Mindfulness Meditation-Related Pain Relief: Evidence for Unique Brain

Neuroscience Letters 520 (2012) 165–173

Contents lists available at SciVerse ScienceDirect

Neuroscience Letters

jou rnal homepage: www.elsevier.com/locate/neulet

Review

Mindfulness meditation-related pain relief: Evidence for unique brain

mechanisms in the regulation of pain

a,∗ b c a a

F. Zeidan , J.A. Grant , C.A. Brown , J.G. McHafﬁe , R.C. Coghill

Wake Forest School of Medicine, Department of Neurobiology and Anatomy, Winston-Salem, NC, United States

Max Planck Institute for Human, Cognitive and Brain Sciences, Department of Social Neuroscience, Stephanstraße 1A, 04103 Leipzig, Germany

University of Manchester, Human Pain Research Group, Clinical Sciences Building, Salford Royal NHS Foundation Trust, Salford M6 8HD, Manchester, England, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: The cognitive modulation of pain is inﬂuenced by a number of factors ranging from attention, beliefs,

Received 18 February 2012

conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events.

Received in revised form 21 March 2012

Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms

Accepted 27 March 2012

including enhanced cognitive and emotional control, as well as altering the contextual evaluation of

sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related

Keywords:

pain relief across different meditative techniques, expertise and training levels, experimental procedures,

Mindfulness

and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness

Meditation

Pain meditation-related pain relief is associated with unique appraisal cognitive processes depending on

Neuroimaging expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related

pain relief may share a common ﬁnal pathway with other cognitive techniques in the modulation of pain.

Contents

1. What is mindfulness? ...... 166

2. Mindfulness meditation practices: focused attention and open monitoring ...... 166

3. Mindfulness meditation and health ...... 166

4. Mindfulness meditation and pain ...... 166

5. Behavioral studies of meditation-related pain relief ...... 167

6. The neural substrates of mindfulness meditation-related pain relief...... 167

7. Trait effects of prior meditation practice on pain ...... 167

8. State effects of active meditation during pain ...... 168

9. An integrated perspective on meditation-based pain relief...... 170

10. Common ﬁnal pathway to the cognitive modulation of pain ...... 171

Acknowledgment ...... 172

References ...... 172

The advent of contemporary neuroimaging techniques has con- increased brain activity in a set of regions including the anterior

tributed greatly to our understanding of the neural mechanisms cingulate cortex (ACC), anterior insula and sensory areas such as

underlying pain perception and, importantly, how pain can be mod- primary and secondary somatosensory cortices (SI/SII), thalamus

ulated. Increases in experienced pain are reliably associated with and posterior insula [1,13,14,19,56].

A variety of factors are now known to either increase or decrease

pain-related brain activation, including: predictive cues [3], dis-

traction [5,58], attention [52,58,63] expectation [41,55], beliefs

∗

Corresponding author at: Wake Forest School of Medicine, Department of Neu-

[68], placebo [54,67], hypnosis [57], stress, anxiety, mood and emo-

robiology, Medical Center Blvd., Winston-Salem, NC 27157, United States.

tional state [51,65]. Many of these factors, however, are difﬁcult for

Tel.: +1 704 578 1271; fax: +1 336 716 4534.

an individual to engage in a self-directed and volitional fashion. By

E-mail addresses: [email protected] (F. Zeidan),

mchafﬁ[email protected] (J.G. McHafﬁe), [email protected] (R.C. Coghill). contrast, there is growing evidence that mindfulness meditation, a

166 F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173

volitionally initiated cognitive act, can signiﬁcantly attenuate the emphasis on refraining from appraisal or elaboration. Unlike FA,

subjective experience of pain. Although mindfulness meditation which likely involves reappraisal, OM ultimately would involve a

has only recently been the subject of scientiﬁc investigation, the complete lack of higher order appraisal. Traditionally it is taught

emerging data indicate that it shares important common neural that training in focused attention, prior to open monitoring, sta-

substrates engaged by other cognitive factors known to modulate bilizes one’s attention and emotions allowing insight, into the

pain. Nevertheless, some facets of mindfulness meditation-related changeability of experience, to occur during OM practice.

pain relief appear to engage brain mechanisms distinct from those

engaged by other cognitive factors and thus may provide novel

insights into how the subjective experience of pain is produced 3. Mindfulness meditation and health

and modulated.

Mindfulness meditation has been found to improve a wide

spectrum of cognitive and health outcomes [29]. Training in mind-

1. What is mindfulness?

fulness meditation improves anxiety [25,38], depression [6,61],

stress [2,10,11,39], and cognition [33,42–44,70]. Mindfulness-

Mindfulness has been described as a “non-elaborative, non-

related health beneﬁts are associated with enhancements in

judgmental awareness” of present moment experience [36].

cognitive control, emotion regulation, positive mood, and accep-

Operational deﬁnitions of mindfulness expand on this description

tance, each of which have been associated with pain modulation

by regarding it as including: (a) regulated, sustained attention to the

[29]. Thus, it seems reasonable to hypothesize that mindfulness

moment-to-moment quality and character of sensory, emotional

meditation itself would attenuate pain through some of these

and cognitive events, (b) the recognition of such events as momen-

mechanisms.

tary, ﬂeeting and changeable (past and future representations of

those events being considered cognitive abstractions), and (c) a

consequent lack of emotional or cognitive appraisal and/or reac-

4. Mindfulness meditation and pain

tions to these events. This latter aspect highlights the assumption

that our normal experiences are typically, but perhaps unnecessar-

For thousands of years, contemplatives have reported that the

ily, framed as enduring due to insufﬁcient mindfulness and thus

practice of mindfulness meditation attenuates the experience of

augmenting mindfulness could have signiﬁcant positive effects.

pain by modulating expectations, the nature and orientation of

Taken together, mindfulness is simultaneously a process of cog-

attention toward the experience, and the corresponding emotional

nitive control, emotional reappraisal or reduced judgment, and

response [7]. In 1980, Clark and Clark reported that “devout Bud-

existential insight. Although there are individual differences in trait

dhist” porters from Nepal exhibited higher pain tolerance and lower

mindfulness [15,20], this characteristic can be developed by mental

subjective pain reports when compared to other, age-matched, eth-

training such as meditation.

nic groups [12]. Although these researchers suggested that religious

practices (i.e., meditation) were associated with greater pain tol-

2. Mindfulness meditation practices: focused attention and erance, it was not clear if mindfulness-based practice itself could

open monitoring reduce pain [12].

