The Emotional Brain as a Predictor and Amplifier of Chronic Pain.

Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain-that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances.

Resting-sate functional reorganization of the rat limbic system following neuropathic injury.

Human brain imaging studies from various clinical cohorts show that chronic pain is associated with large-scale brain functional and morphological reorganization. However, how the rat whole-brain network is topologically reorganized to support persistent pain-like behavior following neuropathic injury remains unknown. Here we compare resting state fMRI functional connectivity-based whole-brain network properties between rats receiving spared nerve injury (SNI) vs. sham injury, at 5 days (n = 11 SNI; n = 12 sham) and 28 days (n = 11 SNI; n = 12 sham) post-injury. Similar to the human, the rat brain topological properties exhibited small world features and did not differ between SNI and sham. Local neural networks in SNI animals showed minimal disruption at day 5, and more extensive reorganization at day 28 post-injury. Twenty-eight days after SNI, functional connection changes were localized mainly to within the limbic system, as well as between the limbic and nociceptive systems. No connectivity changes were observed within the nociceptive network. Furthermore, these changes were lateralized and in proportion to the tactile allodynia exhibited by SNI animals. The findings establish that SNI is primarily associated with altered information transfer of limbic regions and provides a novel translational framework for understanding brain functional reorganization in response to a persistent neuropathic injury.

Chronic pain: the role of learning and brain plasticity.

Based on theoretical considerations and recent observations, we argue that continued suffering of chronic pain is critically dependent on the state of motivational and emotional mesolimbic-prefrontal circuitry of the brain. The plastic changes that occur within this circuitry in relation to nociceptive inputs dictate the transition to chronic pain, rendering the pain less somatic and more affective in nature. This theoretical construct is a strong departure from the traditional scientific view of pain, which has focused on encoding and representation of nociceptive signals. We argue that the definition of chronic pain can be recast, within the associative learning and valuation concept, as an inability to extinguish the associated memory trace, implying that supraspinal/cortical manipulations may be a more fruitful venue for adequately modulating suffering and related behavior for chronic pain. We briefly review the evidence generated to date for the proposed model and emphasize that the details of underlying mechanisms remain to be expounded.

Linking human brain local activity fluctuations to structural and functional network architectures.

Activity of cortical local neuronal populations fluctuates continuously, and a large proportion of these fluctuations are shared across populations of neurons. Here we seek organizational rules that link these two phenomena. Using neuronal activity, as identified by functional MRI (fMRI) and for a given voxel or brain region, we derive a single measure of full bandwidth brain-oxygenation-level-dependent (BOLD) fluctuations by calculating the slope, α, for the log-linear power spectrum. For the same voxel or region, we also measure the temporal coherence of its fluctuations to other voxels or regions, based on exceeding a given threshold, Θ, for zero lag correlation, establishing functional connectivity between pairs of neuronal populations. From resting state fMRI, we calculated whole-brain group-averaged maps for α and for functional connectivity. Both maps showed similar spatial organization, with a correlation coefficient of 0.75 between the two parameters across all brain voxels, as well as variability with hodology. A computational model replicated the main results, suggesting that synaptic low-pass filtering can account for these interrelationships. We also investigated the relationship between α and structural connectivity, as determined by diffusion tensor imaging-based tractography. We observe that the correlation between α and connectivity depends on attentional state; specifically, α correlated more highly to structural connectivity during rest than while attending to a task. Overall, these results provide global rules for the dynamics between frequency characteristics of local brain activity and the architecture of underlying brain networks.

Parsing pain perception between nociceptive representation and magnitude estimation.

Assessing the size of objects rapidly and accurately clearly has survival value. A central multisensory module for subjective magnitude assessment is therefore highly likely, suggested by psychophysical studies, and proposed on theoretical grounds. Given that pain perception is fundamentally an assessment of stimulus intensity, it must necessarily engage such a central module. Accordingly, we compared functional magnetic resonance imaging (fMRI) activity of pain magnitude ratings to matched visual magnitude ratings in 14 subjects. We show that brain activations segregate into two groups, one preferentially activated for pain and another equally activated for both visual and pain magnitude ratings. The properties of regions in the first group were consistent with encoding nociception, whereas those in the second group with attention and task control. Insular cortex responses similarly segregated to a pain-specific area and an area (extending to the lateral prefrontal cortex) conjointly representing perceived magnitudes for pain and vision. These two insular areas were differentiated by their relationship to task variance, ability to encode perceived magnitudes for each stimulus epoch, temporal delay differences, and brain intrinsic functional connectivity. In a second group of subjects (n=11) we contrasted diffusion tensor imaging-based white matter connectivity for these two insular areas and observed anatomical connectivity closely corresponding to the functional connectivity identified with fMRI. These results demonstrate that pain perception is due to the transformation of nociceptive representation into subjective magnitude assessment within the insula. Moreover, we argue that we have identified a multisensory cortical area for "how much" complementary and analogous to the "where" and "what" as described for central visual processing.

