303-250-5138

Studies on Hypnosis and Fibromyalgia Syndrome (FMS)

This is just the smallest tip of a very large iceberg.

In controlled trials it has been found that hypnotherapy for fibromyalgia helps more than physical therapy in those patients who do not seem to respond well to most other forms of treatment. Pain is reduced, fatigue and stiffness on waking is improved and general feeling of wellbeing better.
Reference:
1. Haanen H et al Controlled trial of hypnotherapy in treatment of refractory fibromyalgia Journal of Rheumatology 18 pp 72-75 1991

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Functional anatomy of hypnotic analgesia: a PET study of patients with fibromyalgia

Gustav Wik a, b, Corresponding Author Contact Information, Håkan Fischer d, c, Björn Bragée b, Basil Finer b and Mats Fredrikson c

a Department of Clinical Neurosciences, Karolinska Institute and Hospital, Stockholm, Sweden b Kronan Pain Clinic, Stockholm, Sweden c Department of Clinical Psychology, Uppsala University, Uppsala, Sweden d Uppsala University PET-centre, Uppsala University, Uppsala, Sweden

Abstract

Hypnosis is a powerful tool in pain therapy. Attempting to elucidate cerebral mechanisms behind hypnotic analgesia, we measured regional cerebral blood flow with positron emission tomography in patients with fibromyalgia, during hypnotically-induced analgesia and resting wakefulness. The patients experienced less pain during hypnosis than at rest. The cerebral blood-flow was bilaterally increased in the orbitofrontal and subcallosial cingulate cortices, the right thalamus, and the left inferior parietal cortex, and was decreased bilaterally in the cingulate cortex. The observed blood-flow pattern supports notions of a multifactorial nature of hypnotic analgesia, with an interplay between cortical and subcortical brain dynamics.

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Brain Imaging Studies Investigate Pain Reduction by Hypnosis

March 16, 2005

Source: University of Iowa

Although hypnosis has been shown to reduce pain perception, it is not clear how the technique works. Identifying a sound, scientific explanation for hypnosis' effect might increase acceptance and use of this safe pain-reduction option in clinical settings. Researchers at the University of Iowa Roy J. and Lucille A. Carver College of Medicine and the Technical University of Aachen, Germany, used functional magnetic resonance imaging (fMRI) to find out if hypnosis alters brain activity in a way that might explain pain reduction. The results are reported in the November-December 2004 issue of Regional Anesthesia and Pain Medicine. The researchers found that volunteers under hypnosis experienced significant pain reduction in response to painful heat. They also had a distinctly different pattern of brain activity compared to when they were not hypnotized and experienced the painful heat. The changes in brain activity suggest that hypnosis somehow blocks the pain signal from getting to the parts of the brain that perceive pain. "The major finding from our study, which used fMRI for the first time to investigate brain activity under hypnosis for pain suppression, is that we see reduced activity in areas of the pain network and increased activity in other areas of the brain under hypnosis," said Sebastian Schulz-Stubner, M.D., Ph.D., UI assistant professor (clinical) of anesthesia and first author of the study. "The increased activity might be specific for hypnosis or might be non-specific, but it definitely does something to reduce the pain signal input into the cortical structure." The pain network functions like a relay system with an input pain signal from a peripheral nerve going to the spinal cord where the information is processed and passed on to the brain stem. From there the signal goes to the mid-brain region and finally into the cortical brain region that deals with conscious perception of external stimuli like pain. Processing of the pain signal through the lower parts of the pain network looked the same in the brain images for both hypnotized and non-hypnotized trials, but activity in the top level of the network, which would be responsible for "feeling" the pain, was reduced under hypnosis. Initially, 12 volunteers at the Technical University of Aachen had a heating device placed on their skin to determine the temperature that each volunteer considered painful (8 out of 10 on a 0 to 10 pain scale). The volunteers were then split into two groups. One group was hypnotized, placed in the fMRI machine and their brain activity scanned while the painful thermal stimuli was applied. Then the hypnotic state was broken and a second fMRI scan was performed without hypnosis while the same painful heat was again applied to the volunteer's skin. The second group underwent their first fMRI scan without hypnosis followed by a second scan under hypnosis. Hypnosis was successful in reducing pain perception for all 12 participants. Hypnotized volunteers reported either no pain or significantly reduced pain (less than 3 on the 0-10 pain scale) in response to the painful heat. Under hypnosis, fMRI showed that brain activity was reduced in areas of the pain network, including the primary sensory cortex, which is responsible for pain perception. The imaging studies also showed increased activation in two other brain structures - the left anterior cingulate cortex and the basal ganglia. The researchers speculate that increased activity in these two regions may be part of an inhibition pathway that blocks the pain signal from reaching the higher cortical structures responsible for pain perception. However, Schulz-Stubner noted that more detailed fMRI images are needed to definitively identify the exact areas involved in hypnosis-induced pain reduction, and he hoped that the newer generation of fMRI machines would be capable of providing more answers. "Imaging studies like this one improve our understanding of what might be going on and help researchers ask even more specific questions aimed at identifying the underlying mechanism," Schulz-Stubner said. "It is one piece of the puzzle that moves us a little closer to a final answer for how hypnosis really works. "More practically, for clinical use, it helps to dispel prejudice about hypnosis as a technique to manage pain because we can show an objective, measurable change in brain activity linked to a reduced perception of pain," he added. In addition to Schulz-Stubner, the research team included Timo Krings, M.D., Ingo Meister, M.D., Stefen Rex, M.D., Armin Thron, M.D., Ph.D. and Rolf Rossaint, M.D., Ph.D., from the Technical University of Aachen, Germany. University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com. STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

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Complementary medicine treatments for fibromyalgia syndrome

Brian M. Berman MD, Director, Complementary Medicine Programf1 and James P. Swyers MA, Senior Science Writer, Complementary Medicine Program

University of Maryland School of Medicine, Third Floor, Kernan Mansion, James L. Kernan Hospital, 2200 Kernan Drive, Baltimore, MD 21207-6697, USA

Abstract

Fibromyalgia is a chronic-pain-related syndrome associated with high rates of complementary and alternative medicine (CAM) use. Among the many CAM therapies frequently used by fibromyalgia patients, empirical research data exist to support the use of only three: (1) mind–body, (2) acupuncture, and (3) manipulative therapies for treating fibromyalgia. The strongest data exist for the use of mind–body techniques (e.g. biofeedback, hypnosis, cognitive behavioural therapy), particularly when utilized as part of a multidisciplinary approach to treatment. The weakest data exist for manipulative techniques (e.g. chiropractic and massage). The data supporting the use of acupuncture for fibromyalgia are only moderately strong. Also, for some fibromyalgia patients, acupuncture can exacerbate symptoms, further complicating its application for this condition. Further research is needed not only in these three areas, but also for other treatments being frequently utilized by fibromyalgia patients.