In the early 1980s, clinical studies of mindfulness began with

There are a variety of different meditative practices that are sub- Jon Kabat-Zinn’s seminal work with chronic pain patients. It was

sumed under the general rubric of “mindfulness”. This ambiguity has hypothesized that training in mindfulness would attenuate pain by

lead to confusion within the literature because the speciﬁc medi- altering emotional responses to pain and enhancing acceptance-

tation technique being employed is not always adequately deﬁned related coping strategies [35,37]. Over the course of a ﬁve year

and operationalized [20,42,59]. Because the mechanisms involved study, it was found that chronic pain patients who completed an

in meditation-induced pain-related changes may be dependent on eight-week Mindfulness-Based Stress Reduction (MBSR) program

the speciﬁc technique being investigated (see below), it is critical signiﬁcantly improved their pain symptoms and overall quality of

that the speciﬁcs of the practice being taught or employed be recog- life, even up to four years after completion of this initial training.

nized. In general, mindfulness techniques can be divided into two In other work, eight weeks of mindfulness training was shown to

styles, namely, focused attention and open monitoring [42] (see improve pain acceptance in lower back pain patients [47]. More

Lutz et al. [42] for a comprehensive review). recently, [64] administered a dot-probe task of pain-related threat

Focused attention (FA), also known as Samatha or Shamatha words to ﬁbromyalgia (FM) patients. Increased engagement to

(from Sanskrit), is associated with maintaining focus on a speciﬁc pain-related threat, as measured by dot-probe performance, is

object, often the changing sensation or ﬂow of the breath or an associated with slower response times to a neutral probe where

external object [42]. When attention drifts from the object of focus a pain-related stimulus was previously presented. It was noted

to a distracting sensory, cognitive or emotional event, the practi- that participation in the MBSR program reduced avoidance of

tioner is taught to acknowledge the event and to disengage from it pain-related threat words when compared to FM patients without

by gently returning the attention back to the object of meditation. meditation training [64]. These results are consistent with the work

Along with training stability and ﬂexibility of one’s attention, the of Grossman showing positive inﬂuences of the MBSR program

FA practitioner likely engages in cognitive reappraisal by repeat- on FM patients [30]. Garland and colleagues recently determined

edly reinterpreting distracting events as ﬂeeting or momentary and that eight weeks of mindfulness training signiﬁcantly improved

doing so with acceptance. pain symptoms in irritable bowel syndrome (IBS) patients, even

By contrast, open monitoring (OM), or Vipassana (Sanskrit trans- after three months of training [23,24]. Multivariate path analyses

lation), is associated with a non-directed acknowledgement of any revealed that mindfulness meditation reduced pain symptoms by

sensory, emotional or cognitive event that arises in the mind. reducing anxiety and emotional reactions to IBS symptoms [23].

Zen meditation is considered to be one form of OM practice [4]. Taken together, these ﬁndings provide evidence for the effective-

While practicing OM, the practitioner experiences the current sen- ness of mindfulness meditation in the treatment of clinical pain.

sory or cognitive ‘event’ without evaluation, interpretation, or However, the degree to which these effects are due to the medita-

preference. OM practice is associated with a non-evaluative and tion practices themselves (i.e., the efﬁcacy of mindfulness to reduce

non-elaborative mental stance whereas FA practice places less pain) is less clear.

F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173 167

Addressing this question requires the ability to isolate and short-term training in mindfulness meditation could reduce pain

study the ‘active ingredients’ of meditation by eliminating poten- above and beyond the effects of distraction and relaxation.

tial placebo or regression-to-the-mean effects. Unfortunately, there Taken together, the behavioral studies discussed above pro-

has been a lack of controlled clinical trials that have achieved this vide evidence that mindfulness meditation practice can change the

aim. An alternative approach has been to explore the effects of manner in which noxious stimuli are experienced. While the nature

mindfulness-related pain modulation in highly controlled exper- of these changes remains unclear, brain imaging studies are begin-

imental settings. ning to delineate the mechanisms involved in mindfulness-related

pain relief, allowing them to be distinguished from effects such as

placebo, expectation and belief.

5. Behavioral studies of meditation-related pain relief

6. The neural substrates of mindfulness meditation-related

pain relief

The ﬁrst attempts to evaluate the effects of mindfulness med-

itation on experimentally induced pain compared highly trained

The subjective experience of pain is constructed by interactions

meditators with meditation-naive controls. Grant and Rainville

among sensory, cognitive, and affective processes. Mindfulness

noted that long-term Zen meditation practitioners required higher

meditation is associated, via enhanced cognitive control and emo-

temperatures to report moderate pain [28]. During a focused atten-

tion regulation, with the modulation of sensory representations.

tion condition, where subjects directed their attention toward the

This raises the question, which of these speciﬁc mechanisms are

pain, pain ratings increased in meditation-naive controls whereas

involved, if any, in mindfulness-related pain relief? Secondly, we

meditation practitioners had a non-signiﬁcant reduction in pain.

might ask, to what extent are these mechanisms unique to med-

Conversely, during a mindful attention condition, both sensory

itative practices and to what extent are they shared by other

and affective pain ratings were reduced in experienced practi-

cognitive/affective modulators of pain?

tioners, whereas no effect was seen in meditation-naive controls.