Brain dynamics for perception of tactile allodynia (touch-induced pain) in postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a debilitating chronic pain condition often accompanied by a sensation of pain when the affected region is touched (tactile allodynia). Here we identify brain regions involved in stimulus-induced touch-evoked pain (dynamical mechanical allodynia, DMA), compare brain activity between DMA and spontaneous pain (described earlier for the same patients in [Geha PY, Baliki MN, Chialvo DR, Harden RN, Paice JA, Apkarian AV. Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 2007;128:88-100]), delineate regions that specifically code the magnitude of perceived allodynia, and show the transformation of allodynia-related information in the brain as a time-evolving network. Eleven PHN patients were studied for DMA and its modulation with Lidoderm therapy (patches of 5% lidocaine applied to the PHN affected body part). Continuous ratings of pain while the affected body part was brushed during fMRI were contrasted with non-painful touch when brushing was applied to an equivalent opposite body site, and with fluctuations of a bar observed during scanning, at three sessions relative to Lidoderm treatment. Lidoderm treatment did not decrease DMA ratings but did decrease spontaneous pain. Multiple brain areas showed preferential activity for allodynia. However, mainly responses in the bilateral putamen and left medial temporal gyrus were related to the magnitude of allodynia. Both DMA and spontaneous pain perceptions were best represented within the same sub-cortical structures but with minimal overlap, implying that PHN pain modulates behavioral learning and hedonics. These results have important clinical implications regarding adequate therapy.

Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy.

Postherpetic neuralgia (PHN) is a debilitating chronic pain condition, yet there is a lack of knowledge regarding underlying brain activity. Here we identify brain regions involved in spontaneous pain of PHN (n=11) and determine its modulation with Lidoderm therapy (patches of 5% lidocaine applied to the PHN affected body part). Continuous ratings of fluctuations of spontaneous pain during fMRI were contrasted to ratings of fluctuations of a bar observed during scanning, at three sessions: (1) pre-treatment baseline, (2) after 6h of Lidoderm treatment, and (3) after 2 weeks of Lidoderm use. 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. Generally, these activations decreased at sessions 2 and 3, except right anterior insular activity which increased with treatment. The sensory and affective activations only responded to the short-term treatment (6h of Lidoderm); while the ventral striatum and amygdala (reward-related regions) decreased mainly with longer-term treatment (2 weeks of Lidoderm). Pain properties: average magnitude of spontaneous pain, and responses on Neuropathic Pain Scale (NPS), decreased with treatment. The ventral striatal and amygdala activity best reflected changes in NPS, which was modulated only with longer-term treatment. The results show a specific brain activity pattern for PHN spontaneous pain, and implicate areas involved in emotions and reward as best reflecting changes in pain with treatment.

Single subject pharmacological-MRI (phMRI) study: modulation of brain activity of psoriatic arthritis pain by cyclooxygenase-2 inhibitor.

We use fMRI to examine brain activity for pain elicited by palpating joints in a single patient suffering from psoriatic arthritis. Changes in these responses are documented when the patient ingested a single dose of a selective cyclooxygenase-2 inhibitor (COX-2i). We show that mechanical stimulation of the painful joints exhibited a cortical activity pattern similar to that reported for acute pain, with activity primarily localized to the thalamus, insular, primary and secondary somatosensory cortices and the mid anterior cingulum. COX-2i resulted in significant decreased in reported pain intensity and in brain activity after 1 hour of administration. The anterior insula and SII correlated with pain intensity, however no central activation site for the drug was detected. We demonstrate the similarity of the activation pattern for palpating painful joints to brain activity in normal subjects in response to thermal painful stimuli, by performing a spatial conjunction analysis between these maps, where overlap is observed in the insula, thalamus, secondary somatosensory cortex, and anterior cingulate. The results demonstrate that one can study effects of pharmacological manipulations in a single subject where the brain activity for a clinical condition is delineated and its modulation by COX-2i demonstrated. This approach may have diagnostic and prognostic utility.

Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat.

Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. Several groups of rats were subjected to mononeuropathy following the spared nerve injury model, known to produce evident tactile and cold allodynia and heat hyperalgesia. The activity of the ventrolateral orbital areas was selectively blocked by using either chronic or acute injection of lidocaine, electrolytic lesion, or chemical lesion with kainic acid or 6-hydroxydopamine (6-OHDA). The effects of these manipulations were compared with those following lesion of the somatic sensorimotor cortical areas. Local injection of lidocaine resulted in a reversible depression of all neuropathic manifestations while electrolytic or chemical lesions elicited transient attenuation affecting mainly the heat hyperalgesia and to a lesser extent the cold allodynia. The magnitude of the observed effects with the different procedures used can be ranked as follows: 6-OHDA

The role of the dorsal columns in neuropathic behavior: evidence for plasticity and non-specificity.

