15.1. PSYCHOLOGICAL, COGNITIVE, AND SENSORY ABNORMALITIES

Depression is ranked as one of the strongest predictors for low back pain. This association is observed by multiple studies, with odds ratios increasing with intensity of back pain and severity of depression 55;60. In order to investigate the predictive power of baseline depression on the transition from acute to chronic pain (3 months post-acute back pain), a recent prospective study evaluated the direct and indirect effects of multiple parameters on chronic pain severity and disability 81. The model only accounted for 26% of the variance in chronic pain. Acute pain intensity did not directly predict pain three months later, and baseline pain beliefs failed to predict chronic pain magnitude. Despite these relatively weak relationships to chronic pain, the authors argued that their findings support the growing literature contending that progression to chronic pain is more dependent on psychosocial and occupational factors than on medical characteristics of the spinal condition. In general, a long series of studies now describe psychosocial and psychological factors in predicting functional and social disability, where the interrelationship between ratings of catastrophizing, pain-related fear of (re-) injury, depression, disability, and pain severity are studied and modeled in combination with demographics in various chronic pain conditions. Although these factors may be associated with pain in certain individuals, attempts to create models of CBP based upon them have been unproductive 38;47;74;79; for further details see 2. It is now being recognized that psychosocial factors constitute “non-negligible risks” for the development of low back pain 17 and cannot account for how or why a patient transitions into the chronic pain state.

We have examined cognitive and sensory properties of chronic pain patients, with the simple notion that living with chronic pain may impart a cost in such processing. A long list of cognitive abnormalities has been described in chronic pain patients. The most noteworthy are attentional and memory deficits 18;68. However, little effort has been placed in differentiating such deficits based on chronic pain type. We reported that, in contrast to matched healthy controls, CBP and complex regional pain syndrome (CRPS) patients are significantly impaired on an emotional decisionmaking task 5. Moreover, the performance of CBP patients was highly correlated with their verbal report of pain at the time of performing the task. In contrast to CBP, CRPS patients’ performance was not modified when their pain was manipulated using a sympathetic block. The latter implies that the brain mechanisms underlying the two types of chronic pain, or the impact of each condition on the brain, may be distinct and thus also distinctly modulate emotional states. It should be noted that the CRPS patients were tested on a long battery of other cognitive tasks as well, and their performance on these was not different from healthy control subjects. Two important conclusions are drawn from these observations. Firstly, cognitive disruption in chronic pain is specific to the type of test administered, implying impact on unique brain circuitry. Secondly, there are important differences between chronic pain conditions, even on the same cognitive task, suggesting that each condition may underlie unique brain activity/reorganization, which complicates our understanding of these conditions as it demands that we study each and every chronic pain regarding its cognitive and brain signature. More importantly, the implication that distinct chronic pain conditions have unique brain signatures open the possibility that each one of them may be understood in its own right, enabling the development of novel, specific therapies for each. This theme will be repeated several times below, emphasizing that brain-derived parameters repeatedly indicate the specific properties of distinct chronic pain conditions.

It should be emphasized that the impact of chronic pain does not only result in deficits. When CBP patients were contrasted to healthy subjects as to gustatory abilities, we were able to show decreased threshold to gustatory detection and increased sensitivity to supra-threshold tastants for all modalities examined 69. Thus, these CBP patients are generally more sensitive in taste perception. It is possible that this ability is a predisposing factor. In fact, all the brain and cognitive changes we describe here are cross-sectional studies, and thus in all cases the distinction between predisposition and a consequence to chronic pain remains unsettled. More likely, increased taste sensitivity is a result of brain representation/reorganization as a consequence of living with CBP. We ascribe the deficit in emotional decision-making in CBP and CRPS as a consequence of the representation/reorganization of brain activity between the lateral and medial prefrontal cortex. In fact, our observation of activity in medial prefrontal cortex in CRPS 7 was the initial impetus for testing chronic pain patients with the “gambling test.” We also think that the increased taste sensitivity is a direct result of changes in activity/connectivity of the insular cortex in CBP Our earlier observation that insular cortex activity increases in CBP patients in proportion to the number of years they are in chronic pain 10, and given that parts of the insular cortex are considered primary gustatory cortex, led us to the hypothesis that gestation may be different in CBP Therefore, the cognitive and sensory changes we have observed in chronic pain patients are derived from observations regarding cortical representation and reorganization, and thus these domains are complementary to each other, reinforcing the idea that the brain abnormalities do result in very specific changes in information processing.