Importantly, the largest pain reductions were observed in the

most advanced practitioners. A similar study contrasted focused 7. Trait effects of prior meditation practice on pain

attention and open monitoring in long-term Tibetan practitioners

[50]. Perlman et al. [50] reported that adept meditators practicing Studies of long-term meditation practitioners on pain pro-

OM had lower pain unpleasantness, but not pain intensity rat- cessing have necessarily employed case–control designs to assess

ings. No signiﬁcant differences were found between meditators differences in pain sensitivity during basal states (i.e., non-

and controls during the FA condition and, in contrast to Grant meditation). Using electroencephalography (EEG) and noxious

and Rainville’s ﬁndings [28], no differences in baseline pain sen- laser stimulation, Brown and Jones examined the inﬂuence of

sitivity were observed. While differences exist between these two long-term mindfulness practice on pain and pain anticipation [8]

studies, the ﬁndings suggest that different meditative traditions and postulated that mindfulness meditators would have reduced

(i.e., Zen, Vipassana) employing mindfulness practice, particularly electrophysiological [event related potentials (ERP)] markers of

the OM style of mindfulness, are associated with pain reduction. anticipation. In line with previous ﬁndings of Grant and Rainville

While these reports were important in advancing the concept [28], they determined that greater meditation experience was asso-

of meditation-related analgesia, they did not account for poten- ciated with lower pain unpleasantness ratings [8]. When compared

tial pre-existing differences between meditators and controls and, to controls, the meditation group exhibited smaller anticipation-

therefore, do not allow causal inferences to be made. However, data evoked potentials in right inferior parietal cortex and mid-cingulate

from longitudinal studies suggesting that even short-term training cortex, indicating less anticipation to the noxious stimuli. Lower

in mindfulness can have substantial pain-relieving effects. mid-cingulate cortex activation during anticipation further pre-

Short-term meditation training studies have utilized a within dicted lower pain unpleasantness ratings in the meditation group

subject design to track changes in pain responses over time, as a but not in controls. Importantly, ACC/ventromedial-PFC (vmPFC),

result of training. Kingston et al. found that six, 1-h mindfulness which was more strongly activated in meditators, correlated pos-

meditation training sessions (twice weekly) effectively increased itively with pain unpleasantness in controls and negatively in

pain tolerance on the cold pressor test as compared to a control meditators (i.e., greater activity associated with less unpleasant-

group that underwent 2 h of visual imagery training [40]. Subjects ness, see Fig. 1). These ﬁndings are noteworthy, as the meditation

were taught both body awareness (i.e., FA) and aspects of OM med- group was not formally meditating, thereby suggesting that prac-

itation. In line with these techniques, the authors postulated that titioners have undergone persistent changes that allow them to

mindfulness modiﬁes the subjective pain experience by enhancing process nociceptive information in a unique manner. The authors

acceptance and coping [37,40]. postulated that mindfulness meditation-related pain reduction

Mindfulness-related pain reduction may also involve divided is associated with increased cognitive and emotional control (as

attention, distraction or non-speciﬁc changes in relaxation or mood reﬂected by activation of ACC/vmPFC) produced by cultivating an

[9]. To address this issue Zeidan et al. examined the effects of brief attitude of acceptance towards impending stimuli. The anticipation

mindfulness meditation training on pain, compared to both math or expectation reductions were postulated to be some of the active

distraction and relaxation [69]. The authors found that three days mechanisms of meditation-related pain relief [8].

(20 min/day) of mindfulness meditation training (incorporating In a follow up to their behavioral study of Zen meditators

both FA and OM) signiﬁcantly reduced ratings of “high” and “low” [28], Grant et al. investigated the brain mechanisms involved in

pain when compared to math distraction and relaxation. Although mindfulness-related pain reduction using functional and structural

math distraction reduced “high” pain ratings in response to nox- MRI [27]. It was hypothesized that even during a non-meditative

ious electrical stimulation, it did not signiﬁcantly reduce “low” state, Zen practitioners would differ from controls in a manner

pain ratings. Relaxation had no effect on pain. Surprisingly, three reﬂective of open monitoring meditation, that is, with reduced eval-

days of meditation training signiﬁcantly decreased pain sensitivity uative or elaborative-related brain activity. During pain, meditators

compared to the control group, with the newly trained medita- exhibited greater activation in brain areas responsible for encoding

tors requiring signiﬁcantly higher levels of electrical stimulation to sensory aspects of noxious stimulation [insula, thalamus, mid-

report moderate pain [69]. Zeidan et al. [69] postulated that even cingulate cortex] (Fig. 2). At the same time, brain activity decreases

168 F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173

Fig. 1. Inverse correlations of pain unpleasantness with anticipatory neural activity in mPFC/rACC in meditators and controls. In a study comparing neural responses during

anticipation of pain between a group with meditation experience and a control group with no meditation experience, a region in mPFC/rACC was more greatly activated in

the meditation group, with greater activation predicting reducing pain unpleasantness ratings. In the control group, the opposite correlation was found with overall lower

activity.

From Brown and Jones [8].

were observed for meditators in regions involved in emotion, mem- thalamus) whereas Brown and Jones [8] observed reduced activa-

ory and appraisal [medial-PFC (mPFC), OFC, amygdala, caudate, tion for meditators in SII and insula. Similarly, whereas Brown and

hippocampus] (Fig. 2). Within these areas, the most advanced prac- Jones [8] found stronger activation for meditators in cognitive and

titioners had the largest activation decreases, accompanied by the emotion-related brain regions (ACC, vmPFC), Grant et al. [27] found

lowest pain ratings. Importantly, it was found that the baseline it was quite dramatically reduced in (DLPFC, mPFC, OFC, amyg-

pain sensitivity of meditators, but not controls, was predicted by dala and hippocampus). Such contradictory ﬁndings emphasize the

reduced functional connectivity between DLPFC and mid-cingulate importance of acknowledging differences in dependent measures

cortex regions during pain. These results were interpreted as (fMRI vs. EEG), meditation traditions, meditator experience level,

reﬂecting a mental state wherein the meditators were fully atten- experimental directives and stimulus type (heat vs. laser) which

tive to the sensory properties of the stimuli (highly activated pain likely account for some of these differences. Clearly, more work is

areas) but simultaneously inhibiting appraisal, elaboration and necessary to understand these discrepancies.

emotional reactivity (deactivated DLPFC, OFC, med-PFC, amygdala,

hippocampus). The authors postulated that Zen practitioners learn 8. State effects of active meditation during pain

to adopt such a mental stance following extensive training. In the

accompanying structural imaging study, it was found that, com- While the results discussed above suggest that meditation-

pared to age-matched controls, Zen practitioners exhibited thicker related effects are not necessarily dependent upon a meditative

gray matter in pain-related regions which overlapped with the state, little is actually known about the effects of active mindful-

functional effects. More speciﬁcally, meditators had thicker cor- ness meditation on pain. Gard et al. have recently examined the

tex in mid-cingulate cortex and bilateral SII that, in the case of inﬂuence of Vipassana meditation on pain perception with fMRI

the mid-cingulate cortex area, was correlated with the number [22]. They found that during meditation, long-term mindfulness

of years of experience in practitioners. These regional structural practitioners had signiﬁcant reductions in pain unpleasantness rat-

differences, which overlapped with the functional results and cor- ings to noxious electrical stimulation compared to a control group.

