Cognitive and Emotional Control of Pain and Its Disruption in Chronic Pain

REVIEWS

Cognitive and emotional control of pain and its disruption in chronic pain

M. Catherine Bushnell, Marta Čeko and Lucie A. Low Abstract | Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind–body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states — important components of mind–body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.

Pain is a complex sensory and emotional experience to anatomical and functional alterations in this same Descending pain modulatory systems that can vary widely between people and even within an circuitry, resulting not only in pain but also in altered Networks in the brain involving individual depending on the context and meaning of the cognition and affect. In Eastern cultures, the power of pathways from the cerebral pain and the psychological state of the person. Cognitive the mind to control one’s physical state with the use cortex down to the spinal cord and emotional factors have a surprisingly important of practices such as meditation and yoga has been rec- that can lead to inhibition or excitation of afferent pain influence on pain perception. A negative expectation can ognized for centuries. Today, people in the Western signals at multiple levels of the completely reverse the analgesic effect of a clinical dose world have begun to adopt these techniques to reduce brain. of the opioid agonist remifentanil1, whereas the expecta- stress and control pain, and many pain sufferers now tion of pain relief is an important component of placebo recognize the potential therapeutic effects of psycho- analgesia2. Clinical and experimental studies show that logical procedures. In line with patient reports, new even a simple psychological manipulation, such as dis- experimental studies show that interventions such traction, can have a powerful effect on our perception of as meditation not only decrease pain but also have pain3. Our emotional state also has an enormous influ- powerful protective effects on brain grey matter and ence on pain; a negative emotional state increases pain, connectivity within pain modulatory circuits7–12. The whereas a positive state lowers pain4. Not surprisingly, wealth of new studies showing alterations in the brains complex emotional states such as empathy, which incor- of patients with chronic pain can now be integrated porate emotional and cognitive factors, alter the way an with our increased understanding of the brain circuitry individual feels pain5. Brain imaging studies have allowed involved in the psychological modulation of pain, allow- us to examine the neural basis of psychological modula- ing us to hypothesize a negative-feedback loop between tion of pain (BOX 1). These studies reveal that activity in impaired pain modulatory circuitry and pain processing, afferent pain pathways is altered by the attentional state, leading not only to increased chronic pain but also to National Center for positive and negative emotions, empathy and the admin- cognitive and emotional deficits that are comorbid with Complementary and istration of a placebo6. Additionally, imaging studies show the pain (FIG. 1). Alternative Medicine, that psychological factors activate intrinsic modulatory National Institutes of Health, systems in the brain, including those involved in opioid- Brain regions involved in the experience of pain 35 Convent Drive, descending pain Room 1C917, MSC 3711, related pain relief. Furthermore, multiple Multiple pathways in the CNS are involved in pain pro- Bethesda, modulatory systems are implicated in pain relief, with atten- cessing. Human brain imaging studies have revealed Maryland 20892–3711, USA. tional states and emotions activating different systems in consistent cortical and subcortical networks that are Correspondence to M.C.B. the brain. activated by pain, including sensory, limbic and asso- e‑mail: [email protected]. gov In parallel with our increased understanding of the ciative regions. The brain areas most commonly acti- doi:10.1038/nrn3516 circuitry underlying the psychological modulation of vated by noxious stimuli in human brain imaging studies Published 30 May 2013 pain, recent evidence shows that chronic pain can lead are the primary somatosensory cortex (S1), secondary