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Derbyshire, Whalley & Oakley (2008). Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion: An fMRI analysis

This is the first published study to use fMRI to examine the effects of hypnotic and non-hypnotic suggestion upon brain activity. Thirteen patients suffering from fibromyalgia, a chronic pain condition, were given the same suggestions to increase and decrease their pain while in an fMRI scanner before and after they were hypnotised. Suggestion in both conditions produced significant changes in both pain experience and brain activity in pain-related regions. These activations were of greater magnitude, though, when suggestions followed a hypnotic induction - providing evidence for the greater efficacy of suggestion following a hypnotic induction.

The image above shows brain activity to 'hypnotic' or 'nonhypnotic' suggestions in the same patients as they manipulated their pain. There was activity in both conditions, but significantly more in the hypnotised condition.

Derbyshire, S.W.G., Whalley, M.G., Oakley, D.A. (2008). Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion: An fMRI analysis. European Journal of Pain, in press.

wo randomized controlled trials evaluating the use of hypnotherapy and three studies evaluating the use of guided imagery in people with fibromyalgia. These five randomized controlled trials, the gold standard experimental design in clinical research, found consistent positive results in the treated patients as compared to the control patients.

In one study, 40 patients with fibromyalgia were treated with eight hypnotherapy sessions over the course of 3 months. These hypnosis sessions focused on sensory and affective (emotion-based) approaches to fibromyalgia pain control. The results show that pain intensity was reduced, there was less fatigue on awakening, and the participants sleep patterns were improved.

A second study evaluated the effect of up to five hypnosis sessions on 53 fibromyalgia patients. This study also found that hypnotherapy improved sleep quality in the fibromyalgia patients. In addition, participants who

received hypnosis had less morning stiffness.

The three studies which evaluated the effectiveness of guided imagery in treating fibromyalgia found that pain was reduced in intensity and anxiety was lessened. In particular, one study compared guided imagery that used pleasant imagery with guided imagery focused upon the "active workings of the internal pain control systems". The pleasant guided imagery was significantly more effective in reducing fibromyalgia pain.

Individuals with fibromyalgia have precious few effective treatment options. Fortunately, research is beginning to discover the effectiveness of certain psychotherapeutic treatment options. Hypnosis and guided imagery may be one effective option to improve the mental, emotional, and physical symptoms of fibromyalgia.

Source:

Thieme K, Gracely RH. Are psychological treatments effective for fibromyalgia pain? Curr Rheumatol Rep. 2009 Dec;11(6):443-50.

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Stuart W.G. Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion:

An fMRI analysis

Derbyshire a,*, Matthew G. Whalley b, David A. Oakley b

a School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

b Department of Psychology, Hypnosis Unit, University College London, London WC1E 6BT, UK

a r t i c l e i n f o

Article history:

Received 11 March 2008

Received in revised form 2 June 2008

Accepted 12 June 2008

Available online 23 July 2008

Keywords:

Hypnosis

Human

Brain

Psychosomatic

Chronic pain

Medically unexplained pain

a b s t r a c t

The neuropsychological status of pain conditions such as fibromyalgia, commonly categorized as ‘psychosomatic’

or ‘functional’ disorders, remains controversial. Activation of brain structures dependent upon

subjective alterations of fibromyalgia pain experience could provide an insight into the underlying neuropsychological

processes. Suggestion following a hypnotic induction can readily modulate the subjective

experience of pain. It is unclear whether suggestion without hypnosis is equally effective. To explore

these and related questions, suggestions following a hypnotic induction and the same suggestions without

a hypnotic induction were used during functional magnetic resonance imaging to increase and

decrease the subjective experience of fibromyalgia pain. Suggestion in both conditions resulted in significant

changes in reported pain experience, although patients claimed significantly more control over their

pain and reported greater pain reduction when hypnotised. Activation of the midbrain, cerebellum, thalamus,

and midcingulate, primary and secondary sensory, inferior parietal, insula and prefrontal cortices

correlated with reported changes in pain with hypnotic and non-hypnotic suggestion. These activations

were of greater magnitude, however, when suggestions followed a hypnotic induction in the cerebellum,

anterior midcingulate cortex, anterior and posterior insula and the inferior parietal cortex. Our results

thus provide evidence for the greater efficacy of suggestion following a hypnotic induction. They also

indicate direct involvement of a network of areas widely associated with the pain ‘neuromatrix’ in fibromyalgia

pain experience. These findings extend beyond the general proposal of a neural network for pain

by providing direct evidence that regions involved in pain experience are actively involved in the generation

of fibromyalgia pain.

! 2008 European Federation of Chapters of the International Association for the Study of Pain. Published

by Elsevier Ltd. All rights reserved.

1. Introduction

A network of cortical regions, including the anterior cingulate

cortex (ACC), insula, prefrontal regions and primary (S1) and secondary

(S2) somatosensory cortices, mediates pain experience

(Apkarian et al., 2005; Derbyshire, 1999, 2000, 2003; Treede

et al., 1999). Abnormal activation within this pain network may

cause or partially generate functional pain disorders including

fibromyalgia (Gracely et al., 2002).

Fibromyalgia is a functional somatic syndrome, one of a cluster

of disorders sharing common characteristics and possible etiological

background without known physical disease (Wessely et al.,

1999; Barsky and Borus, 1999; Brown, 2004). The persistence

and intractability of the functional disorders, in the apparent absence

of peripheral disease, has led to an increasing interest in

the possibility of a central etiology and the use of functional imaging

to test central hypotheses (Gracely et al., 2002, 2004; Cook

et al., 2004; Derbyshire et al., 1994, 2002; Naliboff et al., 2001).

Pain research has provided a model of fibromyalgia, for example,

based on early activation, or greater activation, of central regions

responsible for pain experience (Gracely et al., 2002, 2004; Croft,

2000).

Functional imaging of pain in patients, however, has been

dominated by the study of responses to noxious experimental

stimuli rather than the patients’ own pain (Henningsen, 2003).

The use of experimental noxious stimuli to probe the neural generators

of functional disorder confounds any explanation of the

disorder based on the possibility of direct central generation

(Apkarian et al., 2005). Modulation of pain experience with suggestion

avoids this confound. Furthermore, hypnotic suggestion

induces highly responsive individuals to alter their sensory experience

in an expeditious, impromptu fashion, without elaborate

technical preparation, ideal for use with functional imaging. Patterns

of neural activation during hypnotic modulation of experimental

(Rainville et al., 1997) and clinical pain (Willoch et al.,

1090-3801/$36.00 ! 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.ejpain.2008.06.010

* Corresponding author. Tel.: +44 0121 414 4659; fax: +44 0121 414 4897.

E-mail address: This e-mail address is being protected from spambots. You need JavaScript enabled to view it (S.W.G. Derbyshire).

European Journal of Pain 13 (2009) 542–550

Contents lists available at ScienceDirect

European Journal of Pain

journal homepage: www.EuropeanJournalPain.com

2000) are very similar to the patterns observed during direct

physical manipulation.

