiological state of the person. Future studies that include larger cohorts of chronic pain patients and age-matched pain-free control subjects that can be directly compared are needed to disentangle the potential confounding effects of aging on these neural responses.

      Acknowledgments

      The authors thank Rosa Spaeth for her excellent work in the collection of these data and Xiaoyan Chen and Rongjun for their invaluable assistance in the analysis of the fMRI data.

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