15.2. BRAIN METABOLITES

We published the first study showing that brain chemistry is abnormal in CBP patients as compared to matched healthy controls, using magnetic resonance spectroscopy (MRS) 33. Our study revealed decreased N-acetyl-aspartate in the lateral prefrontal cortex, as well as correlations between brain regional chemistry and clinical parameters of pain duration, intensity, and McGill Pain Questionnaire dimensions. We found that the relative concentrations of chemicals in the cingulate cortex and thalamus reflected pain duration (in opposite directions). Moreover, chemical concentrations were found to positively correlate with sensory, affective, and intensity ratings of CBP. A small number of similar studies have been published since, in a number of chronic pain conditions 23;59;70, yet the topic remains in its infancy. It is likely that the method would provide clinically important information regarding various chronic pain conditions, especially as it is becoming an important biomarker in neurodegenerative conditions. For example, metabolic changes are observed in presymptomatic mutation carriers years before onset of Alzheimer’s disease 30, suggesting that metabolic markers may also be useful in predicting predisposition to chronic pain. A recent study in fibromyalgia patients indicates that MRS may also be useful in assessing levels of glutamate in the brain, and further that this signal seems to be modulated with clinical parameters as well as with acute painful stimulation 40. Even though assessment of metabolic signals seems promising, it does suffer from important weaknesses, the main difficulty being the lack of standardized methods for localizing brain regions studied. Thus, reproducing results even in the same subject remains problematic. Moreover, the MRS signal is contaminated with the properties of the tissue examined since the concentration of all metabolites is influenced by the proportion of CSF to white to gray matter within any region examined, and corrections for such contaminations remain inadequate. Current MRS acquisition methods are time-consuming and only enable collecting a small number of single voxels; multi-voxel MRS in turn suffers from more severe tissue cross-contamination artifacts. Given that chronic pain patients find it uncomfortable to remain immobile, head position cannot be assumed to be fixed within and especially across patients and controls. There is no question that MRS signals are distorted by head motion, yet there are currently no acceptable means of correcting for this artifact. Thus, in general, technical difficulties complicate the implementation and interpretation of results obtained by this approach.

An alternative approach is the use of positron emission tomography (PET) to examine binding changes for various ligands in chronic pain. With this approach a recent study identified mu-opiate binding decreases in fibromyalgia, with the decrease being related to the pain characteristics in a number of brain regions 39. Dopamine (D) release in the basal ganglia is also disrupted in fibromyalgia patients 78 and in those with burning mouth syndrome and atypical facial pain 34;35. Additionally, D2 binding in the basal ganglia has been proposed as a marker for diagnosis and treatment of chronic pain 36. A recent review article discusses the impact as well as limitation of PET opiate receptor binding studies in general 41, emphasizing its impact on acute and chronic pain conditions. The authors conclude that a major obstacle in the field is the limited number of tracers available and their binding specificity for subclasses of opiate receptors.

15.3. SPONTANEOUS PAIN

The primary complaint of chronic pain patients is spontaneous pain. The large majority of such patients seek health care to relieve pain that is ongoing, that fluctuates unpredictably, and results in decreased quality of life and increased anxiety and depression. When a physician asks the patient to rate his/her pain, the physician is specifically attempting to capture the intensity of spontaneous pain. Similarly, in the large majority of clinical drug trials, the most commonly used primary outcome is a visual analogue scale of spontaneous pain intensity. Thus, therapies for pain relief by and large have also targeted the diminution or silencing of spontaneous pain. This is an important issue given that there are currently no convincing methods for studying spontaneous pain in animal models. Moreover, perhaps by borrowing from animal studies, human brain imaging studies (outside of our lab) have only studied stimulus-evoked brain activity for acute and chronic pain.