Previously, we used hypnosis to reveal the cerebral mechanisms

of suggested pain in normal volunteers (Derbyshire et al., 2004). A

perceptual experience of pain was achieved with a hypnotic induction

followed by the suggestion of painful heat, but without actual

heat delivery. Functional magnetic resonance imaging (fMRI) measured

cerebral cortical activity related to the pain experience and

revealed activation consistent with the self-report of pain. A further

study independently replicated our findings (Raij et al.,

2005). For the current study we extend our hypnotic technique

to examine brain activation dependent on direct and immediate

changes in fibromyalgia pain experience.

Suggestions for pain control following a hypnotic induction procedure

are highly effective (Montgomery et al., 2000; Hawkins,

2001; Patterson and Jensen, 2003) but the delivery of a formal hypnotic

induction may have less impact on responsiveness to suggestion

than previously thought (Kirsch and Braffman, 2001; Gandhi

and Oakley, 2005; Milling et al., 2005). Pain relief following suggestion,

therefore, might be similar regardless of any formal hypnotic

procedures, questioning the role of the hypnotic induction in

increasing responsiveness to suggestions. Here we directly address

this issue by comparing suggestions of pain relief and augmentation

with and without hypnosis.

2. Methods

2.1. Subjects and screening

Letters were sent out to 397 patients included on the University

of Pittsburgh Rheumatology Registry with a primary diagnosis of

fibromyalgia. Ninety-two patients responded and 46 patients (four

male) took part in the initial screening stage of the study. Average

age of the screened patients was 52.4 (range 21–74). All patients

gave informed consent and the study was approved by the University

of Pittsburgh Institutional Review Board.

2.2. Hypnosis

The 46 patients were prescreened on the Harvard Group Scale

of Hypnotic Susceptibility: Form A (Shor and Orne, 1962). High

scorers (>8 out of a total possible score of 12) were further

screened for the ability to experience significant hypnotic analgesia.

During the second screening session patients were shown a

diagram of a dial (see Fig. 1), labeled from 0 (no pain at all) to

10 (as bad as my pain gets). Patients were informed that the dial

was to represent their level of fibromyalgia pain at any particular

moment during the experiment. The dial image was employed to

rapidly alter and anchor fibromyalgia pain at a high, medium or

low level according to verbal suggestions delivered to each patient

during hypnosis.

The patients were informed that hypnotic suggestions would be

given to allow the dial to move up and down, producing a concomitant

change in their fibromyalgia pain sensation. They were then

hypnotised individually using an induction described in detail elsewhere

(Whalley and Oakley, 2003). Following the hypnotic induction,

patients were asked to bring the dial to mind and to notify the

experimenter of its current position. Suggestions were given for

the dial and the corresponding fibromyalgia pain sensation to be

turned up as high as the patient could allow it to go, dial ratings

were then recorded. Suggestions were then given to turn the dial

down as low as possible and dial ratings were again recorded.

The order of these suggestions was counterbalanced across patients.

This procedure was repeated in order to give patients practice

with these suggestions before the hypnosis was terminated

and the patients debriefed.

Patients who reported that they spontaneously used distractive/

dissociative techniques of pain control (e.g. finding themselves on

a pleasant beach and unaware of the pain), rather than the dial

imagery provided, were excluded. Patients who reported dial

changes of 6 points or more (from maximum to minimum) in their

fibromyalgia pain experience, without the use of distraction or dissociation,

were selected for scanning.

Thirteen patients were selected for the scanning phase of the

study, all were female. The average age of this group was 51.4

(range 21–63). Mean Harvard score was 9.7 (SD 0.92). Seven of

the 13 participants also reported suffering from irritable bowel

syndrome. Six of the patients were currently taking medications

including antidepressants, benzodiazepines and opiates, three

had been off all medication for a period of at least 7 days prior to

the scan and four were not currently prescribed any medication

at the time of study (Table 1). These patients completed the hospital

anxiety and depression (HAD) scale (Zigmond and Snaith,

1983), a short self-report screening tool that was developed to

indicate anxiety and depressive states in patients with physical illness

(Herrmann, 1997).

Fig. 1. Illustrates the fMRI procedures. Each patient was asked to view, in their mind’s eye, a dial representing their own pain. They were told that their current experience of

fibromyalgia pain was yoked to the reading on the dial and that as a consequence changes in the dial setting would be accompanied by corresponding changes in their pain

experience. They were asked to move the dial as close to zero as possible following one tap to the foot, as close to five as possible following two taps, and as close to ten as

possible following three taps. Each tapping signal began a 30 s scanning period during which the patients controlled their pain using the dial and moved their pain as

instructed. The four conditions shown above were presented twice in each fMRI block to yield 4 min of data (2 min of low pain, 1 min of high pain and 1 min of medium pain).

Two blocks of data were collected in the hypnosis condition and two in the no-hypnosis condition to yield four blocks of data for each patient.

S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550 543

2.3. Imaging procedure

Brain activation was inferred based on measurement of the blood

oxygen level dependent (BOLD) contrast (Ogawa et al., 1990). These

measurements were acquired at 3 Tesla using a reverse spiral technique

(TE = 25 ms, TR = 1.5 s, flip angle = 60", 64 ! 64 matrix) described

in detail elsewhere (Noll et al., 1995; Stenger et al., 2000).

Briefly, the single-shot reverse spiral imaging protocol, designed

for the LX MRI system, allows for the acquisition of 24 3.2 mmthick

64 ! 64 slices with a 20 cmfield of view in a TR of 1.5 s. This protocol

provides nearly full brain coverage with isotropic voxel dimensions

(3.2 mm on a side) in a time rapid enough to produce well defined

hemodynamic time courses. The reverse spiral technique and gradient

compensation methods for spirals were designed to reduce susceptibility

artifacts that can occur in brain regions adjacent to air

cavities, such as the orbitofrontal cortex and perigenual cingulate

cortex which are next to the frontal sinus.

Seven patients were hypnotised upon entering the fMRI scanner

using the same induction as during screening (hypnosis condition).

After the collection of two blocks of fMRI data hypnosis was terminated

and two further blocks of data were collected (no-hypnosis

condition). One hundred and sixty volumes were collected in each

of these four blocks. For the remaining six patients the procedure

was the same except that the order of the two conditions was reversed.

As in the screening procedure, patients were told to visualize

the dial labeled from 0 to 10 representing their current level of

fibromyalgia pain. For the purposes of fMRI data collection, verbal

suggestion was replaced by non-verbal signals in the form of a simple

sequence of taps to the patient’s left foot. One tap conveyed the

suggestion that the patient should use the dial to reduce their

fibromyalgia pain experience, getting as close to zero as possible.

Two taps indicated that the patient was to experience their fibromyalgia

pain in the middle range of the dial, as close to 5 as possible.

Three taps indicated that the patient was to increase their

fibromyalgia pain experience to as close to 10 on the dial as possible.

fMRI data were collected in two blocks of 4 min each in both

conditions (hypnosis and no-hypnosis) to derive 4 min of low pain,

2 min of medium pain and 2 min of high pain in each condition.

The fMRI procedures are illustrated in Fig. 1.