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Box 1 | Real-time functional MRI and pain control Some studies show that a noxious insult to the body is not necessary for the experience of pain or for the Real-time functional MRI (rtfMRI) provides direct feedback on the activation of a activation of pain pathways. A number of studies have specific brain area, allowing a person to learn how to control the activity in this brain found that simply observing another individual in pain region. RtfMRI feedback has recently been used to successfully train healthy controls to activates some pain-related brain regions (see REF. 43 for a modulate the activation of their own anterior cingulate cortex (ACC) in order to alter their pain experience169. Participants were given several cognitive strategies that they meta-analysis), with such activation being stronger when 44 could use to manipulate activity in the ACC on the basis of previous studies that showed one observes a loved one in pain rather than a stranger . activation of this region. Participants eventually learned to control the activity in the The activation of these regions in the absence of a pain ACC, and the more control they developed, the more they were able to decrease the stimulus could induce a state of ‘priming’ in the brain, in intensity of the experimental pain stimulus. Importantly, using the same paradigm, which a noxious stimulus given after emotionally prim- patients with chronic pain were able to decrease the level of their ongoing pain by ing a subject elicits an enhanced pain experience. This is controlling the activation of their ACC. Thus, rtfMRI could potentially be used as a tool exactly what was found in a study in which the authors to help patients directly activate pain modulatory systems and better control their pain. created a state of positive or negative empathy towards In the above study, subjects had to try to modify activity in a specific brain region to someone experiencing pain5. When subjects were posi- modify pain. However, as we know that multiple brain regions are involved in the tively empathizing with the individual in pain, their own cognitive and emotional control of pain, training subjects to control the activity in multiple brain regions associated with a particular task170 and applying this skill to pain pain experience was enhanced. Similar empathetically modulation, might maximize the cognitive control of pain. enhanced pain responses have been reported in rodents. In another study, the authors produced intriguing evidence that mice are influenced by the pain state of a cage- somatosensory cortex (S2), anterior cingulate cortex mate45. When mice see cage-mates in pain, they show (ACC), insula, prefrontal cortex (PFC), thalamus and increased pain behaviours themselves — a phenomenon cerebellum13 (FIG. 2). Neural activation in these areas is the authors call ‘emotional contagion’45. consistent with anatomical and electrophysiological Empathy is a complex cognitive and emotional state studies that show possible afferent nociceptive connec- that could involve alterations in attention, emotions and tivity to these regions13–20. Other regions have also been expectations. Nevertheless, simpler cognitive manipula- shown to have nociceptive input through anatomical tions, such as imagining or anticipating a painful experi- and electrophysiological studies, and these findings have ence, can also lead to activation of pain pathways. One been confirmed by brain imaging studies. These regions, study found that imagining a painful hand movement which include the nucleus accumbens and amygdala21,22, in an amputated arm activated pain pathways, involv- probably receive nociceptive input through spinopa- ing the S1, insula and thalamus46. Similarly, a number of rabrachial–amygdala projections23, as well as the periaq- studies have shown that when an individual is anticipat- ueductal grey (PAG)24, which receives nociceptive input ing the onset of pain, pain-related brain regions that are through spinoreticular pathways25. important for pain sensation, pain affect and pain modu- As would be expected, the multiple pain-related brain lation become activated, including the somatosensory pathways are important for different aspects of the pain cortices, ACC, insula, PFC and PAG47–53. experience. Pain involves sensations with qualities such Together, these findings indicate that brain regions as stinging, burning or aching and has identifiable loca- receive afferent pain input via multiple routes and that, tions and durations. However, what makes pain ‘pain’ at least in higher brain regions, there is no ‘labelled line’ is usually the affective component of the experience between the peripheral nociceptive input and the final — that is, how unpleasant it is. It is the unpleasantness cortical representation of that input. This idea is consist- that motivates the individual to engage in a behaviour, ent with evidence of multiple descending modulatory cir- whether it is to flee, fight or freeze. In some cases, a pain- cuits, which either enhance or reduce the afferent signal at ful sensation can be experienced as pleasurable, such as a multiple regions throughout the neuraxis, from the cortex deep massage, and in that case it creates a positive moti- down to the spinal cord. vational state. Brain imaging and lesion studies implicate different brain regions in these different aspects of the + pain experience. The somatosensory cortices (S1 and S2) Emotion Cognition encode information about sensory features, such as the – 26–30 location and duration of pain . Alternatively, the ACC + + and insula, which have long been considered compo- – – nents of the limbic (emotional) part of the brain31,32, are – – more important for encoding the emotional and moti- Pain vational aspects of pain. Patients with lesions of these regions show altered emotional responses to pain33–36, Figure 1 | Feedback loops between pain, emotions and cognition. Pain can have a negative effect on emotions and imaging and stimulation studies show a relation- Nature Reviews | Neuroscience and on cognitive function. Conversely, a negative ship between emotional and motivational aspects of emotional state can lead to increased pain, whereas a pain perception and neural activation in the ACC and positive state can reduce pain. Similarly, cognitive states 37–40 insula . Nevertheless, accumulating evidence impli- such as attention and memory can either increase or cates the insula in both pain sensation and pain affect, decrease pain. Of course, emotions and cognition can also with the anterior portion being particularly important reciprocally interact. The minus sign refers to a negative for the subjective experience of pain41,42. effect and the plus sign refers to a positive effect.