We recently revealed that the spontaneous pain of chronic pain patients fluctuates in the scale of seconds to minutes, that these fluctuations are distinct for various chronic pain conditions, and that normal healthy subjects are unable to mimic them 22. Participants were instructed to continuously rate their subjective assessment of the intensity of pain. The primary observation of this study is the notion that spontaneous pain fluctuates enough that simply monitoring it for 10 minutes is sufficient to characterize and use its properties to distinguish between types of chronic pain. We observed that the fluctuations of spontaneous pain do not possess stable mean or variance, implying that these time series can be characterized better by a non-linear, fractal analysis. To this end, we applied time and frequency domain techniques to characterize variability of pain ratings with a single parameter: fractal dimension, D. We demonstrated that D is distinct between types of chronic pain, and from ratings of thermal stimulation and of imagined pain; and that there is a correspondence between D for pain ratings and D for brain activity in CBP patients using fMRI. This study remains the only one where spontaneous pain fluctuations at such time scales have been characterized. In this study we showed that post-herpetic neuralgia (PHN) patients’ fluctuations of spontaneous pain had temporal properties distinct from that of CBP patients. If we make the simple assumption that the temporal fluctuations of spontaneous pain are a reflection of the interaction between peripheral nociceptive activity and CNS processes, then these results suggest that these interactions are distinct between PHN and CBP, implying that central processes involved should be unique for each.

15.4. BRAIN ACTIVITY DURING CHRONIC PAIN

Once the temporal properties of spontaneous pain were characterized, it provided the background upon which we could begin examining related brain activity using fMRI. We have now used this approach to study CBP 10, PHN 25;28, pelvic pain (PP), and osteoarthritis (OA) 12. The studies in CBP, PHN, and PP examined brain activity for spontaneous pain, while in OA spontaneous pain showed very little temporal modulation, forcing us to instead examine brain activity for pressure applied to the painful knee joint. In PHN, we studied brain activity for spontaneous pain as well as for touch-evoked pain (tactile allodynia) in the same group of patients. In CBP, PHN, and OA we also tested the modulation of resultant brain activity with the use of therapy, testing the specificity of brain activity in relation to pain relief with therapy.

Using non-invasive brain imaging (fMRI) in combination with online ratings of fluctuations of spontaneous pain, we identified the brain activity idiosyncratic to CBP 10. The data were analyzed using two different vectors: (1) when ratings of spontaneous pain were high in contrast to low, and (2) when ratings of spontaneous pain were rapidly increasing in contrast to all other times. The brain activity obtained, after subtracting a visual rating task that corrects for the cognitive, evaluative, and motor confounds, differed greatly for the two conditions. During epochs when pain was high, activation of the medial prefrontal cortex (mPFC) was most robust, with less activity seen in the amygdala and the ventral striatum. However, for periods when pain was rapidly increasing, the insula, anterior cingulate cortex (ACC), multiple cortical parietal regions, and the cerebellum became activated. In the same study, using the same procedures (continuous ratings of perceived pain and subtraction of a visual control), we identified brain activity in back pain patients and healthy controls for an acute thermal stimulus applied to the back. The results showed no difference between patients and healthy controls for brain regions activated during acute thermal pain stimulation of the back. This activity pattern closely matched brain activity observed in earlier studies regarding acute pain in healthy subjects 3 and was similar also to the activity we observed for spontaneous pain for the contrast of rapidly increasing pain. We also studied two separate groups of CBP patients using two MRI magnets and in both groups identified the mPFC as the primary region activated for high pain. Moreover, in both groups mPFC activity was strongly correlated with pain intensity. Moreover, the insula activity, during the increasing phase of pain, predicted the duration of pain in years. In contrast, anxiety or depression levels were not related to brain activations identified in relation to spontaneous pain. These results imply that spontaneous CBP engages the limbic emotional-mentalizing regions of the brain into a state of continued negative emotions (suffering) regarding the self, punctuated by occasional nociceptive inputs that perpetuate the state. The sustained prefrontal activity is most likely related to the maladaptive psychological and behavioral cost associated with chronic pain.

Essentially the same approach was used to study brain activity for spontaneous pain in PHN patients 25. Overall brain activity for spontaneous pain of PHN involved affective and sensory-discriminative areas (thalamus, primary and secondary somatosensory, insula and anterior cingulate cortices), as well as areas involved in emotion, hedonics, reward, and punishment (ventral striatum, amygdala, orbital frontal cortex, and ventral tegmental area). Thus, in PHN more extensive brain regions are involved in spontaneous pain than in CBP, yet similar limbic and prefrontal regions are also observed for both conditions. PHN is the prototypical neuropathic chronic pain condition as it clearly involves peripheral nerve injury. In contrast, CBP is far more complex a condition and can involve multiple sources of nociceptive inputs, including muscle, fascia, joints, and nerve injury. In fact, the majority of CBP cases are idiopathic—that is, we have no clue concerning the source of the peripheral nociceptive signal. A simple, legitimate question is, why should CBP involve a limited prefrontal/limbic brain activity while PHN encompasses a wider brain circuitry including many areas seen for acute pain?