related with meditation experience, were interpreted as further Consistent with Brown and Jones [8] and Perlman et al. [50] but not

evidence for long lasting changes stemming from meditative prac- Grant et al. [26,27], Gard et al. found that meditators and controls

tice and are consistent with other structural imaging studies of did not differ in reported pain intensity [8,50] and did not have

meditation [31,32]. baseline sensitivity differences. While meditating during pain, the

The studies summarized in this section extend the preceding meditation group exhibited greater activation of contralateral SII

behavioral studies by demonstrating that the effects of medita- and posterior insula [22], regions implicated in the sensory dimen-

tion are not limited to a meditative state. Further, they provide the sion of pain processing. Change in activity of this region (from

ﬁrst potential neural mechanisms underlying mindfulness-related mindfulness to baseline) correlated negatively with changes in

pain reduction. Surprisingly, however, the two studies report nearly unpleasantness in meditators (from baseline to mindfulness) but

opposite results: Grant and Rainville [28] found meditators to be positively in controls. The authors interpret this as an increase in

less sensitive to pain at baseline whereas Brown and Jones [8] sensory processing during meditation, which is accompanied by

found no difference between groups. In contrast, whereas Brown pain reduction. This reversed relationship between meditators and

and Jones [8] noted mindfulness-related pain relief to be associated controls mirrors the correlations of vmPFC and ACC with unpleas-

with reductions in anticipation, Grant et al. [27] observed no differ- antness during anticipation in the Brown and Jones study [8]. In

ence during a cue period preceding pain. Furthermore, during the fact, Gard and colleagues also report rACC and vmPFC activation

receipt of pain, Grant et al. [27] found stronger activation for medi- for meditators in the anticipation phase. Thus, these studies con-

tators in pain-related cortices (mid-cingulate cortex, insula, SII, and verge to show increased activation of brain regions implicated in

F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173 169

Fig. 2. Brain areas showing higher and lower activity in meditators compared to controls, during pain, in a non-meditative state. Activation is higher for meditators in

pain-related regions such as dorsal anterior cingulate cortex (dACC), insula (INS) and thalamus (Thal) but is dramatically reduced (particularly on inset B) in areas involved

in appraisal, emotion and memory: medial prefrontal cortex (mPFC)-orbitofrontal cortex (OFC), amygdala, and dorso-lateral prefrontal cortex (DLPFC).

cognitive/emotional control during anticipation of pain (rACC, When compared to rest, meditation signiﬁcantly reduced acti-

vmPFC). Gard et al. [22] interpret their ﬁndings as reﬂecting vation in contralateral SI, corresponding to the stimulation site

decreased cognitive control while Brown et al. suggested that (Fig. 3). Regression analyses revealed that mindfulness meditation

increased ACC and vmPFC activity reﬂects increased cognitive ﬂex- reduced pain through multiple brain mechanisms. Increased acti-

ibility [8]. vation in the rACC during meditation and pain predicted reductions

The results described thus far provide strong conﬁrmatory evi- in pain intensity (Fig. 3). The rACC is associated with the cogni-

dence for an inﬂuence of mindfulness practice on pain processing. tive modulation of pain, cognitive control, and the regulation of

However, each study discussed in the previous section featured a emotions [49,66] (Fig. 3). Interestingly, greater activity in the right

cross-sectional or case–control design. As such, these reports are anterior insula during meditation and noxious heat stimulation was

limited in their ability to make causal claims due to the myriad associated with greater reductions in pain intensity ratings. This

differences that may exist between meditators and controls, above area links somatosensory processing areas with brain regions such

and beyond the speciﬁc meditative practice utilized. as the PFC, amygdala, and ACC [21,48]. The anterior insula may be

Given these differences, a critical question that must be involved in shaping afferent nociceptive processing by providing a

addressed is how much mindfulness training is necessary to have substrate for the integration of cognitive information [60] and has

an inﬂuence on pain perception? Surprisingly, the answer appears been shown to contribute to interoceptive evaluation [17,18,46].

to be very little. Zeidan et al. [71] recently examined the brain Furthermore, greater activity in areas involved in the contextual

mechanisms involved in meditation-related pain relief with a brief evaluation of pain (OFC) was directly related to pain unpleasantness

mindfulness training protocol in previously meditative-naïve par- decreases during meditation and noxious stimulation.

ticipants. Using arterial spin labeling (ASL) fMRI, a technique that Greater reductions in thalamic activity during meditation and

provides a quantiﬁable measure of cerebral blood ﬂow while con- noxious stimulation predicted reductions in pain unpleasantness

trolling for respiratory confounds, they examined the effects of ratings (Fig. 3). Crick and colleagues [16,45] proposed a model

four days (20 min/day) of mindfulness meditation training on pain- in which shifts in executive attention, mediated by activation in

related brain processing. Training consisted of a combination of FA higher order brain regions (PFC), can regulate lower level sen-

and OM techniques. In session 1 (before training), subjects were sory processes, speciﬁcally in the thalamic reticular nuclei. In

◦

stimulated with noxious heat for 6 min at 49 C (12 s OFF/ON) in accordance with this model, Zeidan et al. [71] proposed that

a rest condition and an attention to breath condition (ATB) where meditation-related reductions in pain unpleasantness are asso-

subjects were instructed to “focus on the changing sensations of ciated with OFC regulation of thalamic reticular nuclei (TRN).

the breath.” The ATB condition served as a divided attention con- Existing anatomical connections between SI and TRN [16,34] pro-

trol. Prior to meditation training, although ATB did not reduce pain vide support for a theory in which meditation-related shifts in

intensity ratings, there was a trend towards signiﬁcance in reduc- executive attention (focusing on the changing sensations of the

ing pain unpleasantness ratings (p = .06). After meditation training, breath) produce increased activity in the OFC that inhibit lower

subjects were reassessed in a rest and meditation condition. Med- level nociceptive processing in the thalamus. This process could

itating in the presence of noxious heat stimulation signiﬁcantly attenuate the elaboration of nociceptive information in the cor-

reduced pain intensity (average reduction 40%) and pain unpleas- tex, evidenced by decreased activity in the thalamus and SI.

