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Chronic pain-related remodeling of cerebral cortex – ‘pain memory’: a possible target for treatment of chronic pain
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Avigail Lithwick1,2, Shaya Lev1,2 & Alexander M Binshtok*1,2 Pain related neuronal networks in the cerebral cortex undergo plastic changes following nerve injury. Pattern of activation of pain related neuronal networks is different in acute and chronic pain states. Synaptic connections of individual cortical neurons are remodeled shortly after nerve injury or
inflammation leading to increased network excitability. Timing of treatment is essential to prevent perpetuation of these changes. Understanding of pain-mediated plastic changes in the cerebral cortex is essential for the development
of effective and selective therapies for chronic pain.
SUMMARY Chronic pain is a major health problem worldwide, yet its management is nonspecific and often insufficient. In order to be able to alleviate chronic pain, it is crucial to understand the profound and comprehensive mechanisms by which chronic pain is triggered and processed in higher brain areas. Painful stimuli are processed by an intricate axis of peripheral and central components. Adding to the inherent complexity, the system is highly dynamic, undergoing constant plastic changes that often lead to perpetuation of pain. Given the key role that the cerebral cortex plays in sensory perception, understanding pain-related changes in cortical areas allocated to pain sensation is crucial. This review aims to summarize present research on pain-related plastic changes in the cerebral cortex. Chronic pain is a condition of the nervous system that includes a number of syndromes and ailments, such as fibromyalgia, migraines, irritative bowl syndrome and low back pain. Chronic pain is a widespread disease with a prevalence of 19% in Europe and 30.7% in the USA [1,2] . The prevalence of severe chronic pain is immense: over a third of individuals with chronic pain defined their pain as severe and 40% of those suffering from chronic pain in general were not satisfied with their care [1] . In order to allow for adequate chronic pain treatment, a complete and comprehensive
understanding of pain processing and perception is essential. The etiology of chronic pain is complex and confusing. Injury to the nervous system could potentially lead to chronic, in this case, neuropathic pain. Which component of nerve injury triggers chronicity of pain? Most likely the abnormal activity of injured nerve combined with an ‘unfortunate’ combination of a plethora of immune, genetic and environmental factors ignite the process [3] . In some states of chronic pain, when pain appears without obvious nerve injury, such us fibromyalgia and migraine, peripheral pain
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University Faculty of Medicine, Jerusalem, Israel *Author for correspondence: [email protected] 1
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REVIEW Lithwick, Lev & Binshtok fibers also exhibit abnormal patterns of activity [4,5] . Therefore, it appears that, regardless of the initial etiology, chronic pain can be regarded as a standalone disease of the nervous system, initiated by altered activity of peripheral fibers which entails abnormal structural and functional plastic changes taking place along the neuroaxis, all the way from peripheral nociceptive terminals to convoluted networks of cortical areas [6] . As a result of the neuronal and network plasticity, perception of pain transforms from a normal response to that causing hyperalgesia (increased pain perception [101]), allodynia (pain in response to a stimulus that does not normally provoke pain [101]), and spontaneous pain (when no stimulus is present [6]). The structural and functional changes that occur can be regarded as ‘pain memory’ in the sense that they create an ‘imprint’, similar to experience-dependent learning, which forms the mechanistic basis for abnormal activity underlying chronic pain. It is the goal of this review to focus on these plastic changes, which occur at the level of the cerebral cortex. Regarding plastic changes that occur at the periphery and spinothalamic levels, there are several excellent reviews summarizing our current knowledge [7–11] . While cortical areas are involved in both acute and chronic pain conditions, their activation pattern and plasticity profiles are not identical. The six most common regions activated in acute pain are often referred to as the pain matrix [12] . These regions include five cortical areas: the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), anterior cingulate cortex (ACC), insular cortex (IC) and the prefrontal cortex (PFC). The sixth region of the pain matrix is the thalamus, which is not associated with the processing of pain, but rather relays sensory information to cortical and subcortical structures (Figure 1) [13] . In general, the pain matrix processes sensory information in the following manner: pain discrimination (the lateral pain system), subjective evaluation (the medial pain system) and cognitive assessment [14] . The lateral pain system is comprised of S1, involved in stimulus location [15] , and S2 which is related to the discrimination of pain intensity [16] . The medial pain system consists of the IC, the ACC and the PFC [14] . The IC lies between emotion and sensory discrimination regions: it receives input from the lateral system, but projects to regions associated with emotional processing (i.e., the limbic region), implying an
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integrative function in pain [15] . The ACC is associated with subjective pain assessment, or the ‘suffering’ aspect of pain [16] and the perceived pain intensity, or the cognitive–evaluative aspect of pain processing [12] . The ACC is also involved in endogenous, opiate-mediated mechanisms of pain regulation [17,18] . Cognitive assessment of pain is attributed to the PFC. Activation of the PFC is related to pain as well as to attention, working memory and goal-oriented tasks [19] . From the information discussed above, it is suggested that the activity within the painmatrix reflects the cortical analysis of various parameters of noxious stimuli. However, several lines of evidence suggest that pain matrix activity is not well correlated with the intensity of painful stimuli [20] (see also [21]). Moreover, the response pattern of the pain matrix in general, and of the anterior insula and mid-cingulate cortex in particular, depends on stimulus context whereby the same stimulus could be perceived as painful or not, depending on whether the stimulus was anticipated as harmful or harmless [22] . This implies that the pain matrix is involved not just in the detection of harmful noxious stimuli but in the perception of any prominent (salient) sensory event that could provide a potential threat to the integrity of the organism in situ. There are regions outside of the pain matrix that are also associated with the processing of pain, including the amygdala and the primary and supplementary motor cortices. What does the activity of the pain matrix represent? The common view is that, rather than a particular area attributed to pain, the aforementioned areas form a network that results in the physical and emotional perception of pain. The central question discussed in this review is whether activation of these areas also occurs in chronic pain conditions, and to which extent or in what patterning. Specifically, are the same areas activated? Are they activated in the same way? Is the pattern connectivity the same? Is there a causal relationship between pain triggering at the periphery and the activity seen in the pain matrix? In addition, while in acute pain it is typically the contralateral hemisphere that responds (within the pain matrix), can we expect the same response to a chronic pain state, or will a more extensive, and perhaps bilateral, activation pattern emerge? Several studies have shown that the nature of pain activation processes vary with different pain sources and longevity of the pain sensation
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S1
ACC PFC Thalamus Insula
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t ac l tr
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Figure 1. Connections within the pain network, delineating lateral (black) and medial (gray) pain systems, excluding areas not associated with the pain matrix. ACC: Anterior cingulate cortex; PFC: Prefrontal cortex; S1: Primary somatosensory cortex; S2: Secondary somatosensory cortex.