After each block the participant gave verbal ratings of pain

intensity for the previously experienced low, medium and high

pain trials and a measure of how hypnotised they felt on a 0–10

scale of hypnotic depth, where 0 = not at all hypnotised and

10 = as hypnotised as possible (Oakley et al., 2007). At the end of

the MR session, subjects were debriefed and asked to rate how

much control they felt they had over their pain in the hypnosis

and no-hypnosis conditions using a 0–10 scale (0 = no control,

10 = maximum control).

2.4. Data analysis

Data analysis was performed using the FMRIB Software Library

(FSL release 4.1 – Oxford Centre for Functional Magnetic Resonance

Imaging of the Brain), described in detail elsewhere (Smith et al.,

2004). In summary, head movement between scans was corrected

by aligning all subsequent scans with the first. Each re-aligned set

of scans from every subject was coregistered with his or her own

hi-res structural MRI image, with the non-brain components edited

out, and reoriented into the standardized anatomical space of

the average brain provided by the Montreal Neurological Institute

(MNI). To increase the signal to noise ratio and accommodate variability

in functional anatomy, each image was smoothed in X, Y

and Z dimensions with a Gaussian filter of 8 mm (FWHM).

A box-car model with a hemodynamic delay function, weighted

according to the level of pain reported, was fitted to each voxel,

generating a statistical image corresponding to the hypothesized

changes in pain experience. Baseline drifts were removed by applying

a high-pass filter. Brain regions with a large statistic correspond

to structures whose BOLD response shares a substantial

amount of variance with the hypnotically induced changes in the

patients own experience of fibromyalgia pain. The multiple comparisons

problem of simultaneously assessing all the voxel statistics

was addressed via cluster based thresholding. Clusters of

voxels that exceeded a Z score > 2.3 and P < 0.05 (corrected for

multiple comparisons) were considered statistically significant.

Differences between hypnotic and non-hypnotic suggestion were

assessed using a within-participants t-test to compare the suggestibility

conditions.

The analysis was performed in two complete passes. The first

pass included an independent components analysis (ICA) that provides

images of BOLD change conforming to structure within the

data that is not predicted a priori. Some structure is expected to derive

from the design of the experiment, and is hypothesized, but

other sources of structure can be due to unknown patient effects

and to noise. The ICA results were examined for each subject and

components that were obviously noise (such as patient motion,

physiological or machine noise) were rejected. The original data

was then filtered to remove the components identified as being a

result of noise and the analysis repeated using the filtered data.

In total, 269 components were identified as noise when the patients

were hypnotised and 238 when the patients were not hypnotised.

This difference was not significant.

Final analysis was performed using a fixed effects approach that

only includes the variability within subjects and thus provides results

that are more sensitive to small changes within this group but

with interpretation restricted to the group under study. Studies of

functional pain necessarily involve patients with a heterogeneous

disorder characterized by a wide range of non-specific symptoms

and often receiving a wide variety of medications. The current

study also involved a highly select group of patients who responded

to hypnotic suggestion with changes in their experience

of pain. Variability in the patient sample, and the restrictive criteria

for recruitment, are good reasons for considering our findings a

Table 1

Shows the medication use for each patient

Patient Antidepressant Benzodiazepine Opiate

1 Sertralineb Diazepam None

25 mg once daily 5–15 mg daily, as needed

Desipramine

100 mg once daily

2 Nortriptyline Clonazepam Fentanyl patcha

25 mg three times daily 1 mg once daily

3 Venlafaxine None None

75 mg three times daily

4 None None None

5 None None None

6 None None None

7 Paroxetine None None

40 mg once daily

8 Venlafaxinea None None

75 mg twice daily

Paroxetinea None None

40 mg once daily

Trazadonea

100 mg once daily

10 Fluoxetinea Lorazepam Methadoneb

40 mg once daily 4 mg once daily

11 Trazadone None None

50 mg once daily

12 None None None

13 Venlafaxine None None

75 mg twice daily

a Drug not taken during the 7 days before the study.

b Drug not taken during the 14 days before the study.

544 S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550

proof of principle that should not be generalized beyond the group

studied until further research confirms and extends our findings.

Region of interest (ROI) analysis was also performed for the

midbrain, thalamus, cerebellum, cingulate cortex, insula, S1, S2,

inferior parietal cortex and frontal cortex as the main regions of

the pain neuromatrix described in previous meta-analyses (Apkarian

et al., 2005; Derbyshire, 1999, 2000, 2003). ROIs were drawn

using MRIcro (http://www.sph.sc.edu/comd/rorden/mricro.html)

and were then used as masks in FSL running FEATquery to extract

the mean percentage change in BOLD signal for each ROI when patients

were in the hypnosis or the no-hypnosis condition.

2.5. Drug effects

To assess the influence of centrally acting drugs on the profile of

brain activation, the seven medication free subjects (those currently

not taking their medication and those currently not prescribed

medication) were analyzed separately and compared to

the patients currently taking medication. To formally assess the

overlap in activation from these two subgroups, a conjunction

analysis, described in detail elsewhere (Friston et al., 1999, 2005;

Nichols et al., 2005), was implemented manually. A conjunction

determines whether both group slopes of BOLD response against

pain are significantly different from zero. This is in contrast to

whether the average intergroup slope is different from zero, which

could be driven by one group alone. A conjunction is the minimum

of two statistic images or, equivalently, conjunction regions are the

intersection of suprathreshold regions across two statistic images.

A voxel only appears as significant in the conjunction if both

groups have significant activation and is, therefore, a measure of

significant shared responses in two groups. The conjunction image,

however, is a binary map thresholded at the intensity level and

does not include cluster based thresholding.

3. Results

3.1. Behavioural ratings

Depression ratings averaged slightly above normal (mean

depression rating = 7.7 (SD = 4.6), range 1–13) as did ratings of

anxiety (mean anxiety rating = 9.5 (4.1), 2–15). On average,

moderate fibromyalgia pain was reported by the patients upon

arrival for the study (0 – no pain; 10 – maximal pain) but the

range of pain was broad (mean pain rating = 4.1 (SD = 3.1), range

0–9).

When the patients were hypnotised (hypnosis condition), average

pain ratings (0 – no pain; 10 – maximal pain) following low,

normal and high conditions were 1.3 (SD = 0.8), 5.3 (0.6) and 8.9

(1.1), respectively. When the patients were not hypnotised (nohypnosis

condition) the respective ratings were 2.3 (1.8), 5.7

(1.0) and 8.5 (1.7). A repeated measures ANOVA was used to assess

the main effect of suggestion (high, medium or low) and hypnosis

and any interactions. There was a highly significant effect of suggestion

(F2,24 = 196.4, p < 0.001) but not of hypnosis. Hypnosis

and suggestion did, however, interact due to there being a significantly

greater reduction in reported pain during the ‘low’ suggestion

in the hypnosis condition compared to the no-hypnosis

condition (F2,24 = 7.7, p = 0.003). Patient reports of perceived control

over their pain were significantly higher during hypnosis (7.8

(2.2) vs. 4.7 (2.8); t = 3.4, p = 0.005, 95% CI [2.5, 3.7]). These data

are illustrated in Fig. 2 as well as average measures of fibromyalgia

pain at baseline (when arriving at the research centre) and measures

of hypnotic depth when hypnotised and not hypnotised. Ratings

of hypnotic depth were significantly higher when patients

were hypnotised (6.1 (2.5) vs. 0.5 (1.3); t = 7.9, p < 0.001, 95% CI

[5.3, 6.7]).