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One study found that emotional valence influenced pain ratings and a spinal nociceptive reflex in the same direction S1 but distraction reduced pain while increasing the reflex62. Thus, it appears that different systems may be involved in the modulation of pain by attention and emotions. Human brain imaging studies examining the effects ACC of distraction on pain processing find that when a person S2 focuses on pain, the pain-evoked activity in several corti- Insula cal areas, including the S1, insula and ACC, is stronger PFC than when a person is distracted from the pain4,63–70. Thalamus However, some of these studies used distracting stimuli BG that also alter arousal or emotional state64–68, so that the modulatory effects could be due to either attentional or AMY emotional factors. The studies that varied the direction of attention while controlling for emotional state found that pain-evoked activity was modulated by attentional direc- PAG Cerebellum tion only in the insula and S1 (REFS 4,63,69,70), which is PB consistent with the role of these regions in pain sensation. Neuroimaging studies evaluating the effects of emotional states on pain processing also find that negative emotional states produced by looking at emotional faces, listening to unpleasant music or smelling unpleasant odours alter pain-evoked cortical activation in a number of brain regions but most consistently in the ACC4,69,71–73. The modulation of activity in the ACC is in agreement with evidence that this region is particularly important Figure 2 | Afferent pain pathways include multiple brain regions. Afferent for pain unpleasantness. nociceptive information enters the brain from the spinal cord. Afferent spinal pathways Nature Reviews | Neuroscience include the spinothalamic, spinoparabrachio–amygdaloid and spinoreticulo–thalamic pathways. Nociceptive information from the thalamus is projected to the insula, anterior Different modulatory systems are involved in the atten- cingulate cortex (ACC), primary somatosensory cortex (S1) and secondary tional and emotional control of pain. The finding that somatosensory cortex (S2), whereas information from the amygdala (AMY) is projected attention and emotion have dissimilar effects on pain to the basal ganglia (BG). See the main text for references. PAG, periaqueductal grey; PB, perception and alter pain-evoked activation of different parabrachial nucleus; PFC, prefrontal cortex. cortical regions suggests that separate modulatory systems may underlie attentional and emotional influences on pain. The most commonly studied pain modulatory Attention and emotion influence pain differently pathways involve projections from the midbrain PAG to For centuries there have been anecdotal accounts of indi- brainstem nuclei, including the rostroventral medulla viduals apparently experiencing little or no pain in situa- (RVM) and the locus coeruleus, to the dorsal horn of the tions that by all accounts should be excruciating. Beecher54 spinal cord (for reviews, see REFS 74,75). These pathways described wounded soldiers who felt little pain from involve endogenous opioids, noradrenaline and seroto- grievous injuries in the battlefield but reacted strongly nin, and have both inhibitory and excitatory actions on to minor painful procedures when they returned home. spinal cord afferent projection neurons. Outputs from However, Western medicine has traditionally ignored forebrain regions, including the ACC, PFC and amyg- the role of the mind in pain control and has focused on dala reach the PAG, suggesting that these descending sys- pharmacological treatments of pain. Nevertheless, there tems could be activated by psychological factors. Opioids is now a growing emphasis on mind–body techniques for are particularly powerful analgesics, and their analgesic controlling pain, with many patients with chronic pain action works at multiple sites within these descending turning to cognitive behavioural therapy, yoga, medita- pathways, including the ACC, PAG, RVM and dorsal tion, hypnosis and relaxation procedures to reduce their horn of the spinal cord39,75. pain. These techniques are complex but most have both Several studies that involved distraction from pain a cognitive component, such as attentional focus, and but used distraction procedures that probably increased an emotional component. Growing evidence shows that arousal and/or negative emotions showed activation of these therapies can reduce both chronic and acute pain this fronto–PAG–brainstem circuit67,76–78. However, when (for reviews, see REFS 55–57). emotion and arousal were dissociated from attention4, Both attentional and emotional factors are known to it was the increased negative emotion that was associ- modulate pain perception in the clinic and in the labora- ated with activation of the ACC–fronto–PAG circuitry. tory3,58,59 (BOX 2). However, the nature and mechanisms Furthermore, this activation correlated with negative of this modulation differ60–62. Focusing on pain increases mood-related increases in pain-evoked activity in the the perceived intensity of the sensation, whereas a nega- ACC (FIG. 3). By contrast, when subjects intentionally tive emotional state increases the perceived unpleasant- directed their attention to or away from a painful stimu- ness of the pain without altering the intensity4,59–61 (FIG. 3). lus, attention-related alterations in pain-evoked activity