measured, leading to the conclusion that chronic pain is not a mere manifestation and elongation in the time span of acute pain, but rather constitutes a different mechanism that also involves the pain matrix but in a different manner than in acute pain, as discussed below. Analyzing the activity, plasticity and connectivity of each domain within the pain matrix in chronic states compared with acute pain is crucial to answer the above questions and expand on our understanding of these states. S1 S1 is an essential processing center of the lateral pain pathway, primarily responsible for sensory discrimination; it answers the question of “where does it hurt?” [15] . Exploring the nature of its
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plasticity is highly valuable when considering its potential role in chronic pain conditions. In general, the majority of the studies have demonstrated alterations in location activation patterns when compared with acute-pain triggering of this domain. One study, however, failed to find a difference in activation of S1 between acute and chronic states, though it demonstrated an augmentation of pain sensitivity in terms of pain felt and cortical activation [23] . In the other studies, where a painful response was elicited, a more widespread contralateral activation pattern was found in individuals with chronic pain, compared with healthy individuals with elicited acute pain [24] or the unaffected contralateral side of the same individuals [19] . This was true both in cases
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REVIEW Lithwick, Lev & Binshtok of hyperalgesia [19,24] and allodynia [25–27] as painful end points. In addition, a number of studies found an ipsilateral activation pattern in individuals with chronic pain as opposed to controls elicited with acute pain [26–28] . Spontaneous pain elicits activation patterns different from those of acute pain [29–33] . In particular, the associated limb exhibited a decrease in size of activation pattern in S1. In chronic neuropathic pain, following spinal cord injury [30] or in cases of phantom limb pain [31] , a decreased activation pattern upon imagined movement was found, while the adjacent representation expanded in activation. Whether the pain causes this modulation or whether the modulation is a trigger for chronic pain is obscure. In summary, studies examining activation of S1 in chronic pain conditions indicate reorganization on two levels. Firstly, upon eliciting pain, individuals with chronic pain present a more widespread activation pattern in S1 as compared with the unaffected side or with healthy controls inflicted with acute pain. However, individuals with chronic pain also present a smaller cortical representation of the affected area in S1, implying a dissociation between activation of primary sensory areas and the actual origin of chronic pain. Anterior cingulate cortex The ACC is a key cortical area involved in chronic pain-related plasticity [34] . The activation of the ACC is associated with both the emotional [16] and the cognitive–evaluative [12] aspects of pain processing. It has been demonstrated that following peripheral nerve injury, in an animal model for neuropathic pain, ACC neurons express elevated levels of PKM-z. PKM-z, the protein kinase required for a long-term potentiation type of synaptic plasticity, maintaining persistent synaptic changes, therefore plays a critical role in memory consolidation [35] . Moreover, inhibition of PKM-z abolished synaptic facilitation and blocked neuropathic pain hypersensitivity [35] . This implies that PKM-z plays a crucial role in stabilizing the augmentation of pain in chronic pain states. Furthermore, it indicates that the ACC has an important role in facilitating chronic pain. In a human placebo study, a decrease in ACC activation, along with the anterior insula, correlated with a decrease in pain [36] . The rostral ACC, however, was found to be associated
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with treatment expectation [37] , implicating an emotional aspect. As a result, one can expect plasticity in the ACC to be correlated with sensory discrimination, determining the location of pain, as well as affective perception, or the suffering aspect of pain. In addition, rostral ACC is also involved in endogenous opioidergic modulation of acute and chronic pain [18] . Patients with fibromyalgia, for example, exhibited significantly lower connectivity between rostral ACC and the amygdala [17] . The amygdala, which projects directly into the periaqueductal gray matter area, is directly involved in opioid-dependent analgesia [38] . Thus, reduction of the efficiency of opioidinduced analgesia may underlie increased pain sensitivity of fibromyalgia patients. A number of studies demonstrated an activation pattern that correlated ACC with the somatosensory areas, implicating the ACC to be related to sensory perception [19,24,27,33,39,40] . The majority of these studies showed activation differences between chronic pain patients and controls (those with acute pain), apart from one [24] , which demonstrated a similar activation pattern when both patients and controls experienced a similar rating of pain. In addition, a bilateral ACC activation pattern was displayed, which was more widespread than in healthy controls [19,26,27,33,40] . In a study examining allodynia under various stimuli types, the ACC was activated in response to a cold stimulus, similar to the insula [28] . However, contrary to other studies, the ACC was activated only in outcomes producing pain, dissociating it from sensation alone and implicating its importance in pain. In chronic back pain, it was found that the ACC and the insula demonstrated a significantly altered correlation to the medial PFC(chronic back pain) [41] , which represents the affective (i.e., emotional) aspect of chronic pain [32] . A number of studies found differences in ACC activation in response to various treatments [33,39,40] . One study indicated a significant reduction in ACC activation which occurred during the short-term phase of a lidocaine patch treatment [39] , in addition to sensory areas, thus implicating the ACC to be closely associated with the sensorydiscriminating regions. However, other studies found ACC activation reduction to correspond to a decrease in pain: one in the case of a nonsteroidal anti-inflammatory agent in patients with osteoarthritis [41] and the other employing a
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‘Pain memory’: a possible target for treatment of chronic pain mental imagery technique therapy program for individuals with chronic pain [33] . In conclusion, while it appears that the ACC plays a role in both the sensory–discriminative and affective pathways of pain evaluation in chronic pain states, as in acute pain conditions the actual activation is more widespread, and in some instances bilateral. This indicates that both a stronger emotional and sensory component is involved in cases of chronic pain. S2 S2 is generally associated with the discrimination of pain intensity, or how much pain is felt. However, the amount of research in this area in the context of chronic pain and its effect on plasticity is relatively small. However, most studies found similar trends which displayed an increase in the activation of S1 and S2 compared with acute pain, indicating a coactivation pattern. Moreover, these studies presented a bilateral activation pattern in S2 in response to chronic pain [19,24,26,28,33,39,40] . A portion of these studies found that in healthy controls, only the contralateral S2 area was activated in response to acute pain [33,40] , or was less widespread than in individuals with chronic pain [19,26] . Other studies exhibited deviations from the bilateral activation of S2. Several showed activation in the contralateral limb [23,29] , the ipsilateral limb [27] and in the right hemisphere in the condition of chronic back pain [32] . A few studies showed a different activation pattern than the coactivation of S2 and S1. One study found bilateral S2 activation in cold and tactile pain-evoking conditions (allodynia and pain in healthy controls), while S1 was activated in tactile conditions alone [28] . Another study had determined a significantly altered correlation in connectivity between S2 and chronic back pain [41] . However, the majority of the studies emphasize the activation of S2 in instances whereby S1 is activated, supporting its role in sensory discrimination and indicating network connectivity between the two regions. The bilateral activation pattern, compared with a contralateral activation pattern alone as seen in acute pain, may play a role in the misrepresentation of pain in a chronic pain setting and indicate the widespread connectivity, which might be a hallmark in chronic pain conditions. The S2 activation on the ipsilateral side decreased with short-term treatment [39] . This decrease in activation did not persist, implying