antness (average reduction 57%) ratings compared to rest. Taken together, these ﬁndings contribute to the existing literature

170 F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173

Fig. 3. Mindfulness meditation signiﬁcantly reduced pain through a number of brain mechanisms. In the presence of noxious heat, meditation signiﬁcantly reduced lower

level afferent processing in the primary somatosensory cortex (SI) corresponding to the stimulation site (top). Regression analyses revealed that meditation-related pain

intensity reductions were associated with greater activity in the rostral anterior cingulate cortex (rACC), an area involved in cognitive control (middle). Greater right anterior

insula (aINS) activity also predicted pain intensity reductions during meditation, an area associated with interoceptive awareness (middle). Greater orbitofrontal cortex

(OFC) activity was associated with greater decreases in pain unpleasantness ratings (bottom). Moreover, thalamic (Thl) deactivation was associated with reductions in pain

unpleasantness (bottom).

by demonstrating that brief mindfulness-based mental training forms of mindfulness meditation (see above), it is likely that FA

reduces pain through multiple mechanisms including cortico- and OM practices would inﬂuence pain in different ways. Specif-

cortical and cortico-thalamic interactions. ically, FA is proposed to involve repetitive cognitive reappraisal

and to promote sustained attention whereas OM is proposed to

9. An integrated perspective on meditation-based pain involve non-judgmental appraisal of salient sensory events [42].

relief While the studies of Grant and colleagues were able to show a FA

condition did not signiﬁcantly reduce pain in Zen practitioners (or

Understanding the literature reviewed thus far requires evaluat- increase pain, as it did in controls), Perlman et al. [50] found that

ing the data in the context of the different meditation practices used differences between adept and novice meditators in pain reduc-

(focused attention, open monitoring), different levels of exper- tion were only exhibited with OM practices. Thus, OM meditations

tise (i.e., meditation naive, short-term or long-term practitioners), seem more suited to analgesia than FA when taking into account

and different experimental designs (state effects, trait effects, meditation experience. That is, OM is more effective at reducing

case–control, longitudinal). Inconsistencies and apparent discrep- pain after extensive meditation training, as compared to FA. Sup-

ancies among studies may be partially explained by considering the port for this can be found in Grant et al.’s 2009 study which reports

complex interactions among these factors, for which we will here that the analgesic effect in advanced meditators, performing an

∼

attempt to gain a ﬂavor (Table 1). OM-style of attention, did not arise until 2000 h of practice. On

Given the differences in the neural processes, which undoubt- the other hand, approaches combining elements of both FA and

edly underlie the differences in the mental processes with different OM are effective at reducing behavioral and neural mechanisms

F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173 171

of pain after brief mental training [69,71]. These ﬁndings suggest

rACC,

that cognitive practices employing attentional stability (focused pain UNP

↓ UNP attention) in conjunction with non-evaluative awareness of sen-

INT ↓ activity

↓

UNP

= insula; sory events (open monitoring) can reduce pain, even after brief

with

↑

INT a = ↓

brain

rACC mental training.

= Thal

SI/SII ↑ MCC

↓

posterior MCC,

pINS/SII OFC, DLPFC MCC, aINS,

↑ Mindful correlating ↑ ↓ NA NA ↓ NA NA ↑ ↑ sensitivity

experience

10. Common ﬁnal pathway to the cognitive modulation of pINS,

pain

site

cortex; Cognitive techniques, such as placebo, distraction or changes in HIP

INS

expectation, likely employ similar brain mechanisms in the mod- during

AMG,

ulation of pain [62]. In each case, the ACC has been postulated SII rACC Thal,

to attenuate pain by employing cognitive control mechanisms to prefrontal

stimulation

INS DLPFC, MCC, SI pINS, PFC modulate pain through activation of the descending opioid sys-

PFC, Activation mindful/pain-related contrasts ↑ ↓ NA ↓ NA NA ↓ ↓ ↑ NA NA

tem via the periaqueductal gray. Based on the studies reviewed

above, we suggest that mindfulness operates through an over-

cortex;

lapping network but by unique mechanisms. More speciﬁcally,

placebo analgesia is typically preceded by greater activation of

DLPFC during anticipation of pain, an effect that predicts reduc-

cingulate

tions in pain perception and activity in pain-related brain regions no/no yes/yes

mid experience. [53,67]. Mindfulness, on the other hand, does not appear to involve – –

tested

no/yes

DLPFC activation. Long-term training in Zen as well as Vipas- no/no

–

MCC, –

sana, both forms of OM meditation, is associated with deactivation No/yes OM No/yes Intensity/unpleasantness reduction Yes/yes NA

Mindful FA

Focused NA NA Yes/not

in DLPFC during pain, and in the case of Zen, reduced connec- meditation

tivity between this region and pain-related mid-cingulate cortex and

vs activation [27]. It is not yet clear however, to what extent this

monitoring;

altered relationship of DLPFC with pain processing regions might vs vs

for

open be related to differences in anticipatory processing. Concerning

for for for

sensitivity

DLPFC, we postulate that: where placebo effects exert top-down OM, meditators adepts control

modulatory effects on pain by initiating positive expectations via pain group

sensitivity

tolerance

the PFC, mindfulness meditation seems to reduce the inﬂuence of difference/change

cortex; sensitivity sensitivity sensitivity

unpleasantness.

expectancy on pain, possibly through decreased elaboration (i.e., lower

tested

difference: difference: difference: to

a state of reduced- or non-appraisal) of nociceptive information. pain

meditation controls Increased Lower No Decreased No Lower Lower Not No Baseline meditators

novices

meditators meditators meditators meditators

In support of this interpretation, the reductions in DLPFC in Zen

UNP,

related practitioners are accompanied by ‘deactivation’ of memory- and

orbitofrontal

appraisal-related brain regions, including the hippocampus and also

OFC, OFC, respectively. This is again in contrast to placebo effects (associ-

was

thalamus; ated with activation of the OFC) that are dependent on conditioning,

Heat Cold Electrical

Heat Laser Heat Heat Electrical

Noxious stimuli

expectation and beliefs. Interestingly, the OFC pain-related effects Thal, independent.

intensity; in meditators vary depending on experience level. Newly trained

meditators practitioners [71] showed OFC activation increases that are asso-

adept pain

trained

novices ciated with pain reduction whereas long-term Zen practitioners

cortices; or +

INT,

showed activation decreases associated with reduced pain [27]. We completely

SI/SII

suggest this reﬂects the transition one undergoes, during medita- Adepts novices Adepts Adepts Adepts Novice Trained Novices Trained Novices Trained Adepts

Adepts Heat

meditators

MCC, tive training, from cognitive reappraisal at early phases to a more

attention; appraisal-free state as one advances. However, it is clear that fur-

considered

somatosensory

ther studies are needed to help characterize mindfulness-related be

pain. pain reduction and its relation to other pain modulatory tech-

State focused not

practices thickness on

focused mindful

niques.