3.2. Brain activation correlated with changes in pain report following

suggestion with and without hypnosis

Highly significant and widespread BOLD increases correlating

with patient’s pain reports were apparent during suggestion with

and without hypnosis and are documented in Table 2 and illustrated

in Fig. 3. When the patients were hypnotised BOLD responses

were significantly greater in several regions including

the cerebellum, anterior midcingulate cortex and anterior and posterior

insula compared to the unhypnotised condition. Greater

activity when patients were not hypnotised were demonstrated

in right thalamus, left MCC, bilateral primary sensory cortex (S1)

and left prefrontal cortex.

Fig. 2. Shows the reported fibromyalgia pain rating at baseline (upon arrival at the imaging centre) in grey and shows the reported fibromyalgia pain during the low, medium

and high suggestions (0 – no pain, 10 – maximum pain) with (black) and without (white) hypnosis. Average ratings of the control over pain (0 – no control, 10 – complete

control) and depth of hypnosis (0 – not hypnotised, 10 – complete immersion in hypnosis) are also shown with and without hypnosis. Significant differences (p < 0.05)

between conditions are indicated.

S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550 545

The percentage changes in BOLD activation are graphed and

plotted in Fig. 4 and demonstrate that in every ROI, except left

MCC, there was greater BOLD signal change when patients were

hypnotised compared with unhypnotised.

3.3. Drug effects on the brain activation responses

Patients on medication did not differ significantly in age from

those not on medication (46.5 (13.6) vs. 55.7 (6.7); t = 1.5, p = 0.2,

95% CI ["22.9,4.6]) and no behavioural differences between these

two groups reached significance including baseline pain rating (3.5

(2.9) vs. 5.1 (3.5); t = 0.8, p = 0.4, 95% CI ["6.2, 3.0]), depression (7.5

(5.3) vs. 7.8 (4.2); t = 0.1, p = 0.9, 95% CI ["6.5, 5.8]), anxiety (9.0

(3.8) vs. 10.0 (4.6); t = 0.4, p = 0.7, 95% CI ["6.5, 4.5]) and hypnotisability

(10.3 (0.8) vs. 10.2 (1.2); t = 1.4, p = 0.2, 95% CI ["2.1, 0.5]).

Fig. 5 demonstrates common activation in the midbrain, thalamus,

cerebellum, anterior cingulate cortex, posterior insula, anterior insula,

S2 and PFC for both the medication free patients and those

currently using medication during hypnosis. Common activation

is less apparent when the patients were not hypnotised with nota-

Table 2

The regions with increasing or decreasing (italicized) BOLD response dependent upon changes in reported fibromyalgia pain experience with and without hypnosis

Figure label Hypnotised Unhypnotised

Brain area (x, y, z coordinates) (region) Side Z-score Brain area (x, y, z coordinates) (region) Z-score

1 Pons/midbrain

(4,"20,"20) M 4.1 (2,"22,"24) 3.2

2 Thalamus

("2,"6,0) L 3.1 ("22,"30,10) 3.7

(18,"4,10) R 4.4 (18,"14, 2) 5.4

3 Cerebellum

("14,"58,"18) L 3.9 ("8,"56,"12) 6.2

(12,"50,"14) R 4.0 (4,"62,"14) 4.2

4 sACC

(14, 46,"8) (BA 32) R 4.5 (10, 36,"6) (BA 24/32) 3.1

(6, 24,"18) (BA 25) R 3.4 "3.1

(14,40,2) (BA 24/32) R "2.7 ("14,44,"14) (BA 25/11)

5 aMCC MCC

("4, 14,30) (BA 24/32) L 3.0 ("16,16,38) (BA 32) 3.1

(2, 36,20) (BA 24/32) R 3.8 –

6 Posterior insula

("48,"20,14) L 3.5 ("52,"16, 8) "4.1

(34,"32, 8) R 3.3

7 S2

("58,"28,10) L 5.1 ("64,"26,16) 3.0

(54,"16,12) R 4.4 (70,"34,20) 4.5

8 S1

("28,"36,64) L 3.5 ("52,"40,44) 3.0

(26,"36,62) R 4.4 (30,"28,68)

(64,"22,40) "3.0

9 Anterior insula

("30, 0,"8) L 5.4 ("30,26,"4) 4.7

(40, 10,"2) R 5.2 (46, 16,"18) 3.9

10 Inferior parietal cortex

("60,"38,40) (BA 40) L 4.5 ("40,"56,46) (BA 40)

(52,"52,44) (BA 40) R 4.5 –

11 Prefrontal cortex

("52, 14, 8) (BA 44/45) L 4.5 ("40,50,"10) (BA 10/47) 4.7

("28, 54, 4) (BA 10/46) L 3.7 (48, 36,"12) (BA 10/47) 5.2

(36, 62, 2) (BA 10) R 4.8

The areas are tabulated in terms of the brain region, as illustrated in Fig. 5, and their approximate cytoarchitecture (BA = Brodman’s area). The x, y, z coordinates plot each

peak (defined as the pixel with the highest Z-score within each tabulated region) according to the MNI coordinate system (negative is left, posterior and inferior).

sACC = subgenual anterior cingulate cortex; MCC = mid anterior cingulate cortex; aMCC = anterior MCC; S2 = secondary somatosensory cortex; S1 = primary somatosensory

cortex.

Fig. 3. BOLD activation weighted by suggestion to reduce or increase fibromyalgia pain report during hypnosis (left), without hypnosis (middle) and the difference between

these conditions (right). Clusters of voxels that exceeded a Z score > 2.3 and P < 0.05 (corrected for multiple comparisons) were considered statistically significant and are

shown superimposed on an averaged structural MRI derived from the patient’s own structural scans. At the left of each condition are coronal slices showing the posterior

insula (top) and the anterior insula (bottom). In the middle are saggital slices right lateral (top) and left lateral (bottom) to the midline. To the right are right surface (top) and

left surface (bottom) projections. 1 = midbrain region of the pons; 2 = thalamus; 3 = cerebellum; 4 = subgenual anterior cingulate cortex (sACC); 5 = midcingulate cortex;

6 = posterior insula; 7 = secondary somatosensory cortex (S2); 8 = primary somatosensory cortex (S1); 9 = anterior insula; 10 = inferior parietal cortex; 11 = prefrontal cortex.

546 S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550

bly greater activation in the patients currently taking drugs. There

is particularly obvious dissociation in the thalamus, insula, S2 and

inferior parietal cortex.