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that therapy affects the lateral pathway in a transient manner. However, in a different study, examining cortical reorganization in response to phantom pain treatment, S1 exhibited cortical reorganization while S2 did not [33] . Overall, it appears that S2 is activated in instances where S1 is activated, indicating a causal connectivity pattern between the two and a temporal coactivation process. The bilateral nature of S2 activation in chronic pain indicates a change in individuals with chronic pain. Taking these two into account, S2 activity is affected in individuals with chronic pain, and is of a sensory–discrimination nature, as was found in the case of acute pain indicating that its “classical” role has not changed. However its activation seems to be more widespread with less of a representation of the initial pain and with bilateral connectivity, emphasizing the change in network patterning and dissociation from peripheral pain triggering. Insular cortex The IC is often considered to be related to both sensory (where and how much it hurts) and affective perception of pain (the suffering aspect of pain) [15] . It has been suggested that the anterior insula is responsible for subjective evaluation and is often coactivated with the ACC [42,43] . Moreover, the right anterior insula is crucial for the emotional response to visceral pain as part of its involvement in interoceptive processing – a mental or emotional knowledge of physical state [42–45] . The posterior insula was found to be related to sensory perception and discrimination [42,46] . Thus, it can be expected that the insular cortex, similar to the ACC, may contribute information regarding pain in two ways: both sensory (where and to what degree), as associated with S1 and S2, and affective (the coping aspect of pain-suffering), as attributed to the PFC. It was found, however, that although a division exists, it is far from symmetric in strength. The majority of studies demonstrated an activation pattern similar to that of S2 [19,24,26,27,32,39,41] . Specifically, some studies found a more widespread activation pattern, as compared with controls (an acute pain condition) [40] or the unaffected side [19,26] , while others demonstrated insular activation in both chronic pain patients and healthy controls [23,24] given equal painful responses in both groups. Additionally, a number of studies found insular activation to be
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REVIEW Lithwick, Lev & Binshtok bilateral [19,33,39] . A study on chronic back pain found reorganized connectivity between the mPFC and the IC [41] . However, a small number of studies did not find activation of IC to be strictly associated with somatosensory areas impinged by painful stimuli [28,33] . In a study that examined allodynia based on stimulation type [28] , painful cold stimulation and cold-evoked allodynia resulted in mid-posterior insular activation in healthy controls and chronic pain patients, respectively, while nonpainful cold stimulation in healthy volunteers resulted in anterior insular activation. In a study examining phantom limb pain, activation in response to imagined movement of the phantom hand and actual movement of the real hand was found in insular and somatosensory areas [33] . In addition, S1 and bilateral insular activation in response to pursing of the lip occurred only in individuals with phantom pain [33] . Finally, in a study that examined the effect of a lidocaine patch in postherpetic neuralgia [39] , the contralateral anterior insula was the only region that displayed an increase in activity. This effect was found for short-term treatment alone. Although it was expected that the IC area would exhibit a mixed activation pattern, we conclude that it is generally activated in instances in which the somatosensory areas are activated as well. In chronic pain, the IC appears more closely linked to sensory discrimination rather than emotional processing. This may be a hint to the functional changes occurring in the IC in response to chronic pain: its role in ‘suffering’ is minimized so as to accommodate the vast increase in activation that is seen in S1 and S2 and might indicate a connectivity pattern linking S1 and S2 with IC, all functioning to generate sensory information. Prefrontal cortex The PFC is a region associated with the cognitive evaluation of pain, which involves, among others, how one copes with pain: in terms of depression, difficulty in decision making, or others. Overall, the studies can be examined according to subregions: medial PFC, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. The chronic back pain represents the affective aspect of chronic pain; the ‘suffering’ of pain, as mentioned above [32] . The chronic back pain was correlated with spontaneous pain [40] , implying spontaneous pain is affective by nature,
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particularly in the sustained high intensity phase [32] , and showed an increase in activation, compared with healthy controls [41] . Blood levels of NSAIDs are well correlated with the changes in cortical activation in patients with chronic back pain [41] . In individuals with chronic back pain, the chronic back pain was in a significant hyperactive state, correlating to the duration of this condition [47] . An altered resting state may influence brain activity overall, affecting its ability to perform other tasks; perhaps explaining the effect of changes in cognition and behavior. Chronic back pain was shown to be negatively correlated to the DLPFC, which is activated before chronic back pain, and deactivated when chronic back pain has been activated [32] . The DLPFC is involved in localizing and encoding pain-producing stimuli [16] . This may explain why the DLPFC was activated in healthy and chronic back pain patients alike, in response to a painful thermal stimulus [32] , and in response to a cold-stimulus evoking pain and brush evoked allodynia on the ipsilateral side [28] . Finally, the third sub-PFC region is the orbitofrontal cortex, which serves as a link between areas associated with emotional assessment [48] , coordinating memory and emotion. If disrupted, an imbalance in emotional response may arise, implying the orbitofrontal cortex to be a good target for treatment of chronic pain. One study, which found the orbitofrontal region (and the chronic back pain) to be associated with spontaneous pain, did not demonstrate a change upon treatment using a nonsteroidal antiinflammatory agent [40] . However, another study demonstrated orbitofrontal region activation in spontaneous pain, which ceased with treatment [39] . In this study the authors concluded that this region, along with limbic center regions responded to long-term treatment, while the sensory discrimination pathway responds to short-term treatment. Thus, it appears that the change in the PFC in response to chronic pain represents a shift in the emotional processing. The increase in activation may originate from the increase in activation in the sensory-related areas (S1, S2); however, it appears that over time it evolves into a more independent activation site. It is possible that the suffering and decrease in decision making, as seen above, perpetuate chronic pain, as the suffering from pain is the primary symptom associated with chronic pain disorders. Though the PFC represents a central component in the
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‘Pain memory’: a possible target for treatment of chronic pain acute pain matrix, it appears that its involvement in chronic pain is more significant, more widespread and could be hyperactive due to connectivity with areas such as S1 and S2. Are the above mentioned chronic painmediated changes in cortical functions a result of neuronal plasticity? It has been demonstrated that chronic pain is accompanied by large scale morphological changes in the cerebral cortex, namely cortical thickness [49] . A paper by Baliki et al. demonstrated ‘signature’ changes for different chronic pain conditions [50] . Thus, in patients with chronic low back pain, the changes in gray matter volume spread to the whole brain but primarily affect bilateral posterior insula, secondary somatosensory cortices and temporal lobes. Patients with osteoarthritis demonstrated changes in the density of gray matter localized to parts of the insula, mid ACC and inferior temporal cortex. The signature for complex regional pain syndrome was decreased gray matter density in the anterior insula and orbitofrontal cortex [50] . These changes are well correlated with the duration and intensity of pain [51] and therefore could be used as potential biomarkers for the evaluation and prognosis of chronic pain states. Interestingly, the changes in gray matter content were not observed in patients suffering from rheumatoid arthritis [52] . In this case, the majority of changes were observed in the nucleus accumbens and caudate nucleus [52] , outlining the important role of subcortical areas in chronic pain and specificity in cortical areas devoted to perception of pain. These changes in cortical architecture are correlated to specific functional changes in response to painful stimuli in chronic pain [51] , implying that chronic pain causes plastic changes in the cerebral cortex. In the well-controlled (in terms of location, intensity and type of pain) group of patients with neuropathic trigeminal pain, the areas activated by an allodynia-evoked stimulus were the same areas that exhibited changes in cortical thickness [51] . To show that these large scale changes have a causal relationship with synaptic plasticity [53] , precise temporal and spatial resolution is required. Therefore, multiphoton imaging at the level of single dendritic spines was performed on animals following inflammation [54] or in nerve injury animal models [55,56] which constitute models for chronic pain conditions. These studies demonstrated, that 3 days after ligation of peripheral nerve, when mechanical allodynia starts to develop, there were noticeable changes in the morphology and motility of S1 pyramidal cell