We now have preliminary results for brain activity for spontaneous pain in a small group of PP patients. The results again indicate an activity pattern quite different from both CBP and PHN. We have yet to understand the underlying processes and parameters that are dictating these diverse brain activations for seemingly similar pain conditions. The PP condition can be thought of as a visceral chronic pain, whereas CBP and PHN are certainly dominantly somatic in origin. Yet, brain imaging studies for acute visceral and somatic pain show very small differences 72. Why are the chronic conditions resulting in such diverse activations? It needs to be emphasized that it is unlikely that these patterns are a result of random sampling of diverse conditions where, depending on the number of patients included, one would observe distinct patterns of brain activity. On the contrary, the activity patterns we observe for each of these conditions, be it CBP, PHN, or PP, seem homogeneous in that the brain activity patterns for each condition are robustly reproducible. For example, we have examined CBP brain activity in three separate studies and using 1.5 T magnet and 3.0 T scanners, and in each case the activity patterns are essentially identical. Moreover, if we subdivide any given group data and compare subgroupings, the activations show very similar results to the whole data set. We have recently reported on brain activity for knee OA 11. The study contrasted spontaneous pain for CBP to knee pressure-induced brain activity for knee OA. OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. There was no brain activity overlap between knee OA and CBP spontaneous pain, which again was mainly associated with mPFC activity. In knee OA we were unable to study spontaneous pain because these patients reported minimal spontaneous pain and even when present this pain was for the most part constant. The source of the brain activity differences between these two groups remains unclear. It may be partially due to the type of pain studied, spontaneous versus knee pressure, and partly due to underlying mechanisms (inflammatory vs. other sources) as well as other sources. Still, the knee OA activity best resembles activity observed for acute pain, and yet when OA and CBP patients are examined using questionnaire-based outcomes, they cannot be differentiated from each other 20.

The issue of brain activity and its dependence on pain modality was directly tested in PHN patients, where we studied spontaneous pain and touch-evoked pain (dynamic tactile allodynia) in the same group of patients 25;27. Essentially the same brain regions were activated for spontaneous and touch-evoked pain. However, within each of the brain regions distinct subportions were associated with each modality, with minimal overlap between the conditions. One worries about cross-contamination of activity from one modality into the other. Yet, we had taken multiple steps to correct for such confounds. Thus, at least in PHN we can state that subtle brain activity differences across the same brain regions can give rise to either perception of spontaneous or touch-evoked pain.

Another important issue that needs highlighting is that across the diverse chronic pain conditions we have characterized (CBP, PHN, OA, and PP), there is a large spectrum of brain activity patterns, with some resembling acute pain more than others; and in all cases limbic and prefrontal cortical activity is observed repeatedly, and especially for the more neuropathic conditions. These observations contradict the standard notion that chronic pain is mainly a consequence of peripheral and spinal cord sensitization, in which case the expected brain activity would simply be an enhancement of activity of brain regions involved in acute pain. Novel activations in limbic and prefrontal cortical regions instead imply that the sensory/emotional construct of the pain is distinct between various chronic pain conditions and that the interaction between pain and emotional and hedonic circuitry must be considered as part of the definition of these pain conditions. Our confidence regarding the importance of activated brain regions in chronic pain stems mainly from correlational analyses, where various clinical parameters were tested as to their relationship to observed brain activity. For example, in CBP we could relate the visual analog scale of back pain intensity on the day of scan to mPFC activity and relate the duration of chronic pain in number of years living with the condition with insular activity. Similarly, limbic brain activity in PHN patients was tightly correlated to questionnaire-based outcomes regarding the neuropathic properties of their pain. Thus, fundamental clinical properties of these chronic pain conditions are strongly tied to the specific brain activity underlying at least spontaneous pain.