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Box 2 | Cognitive control of pain in rodents: environmental enrichment when an individual receives a placebo ‘analgesic’ and is expecting a reduction in pain, there is activation of a Does enhancing a rodent’s social life and presenting distracting stimuli alter pain in ACC–fronto–PAG pathway83,84. Interestingly, this involves the same way as has been found in humans? Evidence from studies of environmental similar brain regions as those that are activated when a enrichment indicates that the answer is ‘yes’. Environmental enrichment in rodents positive emotional state reduces pain. Moreover, placebo enhances the complexity of the living conditions of experimental animals: for example, rats or mice are housed in groups in larger cages with toys, tunnels, running treatment alters endogenous opioid activity in parts of 85 wheels, and so on. In healthy animals, environmental enrichment improves learning this pathway, including the PAG, ACC and PFC . Further and memory, enhances neuro- and gliogenesis in the cortex and hippocampus and evidence that this ACC–fronto–PAG pathway is involved induces dendritic and synaptic changes (see REF. 171 for a review). Enrichment can be in placebo analgesia comes from findings showing that classified as social (such as more animals per group), physical (such as access to naloxone (a μ‑opioid antagonist) modulates placebo- running wheels) or both. induced responses in the PAG and RVM and abolishes The beneficial effects of environmental enrichment have been investigated in rodent the coupling between rostral ACC and PAG activity83. pain models. In rats, environmental enrichment may increase the speed of healing after There is also behavioural evidence that naloxone reduces 172,173 an inflammatory injury and reduces the spinal astroglial response to peripheral expectation-related placebo analgesia in humans86 and inflammation174. In mice, enrichment reduces mechanical hypersensitivity after a nerve conditioned placebo-analgesia in rodents87,88. Thus, it injury175 but may actually increase chronic inflammatory responses176. The contradictions in response could partly be due to the stress of group housing in rats and appears that descending modulatory pathways involved mice — rodents establish complex social hierarchies, and dominance or defeat can be in placebo analgesia may overlap with those involved in inherently stressful. the emotional modulation of pain. Conversely, circuitry Recent work has focused on physical enrichment alone as a modulator of pain involved in the attentional modulation of pain, includ- behaviours. In one study, the authors used a shock-avoidance paradigm to force rats ing the superior parietal cortex and the insula, does not to run on a treadmill after nerve injury and saw reductions in thermal and tactile appear to be activated during expectation-related placebo hypersensitivity within 3 weeks after injury, which reversed when exercise was analgesia. This independence of placebo analgesia from stopped177. The effects of exercise were opioid-dependent — opioid antagonists the attentional modulation of pain was further confirmed reversed or prevented the beneficial effects of in a study showing additive reductions in pain caused by exercise, and increased levels of endogenous placebo and distraction89, indicating that placebo analge- opioids were seen in the rostroventral medulla and periaqueductal grey, which are both key areas in sia does not depend on the active redirection of attention. the descending modulation of pain. However, as The finding that emotional factors, anticipation and atten- the running was motivated by shock avoidance, tion alter pain processing is important in the therapeutic analgesia could be stress-related, and