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spines [55,56] . This synaptic rearrangement ceased 6 days after injury when mechanical allodynia persisted – the so called maintenance phase. Since dendritic spines are the location for excitatory synaptic contacts, these changes reflect experiencedependent synaptic plasticity [57–59] – a learning underlying the development of symptoms. The stabilization of the process during the maintenance phase of neuropathic pain resembles the formation of new stable ‘memories’ of pain. Of particular importance was the effect that the immediate sciatic nerve blockade had in terms of cortical plastic changes, exemplified by spine turnover that was prevented. Interestingly, this immediate intervention also prevented development of allodynia. However, the instigation of the nerve blockade at a later phase presented transient recovery. These results denote the importance of the timing of treatment in order to prevent the occurrence of allodynia and thus perhaps chronic pain and help to substantiate a casual relationship between chronic pain and plastic changes. A follow-up study demonstrated that structural changes in S1 circuitry underlie enhancement of responsiveness of neurons to peripheral stimulation as well as an increase in their spontaneous activity [54] . In summary, both animal [54] and human [60,61] studies show that the nerve injury-dependent hyperactivation leads to functional and structural changes in specific areas of the cerebral cortex. This reorganization of local cortical circuits – a pain-related memory – provides a mechanistic as well as molecular basis for abnormal activity underlying chronic pain. In addition, animal and human studies demonstrated that in chronic pain conditions, these connectivity changes within specific cortical areas also project into other areas of the pain matrix, primarily the PFC, ACC and insula. Importantly, following inflammation of the hind paw, application of synaptic blockers directly into the ACC abolished mechanical allodynia [54] , emphasizing the role of inhibition of activity in the ACC as a possible target for treatment of chronic pain. Interestingly, increased functional connectivity between left anterior insular cortex and pregenual ACC was observed in patients suffering from temporamandibular disorder [61] . Since pregenual ACC is involved in antinociception, these changes in connectivity may reflect an adaptive mechanism during the establishment of chronic pain. Several lines of evidence emphasize the role of changes in
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REVIEW Lithwick, Lev & Binshtok functional connectivity between cortical and subcortical areas. In complex regional pain syndrome patients, altered connectivity between PFC and nucleus accumbens was observed [60] ; this proves important as this connectivity plays a crucial role in pain chronicity, and hence can be used to predict the likelihood of development of chronic pain [62] . The chronic pain mediated changes in cortical connectivity may also involve areas not dedicated to pain processing. A series of studies demonstrated that cognitive and behavioral impairments in chronic pain patients could have originated from abnormal functional connectivity of the “default mode network” a cortical circuit consisting of the inferior parietal lobule, the posterior cingulate cortex and precuneus, areas of the medial frontal gyrus, the hippocampal formation and lateral temporal cortex. The connectivity of this network, normally active in resting states, is enhanced in fibromyalgia patients [63] and the deactivation of some of the areas within the default mode network was suppressed in low back pain patients [64] . These data suggest that chronic pain is strongly associated with both modulation of activation of pain related cortical areas and changes in connectivity patterns of pain related and nonpain related networks. Treatment Of the studies presented in this paper, a small number included treatment [33,39,40,65] . Of these, two included pharmacological interventions: the first examined the influence of a nonsteroidal anti-inflammatory agent on individuals with osteoarthritis [40] , and the second investigated the influences of a lidocaine patch on postherpetic neuralgia [39] . Both lead to pain reduction at the site of pain instigation. Additionally, the two studies found a decrease in both pain and activation of affective cortical areas over time. Another approach in targeting pain is the use of a more widespread medication which targets more central areas. A plethora of such medications is currently in use [66] , such as tricyclic antidepressants and anticonvulsants. There were several studies which included treatment towards individuals with phantom pain [33,65] . A sensory discrimination training [65] , and a mental imagery technique [33] were employed in these studies. Both found a reduction in pain and a remodeling of S1, indicating an important role for a nonpharmacological approach in pain intervention.
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The defined location of chronic pain-mediated abnormal activation of somatosensory cortex could be used as a target for focal electrical stimulation. This type of intervention has been shown to be beneficial in reducing neuropathic pain [67] . Conclusion & future perspective A number of studies were included in this review to explore whether cortical plasticity occurs in chronic pain conditions, the extent of this remodeling, and how it compares to the remodeling of these regions in acute pain and in relation to the ‘pain matrix’. We conclude that cortical areas indeed undergo remodeling in response to chronic pain, and that there is a widespread activation with altered local and often abnormal bilateral connectivity patterns that may lead to somatosensory misrepresentation, as supported by the majority of studies reviewed here. In this regard, ‘pain memory’ is a manifestation of these changes which are not transient and could underlie sustained or even spontaneous pain perception. This resembles processes of long-term potentiation underlying activity-dependent learning [68] . Although we cannot be certain that the same process occurs in chronic pain, results from many studies discussed above point to similar plastic changes which occur during chronic pain states. Understanding the nature of these plastic changes, however, has proved challenging. The acute pain network (“pain matrix”) includes six nodes, five in the cortex, that are activated in response to a painful stimulus. Each of the cortical regions was examined to ascertain whether this network is also relevant in chronic pain and, if so, how. Although all of these regions were involved in chronic pain conditions, a trend implicating an activation network was not unequivocal. There may be a number of reasons for this conclusion. Primarily, different types of elicited pain models were examined within various studies which would make determination of a unified network for all conditions too generalized and insufficient in resolution. When approaching evoked pain, whether allodynia or hyperalgesia, a number of trends have emerged. Generally, allodynia represented pain sensitivity to a nonpainful stimulus, whereby the central pain processing is augmented. In studies where more than one stimulus was employed, different regions were activated with different stimuli as opposed to the entire pain matrix, indicating
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‘Pain memory’: a possible target for treatment of chronic pain that allodynia is not merely an amplification of normal pain. The region most frequently activated in response to allodynia was S1. This conclusion is supported by findings showing increased plasticity in this region in studies on live animals who suffered from allodynia. There were few studies that examined nonevoked pain, particularly spontaneous pain and constant pain in the context of chronic pain models. Of those which compared spontaneous pain with evoked pain, different regions were found to ‘light up’ for the two conditions. Of particular interest is the PFC, found to show activity in all studies exploring spontaneous pain. Thus, as the PFC is associated with emotional–cognitive aspects of pain, spontaneous pain and thus perhaps chronic pain, which it represents, might have a strong affective basis, impacting the emotional aspects of the individual with chronic pain. As compared with acute pain, this indicates a strong emotional component of chronic pain. In particular, the often accompanied comorbidities, such as depression and anxiety, may be the results of changes in this area. This explains why these do not accompany acute pain and helps to substantiate the underlying molecular mechanism which discriminates between the emotional components seen in chronic pain compared with that of acute pain. In the second group, examining the somato sensory representation of those with constant pain, it was found that S1 is involved. Specifically, there was a decrease in somatosensory representation in individuals with neuropathic pain representing a constant pain state. The plastic structural changes which underlie this phenomenon can be attributed to a decrease in gray matter and changes in connectivity. References
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Acknowledgements The authors would like to thank T Golan-Lev for designing the graphics of Figure 1.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Examining the changes that occur in the cortex in chronic pain syndromes necessarily lead us to explore whether chronic pain is the catalyst for remodeling, or whether it is the plasticity that causes chronic pain. While the link is undeniable, determining the cause is not yet possible. Understanding and solving this enigma will lead to a better comprehension of chronic pain mechanisms. As stated above, current treatment is neither specific nor does it suffice. Cortical activity is undoubtedly involved: a link between pain decrease and decreased cortical activation was shown, and pharmacological intervention was demonstrated to directly influence cortical activity and relieve pain. Thus, chronic pain is not a manifestation of acute pain but rather constitutes a different entity. Further work is needed to characterize the kind of activation, connectivity and plastic changes which occur in chronic pain states, towards a better understanding and the development of efficient tools and platforms for treating such devastating pathological states.
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Binshtok AM. Mechanisms of nociceptive transduction and transmission: a machinery for pain sensation and tools for selective analgesia. Int. Rev. Neurobiol. 97, 143–177 (2011).
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Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Ann. Rev. Neurosci. 32, 1–32 (2009).
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The authors identified regions associated with spontaneous pain, and indicated a difference in activation location that was associated with a difference in type of pain, thus implicating a strong emotional component.
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Systematic review summarizing activation of brain areas in response to various pain states; the authors identified a brain network in response to acute pain.