4. Discussion

fMRI data were obtained during suggested changes in fibromyalgia

pain experience with and without hypnosis. Suggestion was

highly effective in changing subjective pain reports, regardless of

whether a formal hypnotic induction had taken place, but patients

reported significantly more control over their pain and a greater

ability to reduce their pain during the low pain conditions when

hypnotised. Consistent with these findings, activation of cortical

and subcortical structures commonly associated with the pain

‘‘neuromatrix” were significant in both ‘hypnosis’ and ‘no hypnosis’

conditions but greater activation peaks were associated with the

hypnosis condition in the cerebellum, aMCC, posterior and anterior

insula, inferior parietal cortex and right prefrontal cortex. In the

unhypnotised condition, there was greater activation in the thalamus,

MCC, S1and left prefrontal cortex. ROI analysis demonstrated

that average activation in all regions except the left MCC was increased

when the patients were hypnotised compared with unhypnotised.

These findings support the view that suggestion can

produce significant changes in fibromyalgia pain report and demonstrate

the increased efficacy of these suggestions in producing

both altered sensory experience and corresponding modulation

of brain activity when they follow a hypnotic induction procedure.

This result extends previous findings and demonstrates the specificity

of (hypnotic) suggestion in altering responsiveness to the

stimulus under investigation (Rainville et al., 1997; Willoch et al.,

2000; Derbyshire et al., 2004; Kosslyn et al., 2000; Oakley, 2008;

Raij et al., 2005; Szechtman et al., 1998). The reported changes in

pain experience are also consistent with previous work indicating

the utility of hypnotic techniques in the treatment of fibromyalgia

(Haanen et al., 1991; Castel et al., 2007).

We propose that activation of neural structures comprising

the pain matrix is dependent upon changes in the experience of

fibromyalgia pain rather than the demand characteristics of the

Fig. 5. shows activation in the medication free fibromyalgia patients (left), those taking medication (middle) and the conjunction of activation in those two groups (right)

during the hypnotised (top) and unhypnotised (bottom) conditions.

Fig. 4. Percentage changes in BOLD activation graphed for each ROI as illustrated and tabulated in Table 2.

S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550 547

experiment. Volitional responses to the demands of the experiment

might be expected to activate supervisory neural structures

such as the prefrontal cortex and medial ACC (Spence et al.,

2003; Oakley et al., 2003). These structures were activated during

our procedure and may mediate some of the cognitive processing

thought to underlie hypnotic modulation of pain (Miltner and

Weiss, 2007; Faymonville et al., 2006; Wik et al., 1999; Crawford

et al., 1993). Nevertheless, the additional involvement of the thalamus,

insula, midcingulate and somatosensory cortices is highly

consistent with modulation of pain experience (Derbyshire et al.,

1997, 2004; Coghill et al., 1999, 2003) and with other demonstrations

of pain control during fMRI (deCharms et al., 2005).

Our findings are also directly relevant to current debate regarding

the role of hypnosis in influencing responsiveness to suggestion

(Kirsch and Braffman, 2001; Gandhi and Oakley, 2005; Raz et al.,

2006) and support the view that formal hypnotic induction can alter

the strength or character of a subsequent suggestion providing

for an increased behavioural and neural response. Intriguingly, the

regions demonstrating significantly greater activation during suggestion

with hypnosis vs. without hypnosis were mainly right

lateralised (see Table 3). This finding is broadly consistent with

views that emphasise a greater involvement of right hemisphere

processes in hypnosis in highly hypnotizable individuals (e.g.

Crawford and Gruzelier, 1992; Gruzelier, 1998). It should be

emphasized, however, that the differences between behavioural

and neural responses when hypnotised and unhypnotised were

differences in degree rather than type. The general pattern of BOLD

response and changes in pain experience were comparable

whether the patients had heard a formal induction or not.

As well as investigating the relative effects of hypnotic and

non-hypnotic suggestion this study also explored the brain correlates

of pain perception that might underlie fibromyalgia pain in

this group, though it was not designed to elucidate the distinct

perceptual roles for each of the activations found. Speculation as

to the role of each neural activation is, therefore, properly restrained.

Nevertheless, specific comment on the thalamic activation

is warranted because of observations in previous studies

(Cook et al., 2004; Gracely et al., 2004). The thalamus is a major

gateway for noxious information (Apkarian and Hodge, 1989)

and as we have argued above activation of the thalamus in this

study is particularly compelling evidence for a change in pain

experience directly related to pain report. Previous studies, however,

have suggested reduced thalamic activation in patients with

fibromyalgia (Cook et al., 2004; Gracely et al., 2004) that can be

normalized (increased) using hypnosis for pain relief (Wik et al.,

1999). By necessity, these previous studies used somatic noxious

stimulation to provoke brain activation and thus confounded

fibromyalgia pain with acute pain experience (Cook et al., 2004;

Gracely et al., 2004). In addition, previous hypnotic manipulation

of fibromyalgia pain used a baseline measure of brain activity that

did not involve hypnosis (Wik et al., 1999). Consequently, the

contribution of hypnosis itself, and of somatic stimulation, to

the pattern of brain activation remains unclear. Our study tackles

these confounds by manipulating fibromyalgia pain directly by

the same suggestion with and without hypnosis. Our data indicate

that thalamic and cortical activation are involved in the increased

experience of fibromyalgia pain during suggestion with and without

a hypnotic induction.

Studies of functional pain necessarily involve patients with a

heterogeneous disorder characterized by a wide range of non-specific

symptoms and often receiving a wide variety of medications

(Wessely et al., 1999; Barsky and Borus, 1999). This study also

Table 3

The regions with increasing BOLD response dependent upon hypnotically suggested changes in fibromyalgia pain experience greater than those from suggestion without hypnosis

and vice versa

Figure label Hypnotised > unhypnotised Unhypnotised > hypnotised

Brain area (x, y, z coordinates) (region) Side Z-score Brain area (x, y, z coordinates) (region) Z-score

1 Pons/midbrain

No significant difference M – No significant difference –

2 Thalamus

No significant difference L – – –

R – (18,"14,"2) 3.5

3 Cerebellum

– L – No significant difference –

(10,"52,"4) R 3.5 –

4 sACC

(0, 22,"12) (BA 25/11) M 3.6 No significant difference –

5 aMCC MCC

– L – ("6, 0,28) (BA 24) 3.5

(4, 36,26) (BA 24/32) R 3.2 – –

6 Posterior insula

("52,"20,10) L 3.2 No significant difference –

– R – –

7 S2

No significant difference L – No significant difference –

R – –

8 S1

– L – ("36,"14,62) 3.3

(62,"26,38) R 2.5 (48,"8,50) 3.6

9 Anterior insula

("44, 14,10) L 2.8 No significant difference –

(38, 10, 0) R 3.5 –

10 Inferior parietal cortex

– L – No significant difference –

(60,"42,22) (BA 40) R 3.1 –

11 Prefrontal cortex

– L – (40, 52,"8) (BA 10/47) 4.4

– L – ("42,26,34) (BA 9) 3.6

(40, 40,6) (BA 10/46) R 3.0 – –

All other details as for Table 1.