the shock context. A patient receiving pharmacotherapy may have could have been more stressful for nerve-injured an enhanced or diminished response depending on his animals. Thus, voluntary exercise paradigms are expectations, emotional state or focus of attention. needed to attribute the reductions in pain specifically to exercise. Unfortunately, as in Effects of chronic pain on pain modulation people, there is a wide variability in voluntary Patients with chronic pain often report that stimuli that running behaviour in rats178. In our laboratory, we should be innocuous are in fact painful for them. This found that some rats liked to use their running Nature Reviews | Neuroscience wheel for a quiet nap. can range from normal joint movement causing pain in patients with arthritis, to the touch of clothes against the skin causing burning pain in patients with nerve injuries. in the insula correlated with activity in the superior pari- In laboratory studies, patients with various chronic pain etal cortex (Brodmann area 7 (BA7)). This region is syndromes, including arthritis, back pain, fibromyalgia, part of Corbetta and Shulman’s proposed ‘top-down irritable bowel syndrome (IBS) and vulvar vestibulitis, orienting of attention’ system, which for visual attention show higher pain ratings and enhanced pain-evoked involves the frontal eye fields and the superior parietal neural responses when experimental pain stimuli are cortex79. Parts of BA7 project to the S1, S2 and insula80–82, presented than controls90–95. Even stimuli that are not providing a direct corticocortical pathway for the atten- painful in healthy people but are perceived to be painful tional modulation of pain, and descending pathways from by patients produce a pain-related activation pattern in the insula to the amygdala provide a possible descending the brain91,92,94. component to the attentional modulation of pain14 (FIG. 3). The increased activation of pain pathways may arise Fibromyalgia Note that in addition to a top-down attention system, from peripheral and/or central sensitization in ascending A disorder in which there is nociceptive pathways widespread pain in all four there is a bottom‑up, stimulus-driven attentional circuit , but there is evidence that some of the quadrants of the body for a that is specialized in the detection of salient or unexpected amplification may arise from abnormalities in descending minimum duration of stimuli79, involving the temporoparietal cortex and infe- modulatory systems75,96. Perceptual evidence for abnor- 3 months. Additionally, at least rior frontal cortex (which is largely lateralized to the right malities in descending pain modulation in patients with 11 of 18 specified points on the neck, shoulder, chest, hip, hemisphere). This circuit could be differentially engaged chronic pain comes from studies of conditioned pain knee and elbow regions show when pain is presented in different emotional contexts. modulation. In these paradigms, a painful test stimulus is tenderness to pressure. evaluated in the absence and presence of a second painful Anticipation of pain relief activates descending path- (conditioning) stimulus applied to a remote body region. Vulvar vestibulitis ways. Anticipation of the relief of pain is a primary con- In a normally functioning nociceptive system, the amount A disorder characterized by 2 sensitivity around the vaginal tributor to placebo analgesia . Brain imaging studies of of pain experienced at the primary testing site will be orifice, with pain provoked by expectation-related placebo analgesia find that immedi- reduced when the second noxious stimulus is presented contact or pressure. ately preceding the presentation of a noxious stimulus, (classically termed counter-irritation or ‘pain inhibits