15.5. BRAIN ACTIVITY FOR THERAPIES FOR CHRONIC PAIN

As chronic pain remains mostly intractable, its modulation by therapeutic approaches is complicated and hard to tackle in relation to brain activity. However, we have now demonstrated that therapeutic manipulations are a powerful method with which we can at least improve our confidence that observed brain activity is relevant to the conditions being studied, and perhaps even advance new knowledge of the efficacy and route of action for some of these manipulations. Pharmacology-based fMRI has been commented on in the past 15;77. Here we will concentrate on using this tool in manipulating chronic pain. To simplify analysis and minimize contamination of pain-related brain activity with direct drug effects, we have opted to study drugs that for the most part have minimal central effects. Thus, we have used 5% lidocaine patch as our main tool for reducing pain locally. As the patch is applied to the skin, blood levels of lidocaine are small, and thus the effects must be considered primarily local. We have also tested a cox2-inhibitor, which should also be primarily acting on the local inflamed tissue. However, in this case we cannot rule out a spinal cord effect as well.

In a psoriatic arthritis patient whose pain was adequately managed by a cox2-inhibitor, we examined the effects of this drug on pain relief in relation to brain activity 9. The effort was to first demonstrate that single-subject studies of chronic pain are feasible and useful, especially when coupled with drug manipulation. To generate enough data to perform statistical testing the subject was scanned four times, after he had stopped his medication for 24 hours. Then he ingested a single dose of the drug and was scanned again six more times at different time delays from ingestion. Brain activity was determined for joint pressure pain ratings. The brain activity for palpating the painful joints included bilateral insula, thalamus, and secondary somatosensory cortex, as well as contralateral primary somatosensory cortex and mid-anterior cingulate. This activation pattern is very similar to that seen for acute pain in healthy subjects, suggesting that psoriatic pain is akin to acutely activating nociceptors. It is also very similar to the activity in knee OA, although the latter involves more limbic activations as well. Regarding the effects of the cox2-inhibitor, we observed a decrease in joint palpation pain, and this tightly correlated with decreased activity in the insula and secondary somatosensory cortex. This study demonstrates the feasibility of studying effects of a single dose of an analgesic on brain activity for a clinical pain condition in an individual subject. The methodology provides an objective approach that may be used for drug development and testing effects of drugs in individual cases.

We have now reported changes in brain activity with topical lidocaine patch use in CBP, OA, and PHN patients 12;25;27. The main outcome of these studies is the observation that modulation of chronic pain with this manipulation results in decreased brain activity in specific regions, within the set of regions identified as being active for the pain condition studied, providing an additional line of evidence that the identified brain areas are in fact involved in the perception associated with each condition. It should be emphasized that for each of the conditions, a unique set of brain regions were modulated with lidocaine therapy. We think these results point to the critical nodes of the brain circuitry involved in the pain perception for each condition, suggesting that the cognitive/emotional/sensory properties of each condition are unique. From the viewpoint of developing new therapies for these conditions, these differential responses provide clues concerning molecular pathways and neurotransmitters that may be manipulated for each case. The main weakness of these studies is the fact that they were all open-labeled. Thus, we cannot rule out placebo effects. As such, these studies do not really give us new clues as to the efficacy of the treatment. Instead, they provide a tool with which the properties of the brain activations can be explored pharmacologically.

15.6. BRAIN MORPHOLOGICAL CHANGES WITH CHRONIC PAIN

In 2004 we published the first brain morphometric study showing anatomical evidence for brain atrophy in CBP patients 6. This result has now been replicated in CBP and other types of chronic pain conditions 48;65;66. Notably we were able to show that these morphological changes are correlated with the clinical parameters of the condition. Neocortical gray matter volume, after correcting for intracranial volume, age, and sex, was significantly less in CBP patients than in matched controls. Moreover, this parameter showed dependence on pain duration, with similar slopes for patients with and without neuropathic (radicular) back pain, but only significantly for the neuropathic back pain group. When the same data were analyzed to directly compare regional gray matter differences between CBP patients and controls, two brain areas showed the most robust difference: dorsolateral lateral prefrontal cortex (DLPFC) and right thalamus. When we studied the DLPFC further in relationship to clinical parameters, gray matter density was found to be dependent on the presence and type (neuropathic or non-neuropathic) of CBP. Thus, regional gray matter changes are related to pain characteristics, and this pattern is different for neuropathic compared with non-neuropathic types. This dissociation is consistent with extensive clinical data showing that neuropathic pain conditions are more debilitating and have a stronger negative affect 19, and we suggested that this difference is directly attributable to the larger decrease in gray matter density in the DLPFC of neuropathic CBP patients.