Despite conflicting clinical and experimental evidence, textbook description of somatic sensations continues to follow a rigid dichotomy based on the concept that pain sensation is transmitted cephalad primarily through anterolateral pathways, while touch is mediated through the dorsal column pathway. This study provides an example of the dynamic rerouting in the transmission of the nociceptive signals following injuries to the peripheral and central processes of sensory neurons. In two rat models for mononeuropathy, the chronic constriction injury model [Bennett, G.J., Xie, Y.K., Pain 33 (1988) 87-107] and the spared nerve injury model [Decosterd, I., Woolf, C.J., Pain 87 (2000) 149-158], we demonstrate that selective dorsal columns lesion produced significant decrease of tactile and cold allodynias and thermal hyperalgesia which were assessed by the Von Frey hair filaments, the acetone drop test and the heat-induced paw withdrawal, respectively. These manifestations, however, can reappear 2 weeks after bilateral dorsal column lesion in rats subjected to spared nerve injury mononeuropathy and appear also in animals sustaining chronic bilateral dorsal column lesion followed by either model of mononeuropathy. Lesion of the dorsal column on the side opposite to the neuropathic leg did not alter the neuropathic manifestations in both animal models. Changes in the sequence of timing of the dorsal column lesion and induction of mononeuropathy, suggest that the effects of the former last for 1 to 2 weeks. The results of this study show that the dorsal columns are involved in neuropathic manifestations and at the same time are not necessary for their full development and persistence. Furthermore, these results shade doubts on the validity of the concept of segregation of pathways involved in the transmission of neuropathic manifestations. Therefore, principles governing acute pain transmission are not necessarily applicable to chronic pain situations. The latter conditions seem to engage other available pathways to reestablish the pain signaling system.

Attenuation of neuropathic pain by segmental and supraspinal activation of the dorsal column system in awake rats.

In addition to its involvement in the transmission of neuropathic pain, the dorsal column system has been shown to have analgesic effects when electrically stimulated. The segmental or supraspinal origin of the analgesia, however, has not been clearly delineated. The aim of this study is to demonstrate the contribution of supraspinal mechanisms to the inhibition of allodynia and hyperalgesia in two different rat models of mononeuropathy. Mononeuropathy was induced, under deep anesthesia, in several groups of rats (n=7 each) following either the chronic constriction injury or the spared nerve injury model. Mechanical and cold allodynia were assessed by the Von Frey monofilaments and by the acetone drop test, respectively. Thermal hyperalgesia was assessed by the paw withdrawal and hot plate tests. Bipolar electrodes for dorsal column stimulation were implanted chronically in all rats on the dorsal aspect of the medulla at the level of the obex. Selective dorsal column bilateral lesions were performed at the upper cervical level in some groups of rats. Dorsal column nuclear stimulation, rostral to selective dorsal spinal lesions, produced strong inhibitory effects on the allodynia and hyperalgesia observed in both models of mononeuropathy. These effects were comparable to those observed following similar stimulations in rats with an intact spinal cord. Our results demonstrate strong inhibitory effects of dorsal column stimulation on neuropathic pain. This inhibition can be attributed to the activation of brainstem pain-modulating centers via rostral projections of the dorsal column nuclei.

A perfusion technique for the determination of pro-inflammatory mediators induced by intradental application of irritants.

INTRODUCTION: Several morphological and functional features contribute to the consideration of the tooth as a separate compartment having special type of innervation and special immune mechanisms. This study describes a new method allowing the intradental perfusion of rat incisors for the in vivo assessment of pulpal reaction to inflammatory agents. METHODS: Under deep anesthesia, the distal 2-3 mm of each of the rat lower incisors was cut and wrapped in a polyethylene tubing connected to a perfusion chamber made of tigone tubing (ID 1/8 in., volume 100-150 microl). Several groups of rats (n=5 each) were used for intradental application of either saline, capsaicin (100 microg in 100 microl), or endotoxin (ET, 20 microg in 100 microl) for a period of 40 min followed by filling the tooth chamber with saline and collecting the perfusate every 40 min for a period of 8 h. The collected perfusates were stored at -70 degrees C for subsequent determination of the concentration of prostaglandin E(2) (PGE(2)) and nerve growth factor (NGF) by enzyme-linked immunosorbent assay (ELISA). RESULTS: Dentinal injury produced a moderate increase in the levels of NGF and PGE(2) in incisors perfused with saline. Application of ET or capsaicin, however, produced a highly significant increase in the levels of both mediators. These effects peaked at 1.5-3 h for PGE(2) and at 5 h for NGF. Capsaicin showed the most significant effects. DISCUSSION: The reported results cannot be attributed to any factor other than the inflammation of the incisor's pulp, because the described chamber does not allow any spread or leak of the applied irritants. Further studies using other reagents can allow the determination of the variation of the levels of the various pro-inflammatory mediators and their modulation by treatment with anti-inflammatory drugs.