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The authors demonstrated that the remodeling synaptic efficacy in the primary somatosensory cortex results in the modulation of activity in the anterior cingulate cortex, thus stressing the connective cortical nature, and its importance with regard to treatment of chronic pain.
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DR. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J. Neurosci. 28(6), 1398–1403 (2008). 65 Flor H, Denke C, Schaefer M, Grüsser S.
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Chronic pain-related remodeling of cerebral cortex – ‘pain memory’: a possible target for treatment of chronic pain
Practice Points
Avigail Lithwick1,2, Shaya Lev1,2 & Alexander M Binshtok*1,2 Pain related neuronal networks in the cerebral cortex undergo plastic changes following nerve injury. Pattern of activation of pain related neuronal networks is different in acute and chronic pain states. Synaptic connections of individual cortical neurons are remodeled shortly after nerve injury or
inflammation leading to increased network excitability. Timing of treatment is essential to prevent perpetuation of these changes. Understanding of pain-mediated plastic changes in the cerebral cortex is essential for the development
of effective and selective therapies for chronic pain.
SUMMARY Chronic pain is a major health problem worldwide, yet its management is nonspecific and often insufficient. In order to be able to alleviate chronic pain, it is crucial to understand the profound and comprehensive mechanisms by which chronic pain is triggered and processed in higher brain areas. Painful stimuli are processed by an intricate axis of peripheral and central components. Adding to the inherent complexity, the system is highly dynamic, undergoing constant plastic changes that often lead to perpetuation of pain. Given the key role that the cerebral cortex plays in sensory perception, understanding pain-related changes in cortical areas allocated to pain sensation is crucial. This review aims to summarize present research on pain-related plastic changes in the cerebral cortex. Chronic pain is a condition of the nervous system that includes a number of syndromes and ailments, such as fibromyalgia, migraines, irritative bowl syndrome and low back pain. Chronic pain is a widespread disease with a prevalence of 19% in Europe and 30.7% in the USA [1,2] . The prevalence of severe chronic pain is immense: over a third of individuals with chronic pain defined their pain as severe and 40% of those suffering from chronic pain in general were not satisfied with their care [1] . In order to allow for adequate chronic pain treatment, a complete and comprehensive
understanding of pain processing and perception is essential. The etiology of chronic pain is complex and confusing. Injury to the nervous system could potentially lead to chronic, in this case, neuropathic pain. Which component of nerve injury triggers chronicity of pain? Most likely the abnormal activity of injured nerve combined with an ‘unfortunate’ combination of a plethora of immune, genetic and environmental factors ignite the process [3] . In some states of chronic pain, when pain appears without obvious nerve injury, such us fibromyalgia and migraine, peripheral pain
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University Faculty of Medicine, Jerusalem, Israel *Author for correspondence: [email protected] 1
10.2217/PMT.12.74 © 2013 Future Medicine Ltd
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REVIEW Lithwick, Lev & Binshtok fibers also exhibit abnormal patterns of activity [4,5] . Therefore, it appears that, regardless of the initial etiology, chronic pain can be regarded as a standalone disease of the nervous system, initiated by altered activity of peripheral fibers which entails abnormal structural and functional plastic changes taking place along the neuroaxis, all the way from peripheral nociceptive terminals to convoluted networks of cortical areas [6] . As a result of the neuronal and network plasticity, perception of pain transforms from a normal response to that causing hyperalgesia (increased pain perception [101]), allodynia (pain in response to a stimulus that does not normally provoke pain [101]), and spontaneous pain (when no stimulus is present [6]). The structural and functional changes that occur can be regarded as ‘pain memory’ in the sense that they create an ‘imprint’, similar to experience-dependent learning, which forms the mechanistic basis for abnormal activity underlying chronic pain. It is the goal of this review to focus on these plastic changes, which occur at the level of the cerebral cortex. Regarding plastic changes that occur at the periphery and spinothalamic levels, there are several excellent reviews summarizing our current knowledge [7–11] . While cortical areas are involved in both acute and chronic pain conditions, their activation pattern and plasticity profiles are not identical. The six most common regions activated in acute pain are often referred to as the pain matrix [12] . These regions include five cortical areas: the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), anterior cingulate cortex (ACC), insular cortex (IC) and the prefrontal cortex (PFC). The sixth region of the pain matrix is the thalamus, which is not associated with the processing of pain, but rather relays sensory information to cortical and subcortical structures (Figure 1) [13] . In general, the pain matrix processes sensory information in the following manner: pain discrimination (the lateral pain system), subjective evaluation (the medial pain system) and cognitive assessment [14] . The lateral pain system is comprised of S1, involved in stimulus location [15] , and S2 which is related to the discrimination of pain intensity [16] . The medial pain system consists of the IC, the ACC and the PFC [14] . The IC lies between emotion and sensory discrimination regions: it receives input from the lateral system, but projects to regions associated with emotional processing (i.e., the limbic region), implying an
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integrative function in pain [15] . The ACC is associated with subjective pain assessment, or the ‘suffering’ aspect of pain [16] and the perceived pain intensity, or the cognitive–evaluative aspect of pain processing [12] . The ACC is also involved in endogenous, opiate-mediated mechanisms of pain regulation [17,18] . Cognitive assessment of pain is attributed to the PFC. Activation of the PFC is related to pain as well as to attention, working memory and goal-oriented tasks [19] . From the information discussed above, it is suggested that the activity within the painmatrix reflects the cortical analysis of various parameters of noxious stimuli. However, several lines of evidence suggest that pain matrix activity is not well correlated with the intensity of painful stimuli [20] (see also [21]). Moreover, the response pattern of the pain matrix in general, and of the anterior insula and mid-cingulate cortex in particular, depends on stimulus context whereby the same stimulus could be perceived as painful or not, depending on whether the stimulus was anticipated as harmful or harmless [22] . This implies that the pain matrix is involved not just in the detection of harmful noxious stimuli but in the perception of any prominent (salient) sensory event that could provide a potential threat to the integrity of the organism in situ. There are regions outside of the pain matrix that are also associated with the processing of pain, including the amygdala and the primary and supplementary motor cortices. What does the activity of the pain matrix represent? The common view is that, rather than a particular area attributed to pain, the aforementioned areas form a network that results in the physical and emotional perception of pain. The central question discussed in this review is whether activation of these areas also occurs in chronic pain conditions, and to which extent or in what patterning. Specifically, are the same areas activated? Are they activated in the same way? Is the pattern connectivity the same? Is there a causal relationship between pain triggering at the periphery and the activity seen in the pain matrix? In addition, while in acute pain it is typically the contralateral hemisphere that responds (within the pain matrix), can we expect the same response to a chronic pain state, or will a more extensive, and perhaps bilateral, activation pattern emerge? Several studies have shown that the nature of pain activation processes vary with different pain sources and longevity of the pain sensation
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‘Pain memory’: a possible target for treatment of chronic pain
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S1
ACC PFC Thalamus Insula
S2
Amygdala
t
t ac l tr
trac
hia ac br ra pa
ic alam Spinoth
no
Sp i
Figure 1. Connections within the pain network, delineating lateral (black) and medial (gray) pain systems, excluding areas not associated with the pain matrix. ACC: Anterior cingulate cortex; PFC: Prefrontal cortex; S1: Primary somatosensory cortex; S2: Secondary somatosensory cortex.