FA,

secondary

In this review we have surveyed the rapidly emerging ﬁeld

should

cortical of meditation-related pain reduction. The data indicate that, like and and

and

other cognitive factors that modulate pain, prefrontal and cingulate Zen FA/OM Attention: (separately) Meditation FA/OM Attention: Non-meditative Anticipation FA/OM FA FA/OM OM FA/OM meditation

amygdala;

cortices are intimately involved the modulation of pain by mind- greater

primary

fulness meditation. Mindfulness meditation, like other cognitive sample

AMG,

manipulations, alters the contextual evaluation of pain but is likely

where SI/SII,

mindfulness to do so dynamically over time and experience, such that begin-

insula; (BOLD)(ASL) Zen (BOLD) of

ners reappraise events and the most advanced practitioners may study

cortex; overlapping

refrain from elaboration/appraisal entirely. Admittedly, many of Methodology Psychophysics Psychophysics EEG/ERP Psychophysics Psychophysics Structural MRI fMRI fMRI fMRI MRI

effects

these interpretations are based on reverse inference and assump- anterior

had

the

tions derived from traditional claims and require more scrutiny

cingulate

b b b

aINS,

in future research. Nonetheless, mindfulness-related pain reduc- : structural

(2007) (2010)

tion promises to be an important tool for understanding how our studies

(2010) (2011) (2010)

(2009) (2010) (2011)

assessing

(2012)

anterior awareness of sensory events occurs as well as a potentially impor-

This These tant adjunct to current treatment options for acute and chronic a Study Kingston Grant Zeidan Gard Grant Brown Perlman Grant Zeidan b pain. Table Abbreviations Studies rostral

172 F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173

Acknowledgment [28] J.A. Grant, P. Rainville, Pain sensitivity and analgesic effects of mindful states

in Zen meditators: a cross-sectional study, Psychosomatic Medicine 71 (2009)

106–114.

This work was supported by the National Institute of Health

[29] P. Grossman, L. Niemann, S. Schmidt, H. Walach, Mindfulness-based stress

Grant NS39426 (R.C.). reduction and health beneﬁts. A meta-analysis, Journal of Psychosomatic

Research 57 (2004) 35–43.

[30] P. Grossman, U. Tiefenthaler-Gilmer, A. Raysz, U. Kesper, Mindfulness training

References as an intervention for ﬁbromyalgia: evidence of postintervention and 3-year

follow-up beneﬁts in well-being, Psychotherapy and Psychosomatics 76 (2007)

226–233.

[1] A.V. Apkarian, M.C. Bushnell, R.D. Treede, J.K. Zubieta, Human brain mecha-

[31] B.K. Holzel, J. Carmody, K.C. Evans, E.A. Hoge, J.A. Dusek, L. Morgan, R.K. Pitman,

nisms of pain perception and regulation in health and disease, European Journal

S.W. Lazar, Stress reduction correlates with structural changes in the amygdala,

of Pain 9 (2005) 463–484.

Social Cognitive and Affective Neuroscience 5 (2010) 11–17.

[2] J.A. Astin, Stress reduction through mindfulness meditation. Effects on psy-

[32] B.K. Holzel, U. Ott, T. Gard, H. Hempel, M. Weygandt, K. Morgen, D. Vaitl,

chological symptomatology, sense of control, and spiritual experiences,

Investigation of mindfulness meditation practitioners with voxel-based mor-

Psychotherapy and Psychosomatics 66 (1997) 97–106.

phometry, Social Cognitive and Affective Neuroscience 3 (2008) 55–61.

[3] L.Y. Atlas, N. Bolger, M.A. Lindquist, T.D. Wager, Brain mediators of predictive

[33] A.P. Jha, J. Krompinger, M.J. Baime, Mindfulness training modiﬁes subsystems of

cue effects on perceived pain, Journal of Neuroscience 30 (2010) 12964–12977.

attention, Cognitive, Affective, and Behavioral Neuroscience 7 (2007) 109–119.

[4] J.H. Austin, Zen and the Brain: Toward an Understanding of Meditation and

[34] E.G. Jones, Some aspects of the organization of the thalamic reticular complex,

Consciousness, MIT, Press, Cambridge, MA, 1998, xxiv, 844 pp.

Journal of Comparative Neurology 162 (1975) 285–308.

[5] S.J. Bantick, R.G. Wise, A. Ploghaus, S. Clare, S.M. Smith, I. Tracey, Imaging how

[35] J. Kabat-Zinn, An outpatient program in behavioral medicine for chronic pain

attention modulates pain in humans using functional MRI, Brain 125 (2002)

310–319. patients based on the practice of mindfulness meditation: theoretical consid-

erations and preliminary results, General Hospital Psychiatry 4 (1982) 33–47.

[6] T. Barnhofer, C. Crane, E. Hargus, M. Amarasinghe, R. Winder, J.M. Williams,

[36] J. Kabat-Zinn, Full Catastrophe Living, Delta Publishing, New York, NY, 1990.

Mindfulness-based cognitive therapy as a treatment for chronic depression: a

[37] J. Kabat-Zinn, L. Lipworth, R. Burney, The clinical use of mindfulness meditation

preliminary study, Behaviour Research and Therapy 47 (2009) 366–373.

for the self-regulation of chronic pain, Journal of Behavioral Medicine 8 (1985)

[7] B. Bohdi, In the Buddha’s Words: An Anthology of Discourses from the Pali

163–190.

Canon, Wisdom Publications, Boston, MA, 2005.