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a b Attentional modulation

10 Attended pain S1 9 Distracted from pain SPL 8 ** 7 6 5 ACC 4 S2 Pain score Pain 3 Insula 2 PFC 1 Thalamus 0 Intensity Unpleasantness BG AMY Emotional modulation

PAG Cerebellum 10 Bad mood 9 Good mood 8 7 * PB 6 5 4 RVM Pain score Pain 3 2 1 0 Intensity Unpleasantness

Figure 3 | Attentional and emotional factors modulate pain perception via different pathways.Nature Reviews a | Manipulating | Neuroscience the attentional state primarily alters the perceived intensity of the pain sensation without significantly altering the perceived unpleasantness of the pain (top graph). By contrast, altering the mood state alters the perceived unpleasantness of the pain without altering the intensity of the sensation (bottom graph). b | Attention and emotion alter pain via different descending modulatory systems. Emotions (and placebo analgesia) activate circuitry involving the anterior cingulate cortex (ACC), prefrontal cortex (PFC) and periaqueductal grey (PAG) (shown in green), whereas attention activates circuitry involving projections from the superior parietal lobe (SPL) to the primary somatosensory cortex (S1) and insula (shown in blue). Grey regions show parts of the ascending pain pathways depicted in FIG. 2. AMY, amygdala; BG, basal ganglia; PB, parabrachial nucleus; RVM, rostroventral medulla; S2, secondary somatosensory cortex. * indicates p < 0.05, Ascending nociceptive and ** indicates p < 0.01. Data used in part a are from REF. 4. pathways Fibres travelling to the brain from receptors in body tissues that respond to pain’). Studies in anaesthetized rodents show a spino– PFC, the ACC and the insula. For example, there is less tissue-damaging or potentially tissue-damaging brainstem–spinal modulatory loop that reduces afferent grey matter in the brains of patients with chronic back stimuli (nociceptors). They nociceptive activation, which is termed diffuse noxious pain than in the brains of age-matched control subjects, make synapses with inhibitory control97. However, in conscious humans, especially in the dorsolateral PFC104–106. Grey matter loss second-order neurons in the supraspinal mechanisms also contribute to conditioned has also been reported in patients suffering from other dorsal horn of the spinal cord, pain modulation98. More than 30 studies have now chronic pain disorders, such as fibromyalgia, head- which send projections to the complex regional pain syndrome brainstem, thalamus or other examined conditioned pain modulation in patients with ache, IBS, (CRPS) and brain regions. From there, chronic pain, with varying paradigms and mixed results. osteoarthritis (for a review, see REF. 107). Although grey third- and fourth-order neurons Nevertheless, a recent meta-analysis concluded that con- matter reductions are found in multiple brain regions, send projections to the ditioned pain modulation is impaired in populations the most common regions to manifest such reduc- cerebral cortex. with chronic pain99. This impairment in a system that tions are the insula, ACC and PFC. In addition to grey Complex regional pain normally reduces pain could contribute to the enhanced matter changes, alterations in white matter are begin- syndrome pain perception observed in patients with chronic pain. ning to be revealed using diffusion-weighted imaging (CRPS). A chronic pain Functional brain imaging studies in patients with chronic techniques such as diffusion tensor imaging, in which condition that can affect any pain also support the idea that endogenous pain modu- fractional anisotropy — a measure of directionality of part of the body but most frequently affects an arm or a latory systems may be dysfunctional in these patients. water movement — is measured as a surrogate for white leg. After what is often a minor In response to experimental pain stimuli, patients with matter integrity. These studies suggest that various types injury, such as a sprained chronic pain disorders, including fibromyalgia, IBS and of chronic pain can lead to disruptions in white matter ankle, there is an intense back pain, show abnormal activation patterns in brain tracts108–114. Although conventional MRI cannot deter- burning pain that is much stronger than would be regions involved in pain regulation, including the rostral mine the histopathology underlying grey and white 100–103 expected for the type of injury. ACC and frontal cortex . matter changes, several lines of evidence suggest the The pain gets worse rather possibility that excessive nociceptive input may impair than better with time and is Structural changes in pain modulatory systems in chronic grey matter structure and function, including possible often accompanied by trophic pain. There is now a wealth of evidence suggesting that neuronal loss related to excitotoxicity115. Studies in rats changes, such as altered skin temperature and texture, faster patients with chronic pain may have anatomical altera- and mice suggest that a chronic pain state can cause a 116,117 growth of nails and hair and tions within regions involved in cognitive and emotional supraspinal neuroinflammatory response in addi- even loss of bone density. modulation of pain, such as the dorsolateral and medial tion to changes in dendritic and synaptic structure and