measured, leading to the conclusion that chronic pain is not a mere manifestation and elongation in the time span of acute pain, but rather constitutes a different mechanism that also involves the pain matrix but in a different manner than in acute pain, as discussed below. Analyzing the activity, plasticity and connectivity of each domain within the pain matrix in chronic states compared with acute pain is crucial to answer the above questions and expand on our understanding of these states. S1 S1 is an essential processing center of the lateral pain pathway, primarily responsible for sensory discrimination; it answers the question of “where does it hurt?” [15] . Exploring the nature of its
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plasticity is highly valuable when considering its potential role in chronic pain conditions. In general, the majority of the studies have demonstrated alterations in location activation patterns when compared with acute-pain triggering of this domain. One study, however, failed to find a difference in activation of S1 between acute and chronic states, though it demonstrated an augmentation of pain sensitivity in terms of pain felt and cortical activation [23] . In the other studies, where a painful response was elicited, a more widespread contralateral activation pattern was found in individuals with chronic pain, compared with healthy individuals with elicited acute pain [24] or the unaffected contralateral side of the same individuals [19] . This was true both in cases
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REVIEW Lithwick, Lev & Binshtok of hyperalgesia [19,24] and allodynia [25–27] as painful end points. In addition, a number of studies found an ipsilateral activation pattern in individuals with chronic pain as opposed to controls elicited with acute pain [26–28] . Spontaneous pain elicits activation patterns different from those of acute pain [29–33] . In particular, the associated limb exhibited a decrease in size of activation pattern in S1. In chronic neuropathic pain, following spinal cord injury [30] or in cases of phantom limb pain [31] , a decreased activation pattern upon imagined movement was found, while the adjacent representation expanded in activation. Whether the pain causes this modulation or whether the modulation is a trigger for chronic pain is obscure. In summary, studies examining activation of S1 in chronic pain conditions indicate reorganization on two levels. Firstly, upon eliciting pain, individuals with chronic pain present a more widespread activation pattern in S1 as compared with the unaffected side or with healthy controls inflicted with acute pain. However, individuals with chronic pain also present a smaller cortical representation of the affected area in S1, implying a dissociation between activation of primary sensory areas and the actual origin of chronic pain. Anterior cingulate cortex The ACC is a key cortical area involved in chronic pain-related plasticity [34] . The activation of the ACC is associated with both the emotional [16] and the cognitive–evaluative [12] aspects of pain processing. It has been demonstrated that following peripheral nerve injury, in an animal model for neuropathic pain, ACC neurons express elevated levels of PKM-z. PKM-z, the protein kinase required for a long-term potentiation type of synaptic plasticity, maintaining persistent synaptic changes, therefore plays a critical role in memory consolidation [35] . Moreover, inhibition of PKM-z abolished synaptic facilitation and blocked neuropathic pain hypersensitivity [35] . This implies that PKM-z plays a crucial role in stabilizing the augmentation of pain in chronic pain states. Furthermore, it indicates that the ACC has an important role in facilitating chronic pain. In a human placebo study, a decrease in ACC activation, along with the anterior insula, correlated with a decrease in pain [36] . The rostral ACC, however, was found to be associated
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with treatment expectation [37] , implicating an emotional aspect. As a result, one can expect plasticity in the ACC to be correlated with sensory discrimination, determining the location of pain, as well as affective perception, or the suffering aspect of pain. In addition, rostral ACC is also involved in endogenous opioidergic modulation of acute and chronic pain [18] . Patients with fibromyalgia, for example, exhibited significantly lower connectivity between rostral ACC and the amygdala [17] . The amygdala, which projects directly into the periaqueductal gray matter area, is directly involved in opioid-dependent analgesia [38] . Thus, reduction of the efficiency of opioidinduced analgesia may underlie increased pain sensitivity of fibromyalgia patients. A number of studies demonstrated an activation pattern that correlated ACC with the somatosensory areas, implicating the ACC to be related to sensory perception [19,24,27,33,39,40] . The majority of these studies showed activation differences between chronic pain patients and controls (those with acute pain), apart from one [24] , which demonstrated a similar activation pattern when both patients and controls experienced a similar rating of pain. In addition, a bilateral ACC activation pattern was displayed, which was more widespread than in healthy controls [19,26,27,33,40] . In a study examining allodynia under various stimuli types, the ACC was activated in response to a cold stimulus, similar to the insula [28] . However, contrary to other studies, the ACC was activated only in outcomes producing pain, dissociating it from sensation alone and implicating its importance in pain. In chronic back pain, it was found that the ACC and the insula demonstrated a significantly altered correlation to the medial PFC(chronic back pain) [41] , which represents the affective (i.e., emotional) aspect of chronic pain [32] . A number of studies found differences in ACC activation in response to various treatments [33,39,40] . One study indicated a significant reduction in ACC activation which occurred during the short-term phase of a lidocaine patch treatment [39] , in addition to sensory areas, thus implicating the ACC to be closely associated with the sensorydiscriminating regions. However, other studies found ACC activation reduction to correspond to a decrease in pain: one in the case of a nonsteroidal anti-inflammatory agent in patients with osteoarthritis [41] and the other employing a
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‘Pain memory’: a possible target for treatment of chronic pain mental imagery technique therapy program for individuals with chronic pain [33] . In conclusion, while it appears that the ACC plays a role in both the sensory–discriminative and affective pathways of pain evaluation in chronic pain states, as in acute pain conditions the actual activation is more widespread, and in some instances bilateral. This indicates that both a stronger emotional and sensory component is involved in cases of chronic pain. S2 S2 is generally associated with the discrimination of pain intensity, or how much pain is felt. However, the amount of research in this area in the context of chronic pain and its effect on plasticity is relatively small. However, most studies found similar trends which displayed an increase in the activation of S1 and S2 compared with acute pain, indicating a coactivation pattern. Moreover, these studies presented a bilateral activation pattern in S2 in response to chronic pain [19,24,26,28,33,39,40] . A portion of these studies found that in healthy controls, only the contralateral S2 area was activated in response to acute pain [33,40] , or was less widespread than in individuals with chronic pain [19,26] . Other studies exhibited deviations from the bilateral activation of S2. Several showed activation in the contralateral limb [23,29] , the ipsilateral limb [27] and in the right hemisphere in the condition of chronic back pain [32] . A few studies showed a different activation pattern than the coactivation of S2 and S1. One study found bilateral S2 activation in cold and tactile pain-evoking conditions (allodynia and pain in healthy controls), while S1 was activated in tactile conditions alone [28] . Another study had determined a significantly altered correlation in connectivity between S2 and chronic back pain [41] . However, the majority of the studies emphasize the activation of S2 in instances whereby S1 is activated, supporting its role in sensory discrimination and indicating network connectivity between the two regions. The bilateral activation pattern, compared with a contralateral activation pattern alone as seen in acute pain, may play a role in the misrepresentation of pain in a chronic pain setting and indicate the widespread connectivity, which might be a hallmark in chronic pain conditions. The S2 activation on the ipsilateral side decreased with short-term treatment [39] . This decrease in activation did not persist, implying