[38] J. Kabat-Zinn, A.O. Massion, J. Kristeller, L.G. Peterson, K.E. Fletcher, L. Pbert,

[8] C.A. Brown, A.K. Jones, Meditation experience predicts less negative appraisal of

W.R. Lenderking, S.F. Santorelli, Effectiveness of a meditation-based stress

pain: electrophysiological evidence for the involvement of anticipatory neural

reduction program in the treatment of anxiety disorders, American Journal of

responses, Pain 150 (September (3)) (2010) 428–438.

Psychiatry 149 (1992) 936–943.

[9] J. Buhle, T.D. Wager, Does meditation training lead to enduring changes in the

[39] J. Kabat-Zinn, E. Wheeler, T. Light, A. Skillings, M.J. Scharf, T.G. Cropley, D.

anticipation and experience of pain? Pain 150 (2010) 382–383.

Hosmer, J.D. Bernhard, Inﬂuence of a mindfulness meditation-based stress

[10] L.E. Carlson, M. Speca, K.D. Patel, E. Goodey, Mindfulness-based stress reduction

reduction intervention on rates of skin clearing in patients with moderate

in relation to quality of life, mood, symptoms of stress, and immune parameters

to severe psoriasis undergoing phototherapy (UVB) and photochemotherapy

in breast and prostate cancer outpatients, Psychosomatic Medicine 65 (2003)

571–581. (PUVA), Psychosomatic Medicine 60 (1998) 625–632.

[40] J. Kingston, P. Chadwick, D. Meron, T.C. Skinner, A pilot randomized control trial

[11] L.E. Carlson, Z. Ursuliak, E. Goodey, M. Angen, M. Speca, The effects of a mind-

investigating the effect of mindfulness practice on pain tolerance, psychological

fulness meditation-based stress reduction program on mood and symptoms of

well-being, and physiological activity, Journal of Psychosomatic Research 62

stress in cancer outpatients: 6-month follow-up, Supportive Care in Cancer 9

(2007) 297–300.

(2001) 112–123.

[41] T. Koyama, J.G. McHafﬁe, P.J. Laurienti, R.C. Coghill, The subjective experience of

[12] W.C. Clark, S.B. Clark, Pain responses in Nepalese porters, Science 209 (1980)

410–412. pain: where expectations become reality, Proceedings of the National Academy

of Sciences of the United States of America 102 (2005) 12950–12955.

[13] R.C. Coghill, J.G. McHafﬁe, Y.F. Yen, Neural correlates of interindividual differ-

[42] A. Lutz, H.A. Slagter, J.D. Dunne, R.J. Davidson, Attention regulation

ences in the subjective experience of pain, Proceedings of the National Academy

and monitoring in meditation, Trends in Cognitive Sciences 12 (2008)

of Sciences of the United States of America 100 (2003) 8538–8542.

163–169.

[14] R.C. Coghill, C.N. Sang, J.M. Maisog, M.J. Iadarola, Pain intensity processing

[43] A. Lutz, H.A. Slagter, N.B. Rawlings, A.D. Francis, L.L. Greischar, R.J. Davidson,

within the human brain: a bilateral, distributed mechanism, Journal of Neu-

Mental training enhances attentional stability: neural and behavioral evidence,

rophysiology 82 (1999) 1934–1943.

Journal of Neuroscience 29 (2009) 13418–13427.

[15] J.D. Creswell, B.M. Way, N.I. Eisenberger, M.D. Lieberman, Neural correlates of

[44] K.A. Maclean, E. Ferrer, S.R. Aichele, D.A. Bridwell, A.P. Zanesco, T.L. Jacobs, B.G.

dispositional mindfulness during affect labeling, Psychosomatic Medicine 69

King, E.L. Rosenberg, B.K. Sahdra, P.R. Shaver, B.A. Wallace, G.R. Mangun, C.D.

(2007) 560–565.

Saron, Intensive meditation training improves perceptual discrimination and

[16] F. Crick, Function of the thalamic reticular complex: the searchlight hypothesis,

sustained attention, Psychological Science 21 (2010) 829–839.

Proceedings of the National Academy of Sciences of the United States of America

[45] K. McAlonan, J. Cavanaugh, R.H. Wurtz, Attentional modulation of thalamic

81 (1984) 4586–4590.

reticular neurons, Journal of Neuroscience 26 (2006) 4444–4450.

[17] H.D. Critchley, The human cortex responds to an interoceptive challenge, Pro-

[46] N. Medford, H.D. Critchley, Conjoint activity of anterior insular and anterior

ceedings of the National Academy of Sciences of the United States of America

cingulate cortex: awareness and response, Brain Structure and Function 214

101 (2004) 6333–6334.

(2010) 535–549.

[18] H.D. Critchley, S. Wiens, P. Rotshtein, A. Ohman, R.J. Dolan, Neural systems

[47] N.E. Morone, C.M. Greco, D.K. Weiner, Mindfulness meditation for the treat-

supporting interoceptive awareness, Nature Neuroscience 7 (2004) 189–195.

ment of chronic low back pain in older adults: a randomized controlled pilot

[19] S.W. Derbyshire, A.K. Jones, F. Gyulai, S. Clark, D. Townsend, L.L. Firestone, Pain

study, Pain 134 (2008) 310–319.

processing during three levels of noxious stimulation produces differential

[48] E.J. Mufson, M.M. Mesulam, Insula of the old world monkey. II: afferent cortical

patterns of central activity, Pain 73 (1997) 431–445.

input and comments on the claustrum, Journal of Comparative Neurology 212

[20] J. Dunne, Toward an understanding of non-dual mindfulness, Contemporary

(1982) 23–37.

Buddhism 12 (2011) 69–86.

[49] K.N. Ochsner, J.J. Gross, The cognitive control of emotion, Trends in Cognitive

[21] D.P. Friedman, E.A. Murray, J.B. O’Neill, M. Mishkin, Cortical connections of the

Sciences 9 (2005) 242–249.

somatosensory ﬁelds of the lateral sulcus of macaques: evidence for a cor-

[50] D.M. Perlman, T.V. Salomons, R.J. Davidson, A. Lutz, Differential effects on pain

ticolimbic pathway for touch, Journal of Comparative Neurology 252 (1986)

323–347. intensity and unpleasantness of two meditation practices, Emotion 10 (2010)

65–71.