We recently reported on gray matter morphological changes in CRPS 26 studied in the same lab using similar imaging and data analysis techniques as we had done in CBP. The results indicate that brain atrophy for the two clinical conditions affect non-overlapping brain regions, and yet in both the changes are correlated with duration and/or intensity of the pain. In the CRPS patients, diffusion tensor imaging (DTI) analyses were used to examine the relationship between gray matter decreased density and white matter connectivity. The study generally indicates that brain regions where gray matter is reduced are also accompanied with a general decrease in white matter connectivity, although in some cases this was also accompanied with target-specific increased connectivity as well. This is the first study linking gray matter changes to white matter properties, and the results are consistent with the general idea of loss of neurons but also suggest that it is a result of competitive reorganization of connectivity across brain regions. More importantly, this study demonstrates the power of combining various brain anatomical imaging techniques to begin to unravel the processes underlying brain reorganization with chronic pain.

15.7. PUTTING ALL THE HUMAN OBSERVATIONS TOGETHER

Above we reviewed cognitive abnormalities, brain activity patterns, and brain morphometry and connectivity changes observed in various chronic pain conditions. To what extent are these observations complementary and inter-related or contradict each other? The brain metabolic study suggested cell loss in the lateral PFC in CBP, and in fact we could observe morphologically that the main brain region showing atrophy in CBP is lateral PFC. Moreover, brain activity in CBP was mainly localized to medial PFC. Given that lateral and medial PFC inhibit each other and functionally compete with each other, the activation in medial PFC may be a consequence of the atrophy in lateral PFC. Both CBP and CRPS show deficits in emotional decision making but with distinct properties. The brain morphological results are consistent with this, as both groups show brain regional atrophy but involving distinct regions. Importantly, in CBP the lateral PFC shows atrophy, but in CRPS the medial PFC shows atrophy. These brain regions compete with each other—the former is associated to cognitive and memory-related tasks, and the latter is linked to emotional and self-related tasks. Perhaps the strongest evidence for consistency across these measures is the extent to which each of them is repeatedly observed to correlate with clinical parameters associated with distinct conditions. Moreover, for the same pharmacological treatment (topical lidocaine), pain relief in distinct chronic pain conditions involves distinct brain regional activity decreases.

15.8. ANIMAL MODELS AND CORRELATES FOR HUMAN CHRONIC PAIN

Animal models advanced over the last 20 years have revolutionized our understanding of chronic pain mechanisms. However, this work has for the most part concentrated on delineating abnormalities in afferent sensory inputs, spinal cord reorganization as a result of neuropathic or inflammatory injury, and changes in descending modulatory circuitry. All of this implicitly assumes that the role of the cortex in such conditions is a passive reflection of events occurring in the spinal cord. The above-reviewed human brain imaging studies, however, indicate an active role of the cortex in the processing of pain. In light of these new findings, and consistent with them, there is a growing literature of animal studies focusing on the full role of the central nervous system in chronic pain.

Recent animal studies show that cortical manipulations can modulate pain behavior [8;37;45;46;67. Results emphasize the role of the insula, anterior cingulate, mPFC, and amygdala in pain, which are limbic structures with strong interconnectivity. Particularly relevant is a study by Johansen and Fields 46 demonstrating that anterior cingulate activity is necessary and sufficient for noxious stimuli to produce an aversive memory, via a glutamate-mediated neuronal activation. Anatomically, the anterior cingulate and mPFC are in close proximity to one another and tightly interconnected. It is possible that the two structures are involved in different phases of acquisition and extinction of pain-related memories. Researchers have also demonstrated that the NR2B component of the n-methyl-D-aspartic acid (NMDA) receptor undergoes transient upregulation within the anterior cingulate in rats following an inflammatory injury, and administration of NR2B receptor-selective antagonists inhibit behavioral responses to peripheral inflammation 80. Two recent studies have further implicated anterior cingulate in contextual fear memory acquisition 52;83, as well as the amygdala and hippocampus, and show NMDA in anterior cingulate is critical for fear acquisition. A similar study examined plasticity of amygdala central nucleus neurons following induction of arthritis and showed that pain-related synaptic plasticity is accompanied by protein kinase A (PKA)-mediated, enhanced NMDA-receptor function and increased phosphorylation of NMDA-receptor 1 (NR1) subunits 14. These results provide solid evidence that NMDA receptors undergo long-term plastic changes in the brain after injury and contribute to persistent pain by changing neuronal activity. Consistent and complementary to these results, we have evidence that rats with neuropathic injury show increased expression of cytokines in the prefrontal cortex and thalamus/striatum 4.