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that therapy affects the lateral pathway in a transient manner. However, in a different study, examining cortical reorganization in response to phantom pain treatment, S1 exhibited cortical reorganization while S2 did not [33] . Overall, it appears that S2 is activated in instances where S1 is activated, indicating a causal connectivity pattern between the two and a temporal coactivation process. The bilateral nature of S2 activation in chronic pain indicates a change in individuals with chronic pain. Taking these two into account, S2 activity is affected in individuals with chronic pain, and is of a sensory–discrimination nature, as was found in the case of acute pain indicating that its “classical” role has not changed. However its activation seems to be more widespread with less of a representation of the initial pain and with bilateral connectivity, emphasizing the change in network patterning and dissociation from peripheral pain triggering. Insular cortex The IC is often considered to be related to both sensory (where and how much it hurts) and affective perception of pain (the suffering aspect of pain) [15] . It has been suggested that the anterior insula is responsible for subjective evaluation and is often coactivated with the ACC [42,43] . Moreover, the right anterior insula is crucial for the emotional response to visceral pain as part of its involvement in interoceptive processing – a mental or emotional knowledge of physical state [42–45] . The posterior insula was found to be related to sensory perception and discrimination [42,46] . Thus, it can be expected that the insular cortex, similar to the ACC, may contribute information regarding pain in two ways: both sensory (where and to what degree), as associated with S1 and S2, and affective (the coping aspect of pain-suffering), as attributed to the PFC. It was found, however, that although a division exists, it is far from symmetric in strength. The majority of studies demonstrated an activation pattern similar to that of S2 [19,24,26,27,32,39,41] . Specifically, some studies found a more widespread activation pattern, as compared with controls (an acute pain condition) [40] or the unaffected side [19,26] , while others demonstrated insular activation in both chronic pain patients and healthy controls [23,24] given equal painful responses in both groups. Additionally, a number of studies found insular activation to be
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REVIEW Lithwick, Lev & Binshtok bilateral [19,33,39] . A study on chronic back pain found reorganized connectivity between the mPFC and the IC [41] . However, a small number of studies did not find activation of IC to be strictly associated with somatosensory areas impinged by painful stimuli [28,33] . In a study that examined allodynia based on stimulation type [28] , painful cold stimulation and cold-evoked allodynia resulted in mid-posterior insular activation in healthy controls and chronic pain patients, respectively, while nonpainful cold stimulation in healthy volunteers resulted in anterior insular activation. In a study examining phantom limb pain, activation in response to imagined movement of the phantom hand and actual movement of the real hand was found in insular and somatosensory areas [33] . In addition, S1 and bilateral insular activation in response to pursing of the lip occurred only in individuals with phantom pain [33] . Finally, in a study that examined the effect of a lidocaine patch in postherpetic neuralgia [39] , the contralateral anterior insula was the only region that displayed an increase in activity. This effect was found for short-term treatment alone. Although it was expected that the IC area would exhibit a mixed activation pattern, we conclude that it is generally activated in instances in which the somatosensory areas are activated as well. In chronic pain, the IC appears more closely linked to sensory discrimination rather than emotional processing. This may be a hint to the functional changes occurring in the IC in response to chronic pain: its role in ‘suffering’ is minimized so as to accommodate the vast increase in activation that is seen in S1 and S2 and might indicate a connectivity pattern linking S1 and S2 with IC, all functioning to generate sensory information. Prefrontal cortex The PFC is a region associated with the cognitive evaluation of pain, which involves, among others, how one copes with pain: in terms of depression, difficulty in decision making, or others. Overall, the studies can be examined according to subregions: medial PFC, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. The chronic back pain represents the affective aspect of chronic pain; the ‘suffering’ of pain, as mentioned above [32] . The chronic back pain was correlated with spontaneous pain [40] , implying spontaneous pain is affective by nature,
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particularly in the sustained high intensity phase [32] , and showed an increase in activation, compared with healthy controls [41] . Blood levels of NSAIDs are well correlated with the changes in cortical activation in patients with chronic back pain [41] . In individuals with chronic back pain, the chronic back pain was in a significant hyperactive state, correlating to the duration of this condition [47] . An altered resting state may influence brain activity overall, affecting its ability to perform other tasks; perhaps explaining the effect of changes in cognition and behavior. Chronic back pain was shown to be negatively correlated to the DLPFC, which is activated before chronic back pain, and deactivated when chronic back pain has been activated [32] . The DLPFC is involved in localizing and encoding pain-producing stimuli [16] . This may explain why the DLPFC was activated in healthy and chronic back pain patients alike, in response to a painful thermal stimulus [32] , and in response to a cold-stimulus evoking pain and brush evoked allodynia on the ipsilateral side [28] . Finally, the third sub-PFC region is the orbitofrontal cortex, which serves as a link between areas associated with emotional assessment [48] , coordinating memory and emotion. If disrupted, an imbalance in emotional response may arise, implying the orbitofrontal cortex to be a good target for treatment of chronic pain. One study, which found the orbitofrontal region (and the chronic back pain) to be associated with spontaneous pain, did not demonstrate a change upon treatment using a nonsteroidal antiinflammatory agent [40] . However, another study demonstrated orbitofrontal region activation in spontaneous pain, which ceased with treatment [39] . In this study the authors concluded that this region, along with limbic center regions responded to long-term treatment, while the sensory discrimination pathway responds to short-term treatment. Thus, it appears that the change in the PFC in response to chronic pain represents a shift in the emotional processing. The increase in activation may originate from the increase in activation in the sensory-related areas (S1, S2); however, it appears that over time it evolves into a more independent activation site. It is possible that the suffering and decrease in decision making, as seen above, perpetuate chronic pain, as the suffering from pain is the primary symptom associated with chronic pain disorders. Though the PFC represents a central component in the
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‘Pain memory’: a possible target for treatment of chronic pain acute pain matrix, it appears that its involvement in chronic pain is more significant, more widespread and could be hyperactive due to connectivity with areas such as S1 and S2. Are the above mentioned chronic painmediated changes in cortical functions a result of neuronal plasticity? It has been demonstrated that chronic pain is accompanied by large scale morphological changes in the cerebral cortex, namely cortical thickness [49] . A paper by Baliki et al. demonstrated ‘signature’ changes for different chronic pain conditions [50] . Thus, in patients with chronic low back pain, the changes in gray matter volume spread to the whole brain but primarily affect bilateral posterior insula, secondary somatosensory cortices and temporal lobes. Patients with osteoarthritis demonstrated changes in the density of gray matter localized to parts of the insula, mid ACC and inferior temporal cortex. The signature for complex regional pain syndrome was decreased gray matter density in the anterior insula and orbitofrontal cortex [50] . These changes are well correlated with the duration and intensity of pain [51] and therefore could be used as potential biomarkers for the evaluation and prognosis of chronic pain states. Interestingly, the changes in gray matter content were not observed in patients suffering from rheumatoid arthritis [52] . In this case, the majority of changes were observed in the nucleus accumbens and caudate nucleus [52] , outlining the important role of subcortical areas in chronic pain and specificity in cortical areas devoted to perception of pain. These changes in cortical architecture are correlated to specific functional changes in response to painful stimuli in chronic pain [51] , implying that chronic pain causes plastic changes in the cerebral cortex. In the well-controlled (in terms of location, intensity and type of pain) group of patients with neuropathic trigeminal pain, the areas activated by an allodynia-evoked stimulus were the same areas that exhibited changes in cortical thickness [51] . To show that these large scale changes have a causal relationship with synaptic plasticity [53] , precise temporal and spatial resolution is required. Therefore, multiphoton imaging at the level of single dendritic spines was performed on animals following inflammation [54] or in nerve injury animal models [55,56] which constitute models for chronic pain conditions. These studies demonstrated, that 3 days after ligation of peripheral nerve, when mechanical allodynia starts to develop, there were noticeable changes in the morphology and motility of S1 pyramidal cell