548 S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550

involved a highly select group of patients who responded to hypnotic

suggestion with changes in their experience of pain. Because

of the variability in the patient sample, and the restrictive criteria

for recruitment, our demonstration that hypnosis can be used to

modulate fibromyalgia pain with congruent changes in brain activation

can be considered a proof of principle but generalization

beyond the group studied should be approached with caution.

Fixed effects analysis, which only considers variability in the

group under study, demonstrated widespread and highly significant

BOLD activation during hypnotic modulation of fibromyalgia

pain that was generally attenuated when the patients were not

hypnotised. ROI analysis of our data indicates that hypnosis provided

greater modulation in every region except the left MCC.

It was not possible to find patients matching our criteria who

were all currently medication free or willing to become medication

free. Consequently some of our patients were receiving medication

that may influence the BOLD response. This possibility was

directly assessed via analysis of patients on or off medication at

the time of study. Patients taking medication, and those who were

medication free, demonstrated common activation in the midbrain,

thalamus, cerebellum, anterior cingulate cortex, posterior

insula, anterior insula, S2 and PFC when hypnotised. Patients on

medication had generally greater levels of activation, which is

consistent with the possibility that they were taking medication

because they could experience greater levels of fibromyalgia pain

on a day to day basis. Our findings are consistent with prescribed

medication having little or no effect on brain activation mediating

the hypnotic alteration of pain experience. Consistency in activation,

however, was less apparent when the patients were not hypnotised.

One possibility is that patients able to be off drugs suffer

less pain and discomfort and so were less able to focus on their

pain outside a hypnotic context. Additional psychometric measurements,

however, including baseline pain rating, anxiety,

depression, hypnotic depth and hypnotizability did not produce

significant differences but these findings should be viewed with

caution given the small numbers of patients in the drug and drug

free groups.

The small number of patients also cautions against interpretation

of BOLD differences between the drug and drug free groups.

Fibromyalgia patients are typically heterogenous with extensive

and variable medication histories and current prescription

patterns; we have no a priori basis for interpreting differences

between patients on and off medication using our current procedures.

For these reasons we caution that any interpretation of

these subgroups remains speculative. A similar argument applies

to other subdivisions of the data that we might have performed.

For example, it could be interesting to observe differences between

patients with and without an IBS diagnosis. It is, however, inherent

to fibromyalgia that patients report symptoms overlapping with

other diagnoses (Wessely et al., 1999). An IBS diagnosis can reasonably

be considered a part of the syndrome and so dissociating IBS

from fibromyalgia is not necessarily useful and predicting and

interpreting differences between patients with and without IBS

would be difficult.

In summary, Fig. 3 extends our knowledge of pain processing in

fibromyalgia by providing a map of activations underlying patients’

own pain rather than their responses to external noxious events.

This finding in a clinical pain population is compatible with prior

evidence that intensity of the perceptual experience is tied to the

strength of activity in the pain matrix (Coghill et al., 2003). Critically,

the reported activations correlate with patient’s reports of

changes in their experience of their fibromyalgia pain, not pain

due to an external stimulus, linking regional activation specifically

to the modulation of fibromyalgia pain in this group. In addition,

our results provide evidence that appropriate suggestion can relieve

fibromyalgia pain with and without a formal hypnotic induction.

Pain relief was significantly greater, however, when

suggestion followed a hypnotic induction. Overall, the BOLD activation

patterns were more consistent with changes in pain report

in hypnosis though the differences were somewhat variable. These

findings imply a therapeutic benefit from both hypnotic and nonhypnotic

suggestion but with some additional benefit that is unique

to suggestion following a hypnotic induction.

Acknowledgements

This work was supported by a Grant from the Pittsburgh Foundation

and the John F. and Nancy A. Emmerling Fund. MGW’s participation

in this project was supported by a generous contribution

from the Bogue Fellowship with additional support from the

Department for Work and Pensions (UK Government). We thank

V.A. Stenger and D. Davis for assistance and technical advice in

developing the spiral imaging routine.

References

Apkarian AV, Bushnell MC, Treede R-D, Zubieta J-K. Human brain mechanisms of

pain perception and regulation in health and disease. Eur J Pain 2005;9:463–84.

Apkarian AV, Hodge CJ. Primate spinothalamic pathways: I. A quantitative study of

the cells of origin of the spinothalamic pathway. J Comp Neurol

1989;288:447–73.

Barsky AJ, Borus JF. Functional somatic syndromes. Ann Int Med 1999;130:910–21.

Brown RJ. Psychological mechanisms of medically unexplained symptoms: an

integrative conceptual model. Psychol Bull 2004;130:793–812.

Castel A, Pérez M, Sala J, Padrol A, Rull M. Effect of hypnotic suggestion on

fibromyalgic pain: comparison between hypnosis and relaxation. Eur J Pain

2007;11:463–8.

Coghill RC, Sang CN, Maisog JMA, Iadorola MJ. Pain intensity processing within the

human brain: a bilateral, distributed mechanism. J Neurophysiol

1999;82:1934–43.

Coghill RC, McHaffie JG, Yen Y-F. Neural correlates of inter-individual differences in

the subjective experience of pain. Proc Natl Acad Sci USA 2003;100:8538–42.

Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelosn BH. Functional imaging

of pain in patients with primary fibromyalgia. J Rheumatol 2004;21:364–78.

Crawford HJ, Gur RC, Skolnick B, Gur RE, Benson DM. Effects of hypnosis on regional

cerebral blood flow during ischemic pain with and without suggested hypnotic

analgesia. Int J Psychophysiol 1993;15:181–95.

Crawford HJ, Gruzelier JH. A midstream view of the neuropsychophysiology of

hypnosis: recent research and future directions. In: Fromm E, Nash MR, editors.

Contemporary hypnosis research. New York: Guilford Press; 1992. p. 227–66.

Croft P. Testing for tenderness: what’s the point? J Rheumatol 2000;27:2531–3.

deCharms RC, Maeda F, Glover GH, Ludlow D, Pauly JM, Soneji D, et al. Control over

brain activation and pain learned by using real-time functional MRI. Proc Natl

Acad Sci USA 2005;102:18626–186231.

Derbyshire SWG. Meta-analysis of thirty-four independent samples studied using

positron emission tomography (PET) reveals a significantly attenuated central

response to noxious stimulation in clinical pain patients. Curr Rev Pain

1999;3:265–80.

Derbyshire SWG. Exploring the pain ‘‘neuromatrix”. Curr Rev Pain 2000;6:467–77.

Derbyshire SWG. Review and meta-analysis of neuroimaging data reveals

differential activation from upper and lower gastrointestinal distension. Am J

Gastroenterol 2003;98:12–20.

Derbyshire SWG, Jones AKP, Devani P, Friston KJ, Feinmann C, Harris M, et al.

Cerebral responses to pain in patients with atypical facial pain measured by

positron emission tomography. J Neurol Neurosurg Psychiatry

1994;57:1166–72.

Derbyshire SWG, Jones AKP, Gyulai F, Clark S, Townsend D, Firestone L. Pain

processing during three levels of noxious stimulation produces differential

patterns of central activity. Pain 1997;73:431–45.