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decreases in opioid receptor binding in patients with ACC S1 neuropathic pain, rheumatoid arthritis and fibromy- ↓ FA SPL algia126–129. Decreases in the levels of dopamine in the ↓ Opioids forebrain of patients with fibromyalgia have also been Inﬂammation ↑ reported130. Opioidergic dysfunction was also seen in ACC the cortex and amygdala of mice with chronic inflam- S2 PFC mation or nerve injury, which was related to increases Insula 131,132 ↓ FA PFC in anxiety-like behaviours . Taken together, these ↓ NAA Thalamus studies suggest that changes in neurotransmitter sys- BG ↓ Opioids tems may mean that patients with chronic pain have ↑ Inﬂammation AMY decreased receptor availability or heightened endogenous release of these neurotransmitters. In either case PAG Cerebellum it seems that neurochemicals that are important for placebo analgesia are not acting in the same way as they do IC PB in healthy people. ↓ FA Together, the evidence of altered neuroanatomical and ↓ NAA neurochemical functioning in brain regions involved in ↓ Opioids RVM the cognitive modulation of pain leads to the prediction that patients with chronic pain should have reduced or altered cognitive modulation of pain compared with healthy individuals (FIG. 4). Figure 4 | Consistently identified changes in the brains of patients with chronic Nature Reviews | Neuroscience pain. The three cortical regions that consistently show decreases in grey matter are Is there evidence that disruption of endogenous pain the anterior cingulate cortex (ACC), prefrontal cortex (PFC) and insula. Studies have modulatory systems alters cognitive and emotional also identified changes in white matter integrity in these regions; such changes are modulation of pain in patients with chronic pain? There manifested by decreased fractional anisotropy (FA), which suggests that there is a is now accumulating evidence that the impairments decrease in white matter health. Molecular imaging studies show decreases in opioid observed in patients with chronic pain go beyond the receptor binding in patients with chronic pain in all three regions. Studies using in vivo pain itself. These patients also show changes across cog- proton magnetic resonance spectrometry show chronic pain-related decreases of the nitive and emotional domains, and similar changes are neuronal marker N‑acetyl aspartate (NAA) in the frontal cortex and the insula. Finally, 133 (BOX 3) rodent studies show increased neuroinflammation in the ACC and PFC. Black arrows found in preclinical models of chronic pain . show the descending pathways from FIG. 3. Grey arrows show afferent pain pathways. For example, patients with fibromyalgia are less able to retain new information when rehearsal is prevented by a distraction than healthy controls134–136. Patients with back pain, fibromyalgia or CRPS have all been function in regions involved in pain processing118,119. shown to have deficits in emotional decision-making Together with the anatomical data, this suggests that when they were tested with the Iowa gambling task137–139. patients with chronic pain may undergo degenerative Preclinical studies confirm deficits in emotional deci- processes or at least functional alterations within brain sion-making tasks in rodent chronic pain models140. areas involved in cognitively modulated analgesia. Deficits in these tasks are also observed in patients with disorders such as traumatic brain injury and multiple The neurochemical basis of cognitive and emotional sclerosis who have lesions in brain regions implicated modulation of pain. Studies are now beginning to in descending pain modulation, including the medial show that patients with chronic pain may have altered PFC and rostral ACC141–145. Furthermore, the brain neurochemistry in brain systems that are involved in regions that are altered in patients with chronic pain psychologically modulated analgesia. Findings from are among those that are activated during the tasks in studies using in vivo proton magnetic resonance spec- which patients perform poorly146,147. Thus, the anatomi- trometry show increases in glutamate and/or decreases cal changes observed in patients with chronic pain may of the neuronal marker N‑acetyl aspartate in frontal well be an underlying factor in their altered performance Iowa gambling task cortices of patients with chronic back pain and fibromy- in cognitive tasks. A psychological task used to 120–124 investigate emotional algia ; such findings support the idea that reduced If the chronic pain-related anatomical alterations in decision-making. It involves grey matter in patients with chronic pain may be related brain regions involved in cognition, emotions and pain playing with four card decks in to possible excitotoxicity. One study using transcranial modulation truly have a functional consequence, then one order to win money. Playing magnetic stimulation found lower intracortical facilita- would predict that patients with chronic pain should have with two of the decks leads to more wins than losses, whereas tion and shorter intracortical inhibition in patients with altered psychological modulation of pain, including pos- 125 playing with the other decks fibromyalgia than in controls , suggesting that there sible alterations in placebo responsiveness. Alternatively, leads to more losses than wins. are deficits in intracortical modulation involving both the patients could have normal psychological modulation Healthy people quickly GABAergic and glutamatergic mechanisms. Other stud- of pain, but they may be using different brain circuitry gravitate to the ‘good’ decks. ies showed changes in opioidergic and dopaminergic to achieve the modulation. Few studies have tested this Patients with various types of frontal lobe lesions do not systems in patients with chronic pain and rodent mod- concept, but there is some evidence pointing to both learn to preferentially use the els of chronic pain. Several molecular imaging studies decreased psychological modulation of pain and the ‘good’ decks. using positron emission tomography showed cerebral involvement of novel pathways in such modulation. For