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spines [55,56] . This synaptic rearrangement ceased 6 days after injury when mechanical allodynia persisted – the so called maintenance phase. Since dendritic spines are the location for excitatory synaptic contacts, these changes reflect experiencedependent synaptic plasticity [57–59] – a learning underlying the development of symptoms. The stabilization of the process during the maintenance phase of neuropathic pain resembles the formation of new stable ‘memories’ of pain. Of particular importance was the effect that the immediate sciatic nerve blockade had in terms of cortical plastic changes, exemplified by spine turnover that was prevented. Interestingly, this immediate intervention also prevented development of allodynia. However, the instigation of the nerve blockade at a later phase presented transient recovery. These results denote the importance of the timing of treatment in order to prevent the occurrence of allodynia and thus perhaps chronic pain and help to substantiate a casual relationship between chronic pain and plastic changes. A follow-up study demonstrated that structural changes in S1 circuitry underlie enhancement of responsiveness of neurons to peripheral stimulation as well as an increase in their spontaneous activity [54] . In summary, both animal [54] and human [60,61] studies show that the nerve injury-dependent hyperactivation leads to functional and structural changes in specific areas of the cerebral cortex. This reorganization of local cortical circuits – a pain-related memory – provides a mechanistic as well as molecular basis for abnormal activity underlying chronic pain. In addition, animal and human studies demonstrated that in chronic pain conditions, these connectivity changes within specific cortical areas also project into other areas of the pain matrix, primarily the PFC, ACC and insula. Importantly, following inflammation of the hind paw, application of synaptic blockers directly into the ACC abolished mechanical allodynia [54] , emphasizing the role of inhibition of activity in the ACC as a possible target for treatment of chronic pain. Interestingly, increased functional connectivity between left anterior insular cortex and pregenual ACC was observed in patients suffering from temporamandibular disorder [61] . Since pregenual ACC is involved in antinociception, these changes in connectivity may reflect an adaptive mechanism during the establishment of chronic pain. Several lines of evidence emphasize the role of changes in
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REVIEW Lithwick, Lev & Binshtok functional connectivity between cortical and subcortical areas. In complex regional pain syndrome patients, altered connectivity between PFC and nucleus accumbens was observed [60] ; this proves important as this connectivity plays a crucial role in pain chronicity, and hence can be used to predict the likelihood of development of chronic pain [62] . The chronic pain mediated changes in cortical connectivity may also involve areas not dedicated to pain processing. A series of studies demonstrated that cognitive and behavioral impairments in chronic pain patients could have originated from abnormal functional connectivity of the “default mode network” a cortical circuit consisting of the inferior parietal lobule, the posterior cingulate cortex and precuneus, areas of the medial frontal gyrus, the hippocampal formation and lateral temporal cortex. The connectivity of this network, normally active in resting states, is enhanced in fibromyalgia patients [63] and the deactivation of some of the areas within the default mode network was suppressed in low back pain patients [64] . These data suggest that chronic pain is strongly associated with both modulation of activation of pain related cortical areas and changes in connectivity patterns of pain related and nonpain related networks. Treatment Of the studies presented in this paper, a small number included treatment [33,39,40,65] . Of these, two included pharmacological interventions: the first examined the influence of a nonsteroidal anti-inflammatory agent on individuals with osteoarthritis [40] , and the second investigated the influences of a lidocaine patch on postherpetic neuralgia [39] . Both lead to pain reduction at the site of pain instigation. Additionally, the two studies found a decrease in both pain and activation of affective cortical areas over time. Another approach in targeting pain is the use of a more widespread medication which targets more central areas. A plethora of such medications is currently in use [66] , such as tricyclic antidepressants and anticonvulsants. There were several studies which included treatment towards individuals with phantom pain [33,65] . A sensory discrimination training [65] , and a mental imagery technique [33] were employed in these studies. Both found a reduction in pain and a remodeling of S1, indicating an important role for a nonpharmacological approach in pain intervention.
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The defined location of chronic pain-mediated abnormal activation of somatosensory cortex could be used as a target for focal electrical stimulation. This type of intervention has been shown to be beneficial in reducing neuropathic pain [67] . Conclusion & future perspective A number of studies were included in this review to explore whether cortical plasticity occurs in chronic pain conditions, the extent of this remodeling, and how it compares to the remodeling of these regions in acute pain and in relation to the ‘pain matrix’. We conclude that cortical areas indeed undergo remodeling in response to chronic pain, and that there is a widespread activation with altered local and often abnormal bilateral connectivity patterns that may lead to somatosensory misrepresentation, as supported by the majority of studies reviewed here. In this regard, ‘pain memory’ is a manifestation of these changes which are not transient and could underlie sustained or even spontaneous pain perception. This resembles processes of long-term potentiation underlying activity-dependent learning [68] . Although we cannot be certain that the same process occurs in chronic pain, results from many studies discussed above point to similar plastic changes which occur during chronic pain states. Understanding the nature of these plastic changes, however, has proved challenging. The acute pain network (“pain matrix”) includes six nodes, five in the cortex, that are activated in response to a painful stimulus. Each of the cortical regions was examined to ascertain whether this network is also relevant in chronic pain and, if so, how. Although all of these regions were involved in chronic pain conditions, a trend implicating an activation network was not unequivocal. There may be a number of reasons for this conclusion. Primarily, different types of elicited pain models were examined within various studies which would make determination of a unified network for all conditions too generalized and insufficient in resolution. When approaching evoked pain, whether allodynia or hyperalgesia, a number of trends have emerged. Generally, allodynia represented pain sensitivity to a nonpainful stimulus, whereby the central pain processing is augmented. In studies where more than one stimulus was employed, different regions were activated with different stimuli as opposed to the entire pain matrix, indicating
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‘Pain memory’: a possible target for treatment of chronic pain that allodynia is not merely an amplification of normal pain. The region most frequently activated in response to allodynia was S1. This conclusion is supported by findings showing increased plasticity in this region in studies on live animals who suffered from allodynia. There were few studies that examined nonevoked pain, particularly spontaneous pain and constant pain in the context of chronic pain models. Of those which compared spontaneous pain with evoked pain, different regions were found to ‘light up’ for the two conditions. Of particular interest is the PFC, found to show activity in all studies exploring spontaneous pain. Thus, as the PFC is associated with emotional–cognitive aspects of pain, spontaneous pain and thus perhaps chronic pain, which it represents, might have a strong affective basis, impacting the emotional aspects of the individual with chronic pain. As compared with acute pain, this indicates a strong emotional component of chronic pain. In particular, the often accompanied comorbidities, such as depression and anxiety, may be the results of changes in this area. This explains why these do not accompany acute pain and helps to substantiate the underlying molecular mechanism which discriminates between the emotional components seen in chronic pain compared with that of acute pain. In the second group, examining the somato sensory representation of those with constant pain, it was found that S1 is involved. Specifically, there was a decrease in somatosensory representation in individuals with neuropathic pain representing a constant pain state. The plastic structural changes which underlie this phenomenon can be attributed to a decrease in gray matter and changes in connectivity. References
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Acknowledgements The authors would like to thank T Golan-Lev for designing the graphics of Figure 1.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Examining the changes that occur in the cortex in chronic pain syndromes necessarily lead us to explore whether chronic pain is the catalyst for remodeling, or whether it is the plasticity that causes chronic pain. While the link is undeniable, determining the cause is not yet possible. Understanding and solving this enigma will lead to a better comprehension of chronic pain mechanisms. As stated above, current treatment is neither specific nor does it suffice. Cortical activity is undoubtedly involved: a link between pain decrease and decreased cortical activation was shown, and pharmacological intervention was demonstrated to directly influence cortical activity and relieve pain. Thus, chronic pain is not a manifestation of acute pain but rather constitutes a different entity. Further work is needed to characterize the kind of activation, connectivity and plastic changes which occur in chronic pain states, towards a better understanding and the development of efficient tools and platforms for treating such devastating pathological states.
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