Derbyshire SWG, Jones AKP, Creed F, Starz T, Meltzer CC, Townsend DW, et al.

Cerebral responses to noxious thermal stimulation in chronic low back pain

patients and normal controls. Neuroimage 2002;16:158–68.

Derbyshire SWG, Whalley MG, Stenger VA, Oakley DA. Cerebral activation during

hypnotically induced and imagined pain. Neuroimage 2004;23:392–401.

Faymonville ME, Boly M, Laureys S. Functional neuroanatomy of the hypnotic state.

J Physiol 2006;99:463–9.

Friston KJ, Holmes AP, Price CJ, Buchel C, Worsley KJ. Multisubject fMRI studies and

conjunction analyses. Neuroimage 1999;10:385–96.

Friston KJ, Penny WD, Glaser DE. Conjunction revisited. Neuroimage

2005;25:661–7.

Gandhi B, Oakley DA. Does ‘hypnosis’ by any other name smell as sweet? The

efficacy of ‘hypnotic’ inductions depends on the label ‘hypnosis’. Consciousness

Cogn 2005;14:304–15.

Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging

evidence of augmented pain processing in fibromyalgia. Arthrit Rheum

2002;46:1333–43.

S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550 549

Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, et al. Pain

catastrophizing and neural responses to pain among persons with fibromyalgia.

Brain 2004;127:835–43.

Gruzelier JH. A working model of the neurophysiology of hypnosis: a review of the

evidence. Contemporary Hypnosis 1998;15:3–21.

Haanen HC, Hoenderdos HT, van Romunde LK, Hop WC, Mallee C, Terwiel JP, et al.

Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia. J

Rheumatol 1991;18:72–5.

Hawkins RMF. A systematic meta-review of hypnosis as an empirically supported

treatment for pain. Pain Rev 2001;8:47–73.

Henningsen P. The body in the brain: towards a representational neurobiology of

somatoform disorders. Acta Neuropsychiatrica 2003;15:157–60.

Herrmann C. International experiences with the hospital anxiety and depression

scale – a review of validation data and clinical results. J Psychosom Res

1997;42:17–41.

Kirsch I, Braffman W. Imaginative suggestibility and hypnotizability. Curr

Directions Psychol Sci 2001;10:57–61.

Kosslyn SM, Thompson WL, Costantini-Ferrando MF, Alpert NM, Spiegel D. Hypnotic

visual illusion alters color processing in the brain. Am J Psychiatry

2000;157:1279–84.

Milling LS, Kirsch I, Allen GJ, Reutenauer EL. The effects of hypnotic and

nonhypnotic suggestion on pain. Ann Behav Med 2005;29:116–27.

Miltner WHR, Weiss T. Cortical mechanisms of hypnotic pain control. In: Jamieson

GA, editor. Hypnosis and conscious states. The cognitive neuroscience

perspective. Oxford: Oxford University Press; 2007. p. 51–66.

Montgomery GH, DuHamel KN, Redd WH. A meta-analysis of hypnotically induced

analgesia. Int J Clin Exp Hypn 2000;48:138–53.

Naliboff BD, Derbyshire SWG, Munakata J, Berman S, Mandelkern M, Chang L, et al.

Cerebral activation in irritable bowel syndrome patients and control subjects

during rectosigmoid stimulation. Psychosom Med 2001;63:365–75.

Nichols T, Brett M, Andersson J, Wager T, Poline JB. Valid conjunction inference with

the minimum statistic. Neuroimage 2005;15:653–60.

Noll DC, Cohen JD, Meyer CH, Schneider W. Spiral K-space MR imaging of cortical

activation. J Magn Reson Imaging 1995;5:49–56.

Oakley DA. Hypnosis, trance, and suggestion: evidence from neuroimaging. In: Nash

MR, Barnier AJ, editors. The Oxford handbook of hypnosis: theory, research, and

practice. Oxford, UK: Oxford University Press; 2008. p. 365–92.

Oakley DA, Deeley Q, Halligan PW. Hypnotic depth and responses to suggestion

under standardized conditions and during fMRI scanning. Int J Clin Exp

Hypnosis 2007;55:32–58.

Oakley DA, Ward NS, Halligan PW, Frackowiak SJ. Differential brain activations for

malingered and subjectively ‘real’ paralysis. In: Halligan PW, Bass C, Oakley DA,

editors. Malingering and illness deception. Oxford, UK: Oxford University Press;

2003. p. 267–86.

Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic resonance imaging with

contrast dependent on blood oxygenation. Proc Natl Acad Sci USA

1990;87:9868–72.

Patterson DR, Jensen MP. Hypnosis and clinical pain. Psychol Bull

2003;129:495–521.

Raij TT, Numminen J, Hiltunen J, Hari R. Brain correlates of subjective reality of

physically and psychologically induced pain. Proc Natl Acad Sci USA

2005;102:2147–51.

Rainville P, Duncan GH, Price DD. Pain affect encoded in human anterior cingulate

but not somatosensory cortex. Science 1997;277:968–71.

Raz A, Kirsch I, Pollard J, Nitkin-Kaner Y. Suggestion reduces the Stroop effect.

Psychol Sci 2006;17:91–5.

Shor RE, Orne EC. Harvard group scale of hypnotic susceptibility, form A. Palo Alto,

CA: Consulting Psychologists Press; 1962.

Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H,

et al. Advances in functional and structural MR image analysis and

implementation as FSL. Neuroimage 2004;23:208–19.

Spence S, Farrow T, Leung D, Shah S, Reilly B, Rahman A, et al. Lying as an executive

function. In: Halligan P, Bass C, Oakley DA, editors. Malingering and illness

deception. OUP; 2003. p. 255–66.

Stenger VA, Boada FE, Noll DC. Three-dimensional tailored RF pulses for the

reduction of susceptibility artifacts in T2#-weighted functional MRI. Magn

Reson Med 2000;44:525–31.

Szechtman H, Woody E, Bowers KS, Nahmias C. Where the imaginal appears real: a

positron emission tomography study of auditory hallucination. Proc Natl Acad

Sci USA 1998;95:1956–60.

Treede RD, Daniel R, Kenshalo DR, Richard H, Gracely RH, Jones AKP. The cortical

representation of pain. Pain 1999;79:105–11.

Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many?

Lancet 1999;354:936–9.

Whalley MG, Oakley DA. Psychogenic pain: a study using multidimensional scaling.

Contemporary Hypnosis 2003;20:16–24.

Wik G, Fischer H, Bragée B, Finer B, Fredrikson M. Functional anatomy of hypnotic

analgesia: a PET study of patients with fibromyalgia. Eur J Pain 1999;3:

7–12.

Willoch F, Rosen G, Tolle TR, Oye I, Wester HJ, Berner N, et al. Phantom limb pain in

the human brain: unraveling neural circuitries of phantom limb sensations

using positron emission tomography. Ann Neurol 2000;48:842–9.

Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr

Scand 1983;67:361–70.

550 S.W.G. Derbyshire et al. / European Journal of Pain 13 (2009) 542–550