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Box 3 | Possible mechanisms for human pain-related brain changes that grey matter decreases related to chronic pain are not necessarily caused by neuronal death, but instead by other Rodents may not be able to tell us how they are feeling, but they do behave in ways that changes in neuronal tissue, such as reduced dendritic or can inform us of their mental states, with the added advantage of giving us insight into synaptic density and possible changes in non-neuronal the neurobiological changes that are induced by pain in a way that is just not possible in tissue119,157,158. Nevertheless, the anatomical normalization humans. Similar to findings in humans, behavioural studies in rats have confirmed that of brain regions involved in the psychological modula- acute pain interrupts attention179 and that distracting attention from that pain can tion of pain corresponds with chronic pain reductions reduce pain behaviours180. These interruptions in cognition can be traced to the after surgical or pharmacological treatment. circuitry involved — for example, arthritis pain in rats impaired decision-making in a ‘rat If cognitive and emotional factors can intrinsically gambling task’ owing to feedforward inhibition of the medial prefrontal cortex from the activate modulatory circuitry in brain regions showing basolateral amygdala181. anatomical changes due to chronic pain, can psycho- Cognitive deficits can also be seen in animal models of chronic pain. Inducing an logical treatments reverse brain changes associated with inflammatory or neuropathic state in a rat can cause problems with attention168, chronic pain? Although there is little research available 182 183 decision-making and learning and memory . Importantly, the neural bases of these to date, some evidence suggests that answer may be can be investigated. Grey matter decreases can be shown via MRI167, and the cellular ‘yes’. Cognitive behavioural therapy has been shown to and molecular changes can be documented. For example, neuropathy has been shown to increase basal dendritic branching and spine density in medial prefrontal cortical increase pain-evoked neural activation in the dorsolat- areas, and the degree of hypersensitivity is related to the NMDA/AMPA ratio119. Other eral and ventrolateral PFC: that is, in regions involved 159 studies have shown increased neuroinflammation in frontal cortices after injury116,117 as in pain modulation . Meditation, alternatively, reduces well as shifts in opioidergic function131,132. Together, these studies suggest potential pain-evoked PFC activity160,161 but increases activity in mechanisms to explain the changes in brain function seen in patients with chronic pain the rostral ACC and the anterior insula: that is, in areas and the alterations seen in pain-related brain regions. involved in the cognitive regulation of nociceptive pro- cessing162. Although there is no direct evidence that activation of the pain regulatory circuitry has long-term example, in response to relaxation, patients with IBS dem- functional consequences, there are a few studies showing onstrate reduced modulation of rectal distension-induced that people who meditate have thicker cortices in fron- pain and reduced activation of the insula148. Conversely, tal regions, including the PFC, ACC and insula8,163–165. these patients demonstrate more pronounced stress- Studies have not yet addressed the impact of such mind– induced modulation of neural activation in multiple brain body therapies on the brains of patients with chronic sites involved in pain modulation, including the insula pain, but current evidence suggests that they may have and ventrolateral PFC148. Whereas some studies find a neuroprotective effect. similar attentional149 and affective150 modulation of pain between patients with fibromyalgia and healthy controls, Conclusions, implications and limitations other studies have observed deficits in attentional pain There are huge inter-individual as well as intra-indi- modulation in patients with chronic pain151 and abnor- vidual differences in pain perception depending on the mal affective modulation of somatosensory brain process- context and meaning of the pain. Evidence presented ing in patients with fibromyalgia152. In terms of placebo in this Review shows that much of this variation can be analgesia, a study conducted in patients with IBS (a type explained by the interplay between afferent nociceptive of chronic visceral pain) found a placebo-related percep- signals to the brain and descending modulatory sys- tual pain reduction but observed, contrary to findings tems that are activated endogenously by cognitive and in healthy subjects, that the opioid receptor antagonist emotional factors. The descending modulatory systems naloxone did not reduce the placebo response, suggesting involve brain regions that are important not only for that any placebo response shown in patients with IBS was pain but also for cognitive and emotional functioning not opioid-mediated153. Although accumulating evidence in general166. Thus, alterations in the anatomical integ- suggests that patients with chronic pain may have altered rity and functioning of brain regions involved in both psychological modulation of pain and altered modulatory pain control and cognitive and/or emotional function- systems in the brain, more direct comparisons between ing could explain why patients with long-term chronic patients with chronic pain and healthy subjects need to be pain develop cognitive deficits as well as anxiety disor- made to fully understand how these modulatory systems ders and depression. Whereas the temporal relationship may be affected by the continued presence of pain. between pain, cognitive deficits, anxiety and depression is difficult to determine in most patients with pain, lon- Can altered pain modulatory circuitry be reversed in gitudinal animal studies now suggest that emotional and patients with chronic pain? Several studies reveal that cognitive alterations may sometimes begin long after when a painful condition, such as hip osteoarthritis, the onset of pain. For example, in a rodent model of headache or back pain, is eliminated after an individual neuropathic pain, rats exhibited anxiety-like behaviour has suffered chronic pain for years, grey matter reduc- and attentional deficits months after the injury and the tions can be reversed. In these studies, brain regions onset of hypersensitivity, which was temporally coinci- implicated in pain modulation, including the dorsolat- dent with anatomical changes in the frontal cortex167,168. eral PFC and ACC, had reduced grey matter in patients, Thus, there is growing evidence that pain may be det- but after successful treatment for the pain, the grey mat- rimental to the brain and that long-term pain itself can ter reductions were reversed so that the affected brain both decrease an individual’s ability to endogenously regions normalized in size104,154–156. These findings suggest control the pain and lead to many of the comorbidities

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that plague individuals with chronic pain. The old adage most of the brain imaging studies are cross-sectional, ‘no pain, no gain’ should probably be discarded in favour so causal relationships are difficult to ascertain. Thus, of ‘no pain, healthy brain’. longitudinal studies involving larger groups, as well as Nevertheless, caution is required when interpreting more preclinical studies back-translating clinical obser- the results of the studies cited in this Review, as many vations, will be important to fully confirm the hypothesis of them involve small sample sizes and do not always that chronic pain can alter pain modulatory systems in include comprehensive control measures. Furthermore, the brain.

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