A nagging issue regarding existing animal models of chronic pain remains their correspondences to the human conditions. There are no reliable tests for establishing such correspondences. For example, chronic constriction injury (CCI) or spared nerve injury (SNI) models are equated to human CRPS or CBP by different investigators using arbitrary criteria. One hopes that future animal functional brain imaging studies may provide direct links between the models and human pain conditions. Recent studies have started exploring this issue, using other approaches. An animal model was recently developed to test gambling-like behavior in rodents 58. The paradigm was developed to enable performing rodent studies for emotional decision making, in analogy to the human study where CBP and CRPS patients show impairments 5. As this task requires intact medial PFC in humans, the rodent study examined changes in decision making in healthy animals and in animals with orbital frontal lesions, and demonstrated that the lesion enhances risky behavior in similarity to the human results. Moreover, the authors have preliminary results showing that rodents with inflammatory or neuropathic injuries also exhibit enhanced risky behavior, thus establishing a behavioral correspondence between rodents with persistent pain and human chronic pain patients on emotional decision making. Increased anxiety is an important comorbidity in patients with chronic pain. The first study on its prevalence in rodents with neuropathic injury examined its presence and modulation by morphine and gabapentin 62. Importantly the authors show that some neuropathic models induce anxiety (CCI) but not others (partial sciatic nerve ligation), the implication being that human chronic pain conditions should also be differentiable along anxiety dimension. Other investigators have started differentiating the emotional component of neuropathic pain from its sensory properties 49. Bushnell and colleagues (IASP abstract) recently demonstrated a direct correspondence of brain atrophy in rodents following neuropathic injury, where they tracked brain morphological changes in SNI animals and observed that months after the injury the animals exhibit prefrontal cortex atrophy as well as increased anxiety. We have previously shown that lateral thalamic electrophysiological properties of groups of neighboring neurons show multiple signs of reorganization minutes after a peripheral nerve injury and the process is sustained for the duration of monitoring 16. More recently a study in Martina’s lab demonstrated morphological and electrophysiological reorganization of medial PFC in SNI rats a week following the peripheral injury 54. Although the body of literature is small, important advances are being made in relating the fundamental observations in human chronic pain to animal models. These approaches promise to lay a new foundation for developing objective methods with which human and rodent brain properties can be equated for specific chronic pain conditions.

15.9. NOVEL PHARMACOTHERAPY BASED ON THE ROLE OF THE CORTEX IN CHRONIC PAIN

The human studies regarding spontaneous pain suggest medial PFC and amygdala to be importantly involved in chronic pain, and also imply that lateral PFC atrophy may underlie the enhanced activity in medial PFC. Moreover, the rodent studies suggest that NMDA transmission in the cingulate cortex may play a critical role in neuropathic painlike behavior. These observations provide the notion that D-cycloserine (DCS) may be an antineuropathic drug acting through these cortical sites. We tested this by examining the effects of treatment of neuropathic injured rats with DCS 57. DCS given systemically or centrally enhances cognitive processes 71, improves attention and memory 42;73, and facilitates fear extinction 61;75 through de novo memory trace formation involving NMDA plasticity 21;56;64. We tested the effects of DCS on chronic neuropathic pain behavior, hypothesizing that it should enhance the extinction of pain-related memories and, thus, exhibit antinociceptive properties for neuropathic pain. The main finding was that repeated treatment with DCS, a partial agonist at the strychnine-insensitive glycine-recognition site on the NMDA receptor complex 24, reduces tactile sensitivity and protective paw posturing in rat models of neuropathic pain. This antinociception was dose-dependent and increased in efficacy for up to three weeks. Upon cessation of treatment, DCS effects on pain behavior persisted for a duration proportional to the length of treatment. When antinociception was assessed by measuring changes in mechanical sensitivity, the effect of the treatment was relatively small; however, a much larger effect of DCS treatment was revealed when antinociception was assessed by an operant stimulus avoidance task. Moreover, selective infusions of DCS into mPFC and amygdala (but not the spinal cord, thalamus, insula, or occipital cortices) were antinociceptive and dependent on NMDA receptor availability. We presume that DCS-induced reinforcement of NMDA-receptor mediated transmission within mPFC works to disengage spontaneous pain from its associations previously formed in learning and memory. To our knowledge this is the first drug therapy study directly derived from human brain imaging results, and thus its success reinforces the tenant that the human results can be used to study molecular pathways in rodents for efficacy in chronic pain. The effects of DCS remain to be studied in humans, and until we observe an effect in humans these results remain mostly of theoretical interest.