[22] T. Gard, B.K. Holzel, A.T. Sack, H. Hempel, D. Vaitl, U. Ott, Pain attenua-

[51] P. Petrovic, T. Dietrich, P. Fransson, J. Andersson, K. Carlsson, M. Ingvar, Placebo

tion through mindfulness is associated with decreased cognitive control and

in emotional processing – induced expectations of anxiety relief activate a

increased sensory processing in the brain, Cerebral Cortex 191 (2011) 36–43.

generalized modulatory network, Neuron 46 (2005) 957–969.

[23] E.L. Garland, S.A. Gaylord, O. Palsson, K. Faurot, J. Douglas Mann, W.E. White-

[52] P. Petrovic, M. Ingvar, Imaging cognitive modulation of pain processing, Pain

head, Therapeutic mechanisms of a mindfulness-based treatment for IBS:

95 (2002) 1–5.

effects on visceral sensitivity, catastrophizing, and affective processing of pain

[53] P. Petrovic, E. Kalso, K.M. Petersson, J. Andersson, P. Fransson, M. Ingvar, A

sensations, Journal of Behavioral Medicine (2011), Epub ahead of print.

prefrontal non-opioid mechanism in placebo analgesia, Pain 150 (2010) 59–65.

[24] S.A. Gaylord, O.S. Palsson, E.L. Garland, K.R. Faurot, R.S. Coble, J.D. Mann, W.

[54] P. Petrovic, E. Kalso, K.M. Petersson, M. Ingvar, Placebo opioid analgesia – imag-

Frey, K. Leniek, W.E. Whitehead, Mindfulness training reduces the severity of

ing a shared neuronal network, Science 295 (2002) 1737–1740.

irritable bowel syndrome in women: results of a randomized controlled trial,

[55] A. Ploghaus, I. Tracey, J.S. Gati, S. Clare, R.S. Menon, P.M. Matthews, J.N. Rawlins,

American Journal of Gastroenterology 106 (2011) 1678–1688.

Dissociating pain from its anticipation in the human brain, Science 284 (1999)

[25] P.R. Goldin, J.J. Gross, Effects of mindfulness-based stress reduction (MBSR) on

1979–1981.

emotion regulation in social anxiety disorder, Emotion 10 (2010) 83–91.

[56] C.A. Porro, V. Cettolo, M.P. Francescato, P. Baraldi, Temporal and intensity cod-

[26] J.A. Grant, J. Courtemanche, E.G. Duerden, G.H. Duncan, P. Rainville, Cortical

ing of pain in human cortex, Journal of Neurophysiology 80 (1998) 3312–3320.

thickness and pain sensitivity in zen meditators, Emotion 10 (2010) 43–53.

[57] P. Rainville, G.H. Duncan, D.D. Price, B. Carrier, M.C. Bushnell, Pain affect

[27] J.A. Grant, J. Courtemanche, P. Rainville, A non-elaborative mental stance and

encoded in human anterior cingulate but not somatosensory cortex, Science

decoupling of executive and pain-related cortices predicts low pain sensitivity

277 (1997) 968–971.

in Zen meditators, Pain 152 (2011) 150–156.

F. Zeidan et al. / Neuroscience Letters 520 (2012) 165–173 173

[58] D.A. Seminowicz, D.J. Mikulis, K.D. Davis, Cognitive modulation of pain-related [65] C. Villemure, B.M. Slotnick, M.C. Bushnell, Effects of odors on pain perception:

brain responses depends on behavioral strategy, Pain 112 (2004) 48–58. deciphering the roles of emotion and attention, Pain 106 (2003) 101–108.

[59] S.L. Shapiro, L.E. Carlson, J.A. Astin, B. Freedman, Mechanisms of mindfulness, [66] B.A. Vogt, Pain and emotion interactions in subregions of the cingulate gyrus,

Journal of Clinical Psychology 62 (2006) 373–386. Nature Reviews Neuroscience 6 (2005) 533–544.

[60] C.J. Starr, L. Sawaki, G.F. Wittenberg, J.H. Burdette, Y. Oshiro, A.S. Quevedo, R.C. [67] T.D. Wager, J.K. Rilling, E.E. Smith, A. Sokolik, K.L. Casey, R.J. Davidson, S.M. Koss-

Coghill, Roles of the insular cortex in the modulation of pain: insights from lyn, R.M. Rose, J.D. Cohen, Placebo-induced changes in FMRI in the anticipation

brain lesions, Journal of Neuroscience 29 (2009) 2684–2694. and experience of pain, Science 303 (2004) 1162–1167.

[61] J.D. Teasdale, Z.V. Segal, J.M. Williams, V.A. Ridgeway, J.M. Soulsby, M.A. Lau, [68] K. Wiech, M. Farias, G. Kahane, N. Shackel, W. Tiede, I. Tracey, An fMRI study

Prevention of relapse/recurrence in major depression by mindfulness-based measuring analgesia enhanced by religion as a belief system, Pain 139 (2008)

cognitive therapy, Journal of Consulting and Clinical Psychology 68 (2000) 467–476.

615–623. [69] F. Zeidan, N.S. Gordon, J. Merchant, P. Goolkasian, The effects of brief mindful-

[62] I. Tracey, P.W. Mantyh, The cerebral signature for pain perception and its mod- ness meditation training on experimentally induced pain, Journal of Pain 11

ulation, Neuron 55 (2007) 377–391. (2010) 199–209.

[63] I. Tracey, A. Ploghaus, J.S. Gati, S. Clare, S. Smith, R.S. Menon, P.M. Matthews, [70] F. Zeidan, S.K. Johnson, B.J. Diamond, Z. David, P. Goolkasian, Mindfulness med-

Imaging attentional modulation of pain in the periaqueductal gray in humans, itation improves cognition: evidence of brief mental training, Consciousness

Journal of Neuroscience 22 (2002) 2748–2752. and Cognition 19 (2010) 597–605.

[64] D. Vago, Y. Nakamura, Selective attentional bias towards pain-related threat [71] F. Zeidan, K.T. Martucci, R.A. Kraft, N.S. Gordon, J.G. McHafﬁe, R.C. Coghill, Brain

in ﬁbromyalgia: preliminary evidence for effects of mindfulness meditation mechanisms supporting the modulation of pain by mindfulness meditation,

training, Cognitive Therapy and Research 35 (2011) 581–594. Journal of Neuroscience 31 (2011) 5540–5548.