15.10. TOWARD A NEW THEORY OF CHRONIC PAIN

In light of the above briefly outlined results, chronic pain can no longer be viewed as a pure perceptual state, that is, persistence of pain. Instead it needs to incorporate emotional suffering and related behavioral/cognitive/hedonic modifications that in turn also modify decision making and behavior as a consequence of reorganization of brain circuitry. Overall, the brain activity patterns and the changes in morphology and connectivity show a general picture that more closely resembles the addicted brain and provides no evidence for increased sensory processing of pain. Reorganization and representation primarily involve limbic and prefrontal brain circuitry and minimally impinge on sensory properties of pain. We presume and hypothesize that these changes are a reflection of both the suffering and coping strategies that impinge on learning and memory and on hedonics of everyday experience. The cumulative cost of these behaviors and their specific interaction with peripheral and spinal cord reorganization as a consequence of the specific nociceptive barrage associated with the condition provide a unique cortical imprint for each chronic pain condition, which continues to reorganize due to the dynamics of the interaction of the presence of pain with everyday experiences.

We have proposed a new theory regarding mechanisms of transition to chronic pain based on the interaction between pain and memory, and based on the accumulating evidence of circuits involved or reorganized with distinct chronic pain conditions [1;2]: we argue that the state of the brain’s emotional and motivational circuitry determines the suffering of chronic pain. Emotional suffering with chronic pain is manifested by increased anxiety, depression, and dramatically reduced quality of life, as well as cognitive and behavioral impairments. Clinicians treating chronic pain patients commonly observe that this suffering is maintained even when the intensity of chronic pain is reduced by therapies. It is also a common observation that patients complain far more, and in disproportion to the pain intensity, about the emotional load associated with chronic pain. Moreover, in many cases the emotional suffering is maintained even though the peripheral signs of the injury, and thus a source of nociceptive activity, have long disappeared. Furthermore, there is ample evidence that drugs that are highly effective in treating acute pain, like aspirin and opiates, show little or no effect on treating chronic pain. Non-invasive human brain imaging studies have provided the opportunity to directly peer into the brain of chronic pain patients. These studies show no evidence of increased nociceptive representation but rather point to enhanced activity in the emotional and motivational cortical-limbic circuitry. Therefore, we theorize that identifying and manipulating processes underlying the emotional suffering (cortical-limbic circuitry) should be more successful in treating chronic pain than the standard approaches that have been tested for decades and that have concentrated on the source of nociceptive signals in the skin and spinal cord.

Since the work of Pavlov it has been known that pain is a potent stimulus for creating memories. It induces single-event learning, and associated memories can last for the rest of one’s life. These properties have been used in the field of learning and memory for more than 100 years. Surprisingly they have had little impact on pain research. The human brain imaging studies also point to reorganization of cortical-limbic circuitry that seems specific for distinct chronic pain conditions. Hence the suffering of chronic pain is likely the consequence of plastic changes in cortical-limbic processing leading to new learning and memories that are mediated through emotional and motivational associations with the persistent pain. Regarding the involvement of cortico-limbic circuits in behavior we adopt the strong position, best formulated by E. Rolls 63, stating: “operation of the brain to evaluate rewards and punishers is the fundamental solution of the brain to interfacing sensory systems to action selection and execution systems.” Thus, we conclude that the reorganization of this circuitry in chronic pain affects emotions, decisions, and behavior.

Given our theoretical position we suggest that translational studies should be targeted to these novel mechanisms:

1.

New drug development for chronic pain conditions should be based on the processes/pathways/molecules derived directly from human data (top-down translational approach based on brain imaging).

2.

The tight relationship between pain and learning suggests that circuits involved in such processes are candidate targets that can be studied as to their role in chronic pain, and in an effort to explore new therapies.

3.

Even though there are growing human brain imaging and animal model results showing either disruption or involvement of brain learning circuitry in specific chronic pain conditions, all of such studies have explored the brain after chronic pain was established. Therefore, there is a dire need for studies exploring mechanisms and circuits for the transition to chronic pain.

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