Laterality of Pain Representation

Many nociceptive pathways are bilateral, but the spinothalamic pathway is mainly contralateral, and its ipsilateral component becomes smaller from rats to monkeys (see Chapter 12). Generally, brain imaging studies of pain show bilateral activity in S2 and the IC and contralateral activity in S1. Activity in the ACC seems predominantly contralateral, although this is hard to quantify given its midline location. Coghill and colleagues (see Fig. 7-4) found that for low-intensity stimuli, activity that is dependent on stimulus intensity is mainly contralateral whereas activity that is not correlated with stimulus intensity is mainly right brain dominant. Still, regardless of whether the stimulus intensity is high or low, humans have little difficulty identifying the body side where a painful stimulus is applied. It is remarkable that although IC activity, as observed in human brain imaging studies, is almost always bilateral, stimulation within the IC evokes pain sensations that are mostly contralateral for body and trunk sensations and more bilateral for facial sensations (Mazzola et al 2009). It therefore seems that the IC and perhaps the S1 cortex are the best candidates for detecting the laterality of a painful stimulus since these cortical structures show laterality of activity for evoked sensations, have a somatotopic organization, and are thought to be important in untangling the sensory-discriminative aspects of pain.

Distinct Brain Responses to Nociception and to Subjective Perceived Pain

A recent study examined discrimination between stimulus localization and stimulus intensity to subdivide the brain areas related to acute pain (Oshiro et al 2009) and advance the exciting notion that pain, similar to vision and audition, may also consist of a ventral, in this case intensity-coding, stream terminating in the IC and a dorsal, spatial localization stream. A number of studies have now emphasized the need to identify brain activity relative to the subjective perception of pain (Davis et al 2002, Lorenz et al 2002, Giesecke et al 2004, Kwan et al 2005, Mazzola et al 2009). After all, the brain should reflect perception, and in fact the classic view has been that even peripheral primary afferent nociceptors show close correspondence in their stimulus–response curves to the psychophysical power function for pain. A study by Baliki and associates (2009) differentiated between perceived pain and stimulus representation for thermal painful stimuli and demonstrated that the part of the IC in contiguity with more dorsal cortex best related to the perceived subjective magnitude of acute pain; surprisingly, the same region encoded just as faithfully magnitudes for rating sizes of bars presented visually. Thus, although this part of the IC reflects subjective pain best, it is a multimodal area that might distill magnitude information for various sensory modalities. The study also demonstrated a 1:1 correspondence between activity in this region and ratings of perceived pain for each and every stimulus across all subjects, thus showing that the region responds proportionally every time that a subject reports perception of pain. Relative to subjective rating of perceived pain, IC responses could be divided into two regions—nociceptive and pain-perceptive regions—with each showing distinct anatomical connectivity as determined by diffusion tensor imaging (Baliki et al 2009; also see Craig 2009 for a review of insula function).

Temporal Sequence of Cortical Activity during Pain Perception

Most information about the temporal sequence of pain-evoked brain activation comes from EEG or MEG studies. The dual pain sensation elicited by a single brief painful stimulus that is due to the different conduction times in nociceptive A and C fibers (about a 1-second difference) is reflected in two sequential brain activations on EEG and MEG recordings from the S1, S2, and ACC (Bromm and Treede 1983, Arendt-Nielsen 1990, Bragard et al 1996, Magerl et al 1999, Opsommer et al 2001, Ploner et al 2002, Tran et al 2002, Iannetti et al 2003). EEG mapping studies (Kunde and Treede 1993, Miyazaki et al 1994), source analysis (Tarkka and Treede 1993, Valeriani et al 1996, Ploner et al 1999), and intracranial recordings (Lenz et al 1998, Frot et al 1999) show that the earliest pain-induced brain activity originates in the vicinity of S2. In contrast, tactile stimuli activate this region only after processing in S1 (Ploner et al 2000). The adjacent dorsal IC is activated slightly but significantly later than the operculum (Frot and Mauguiere 2003). These observations support the suggestion derived from anatomical studies that the S2 region and adjacent IC are primary receiving areas for nociceptive input to the brain (Apkarian and Shi 1994, Craig 2002, Dum et al 2009). Another study has shown that brief painful stimuli evoke sustained cortical activity corresponding to sustained pain perception. The time courses of activation disclosed that the first pain was particularly related to activation of S1 whereas the second pain was closely related to activation of the ACC. Both sensations were associated with S2 activation. These results are interpreted in view of the different biological functions of the first and second pain. The first pain signals threat and provides precise sensory information for immediate withdrawal, whereas the second pain attracts longer-lasting attention and motivates behavioral responses to limit injury and optimize recovery (Ploner et al 2002). An MEG study by Maihofner and colleagues (2002) differentiated between brain regions involved in cold perception from those involved in painful cold. Cold perception resulted in activity in the posterior IC with a mean peak latency of 190 msec for contralateral and 240 msec for ipsilateral insular activity. Noxious cold stimulation initially activated the IC in the same latency ranges as innocuous cold stimuli. Additionally, activations were found in the contralateral and ipsilateral S2 areas (peak latencies of 304 ± 22.7 and 310.1 ± 19.4 msec, respectively), and more variable activation was found in the cingulate cortex. Neither cold nor painful cold produced detectable activation of S1. The results suggest different processing of cold, painful cold, and touch in the human brain.

Temporal differences in brain activity for pain have also been studied by blood flow techniques. Casey and associates (2001) showed that the brain activity pattern for a repetitive thermal painful stimulus is different depending on the past history. When the brain was imaged immediately after the start of the pain, the authors observed very different brain regional responses than when the scan began after the pain had been present for 40 seconds. Perceptually, participants perceived the ongoing pain as more intense and unpleasant than the same stimulus at its onset. A number of brain regions increased in activity between early and late scans (e.g., contralateral S1, bilateral S2, parts of the IC and thalamus). Other brain regions were active only in the early stimulation scans (e.g., perigenual ACC, PFC, and anterior IC). The full significance of these differences remains unclear, although these results undoubtedly imply that the temporal dynamics of brain activity should be taken into consideration to understand the role of the brain circuitry in pain perception. More recently, fMRI has been used to examine the temporal sequence of brain activity for acute thermal pain (Baliki et al 2009; see also Apkarian et al 2011), and the authors could chart transfer of brain regional information as noxious stimuli are converted to perceived pain. The analysis showed that parts of the ACC and amygdala responded in a predictive pattern; the thalamus, basal ganglia, part of the IC, and the supplementary motor region were activated next, and these regions better related to the stimulus; and the perception-related part of the IC was activated last, together with the higher cognitive frontal and parietal regions (Fig. 7-5). Thus there seems to be a well-organized temporal sequence of brain activity that transforms noxious stimulus parameters to pain perception, even to pain relief (for more details see also Apkarian et al 2011).

Opiates in the Brain

Opiate responses in the human brain have been studied by two approaches: examination of brain metabolic function in response to pharmacological agents and direct measurement of receptors, whether static or before and after various challenges. The latter involves the use of radiolabeled pharmaceuticals introduced at tracer doses. Acquisition of data over time, as the radiotracer binds to specific receptor sites, together with appropriate kinetic models, allows quantification of receptor sites and enzyme function in human subjects with PET or SPECT. Exogenous administration of μ-opioid receptor agonist drugs has been shown to dose dependently increase metabolic activity in regions rich in μ-opioid receptors, such as the ACC, PFC, thalamus, basal ganglia, and amygdala (Firestone et al 1996, Schlaepfer et al 1998, Wagner et al 2001, Wise et al 2002, 2004, Pattinson et al 2007). The effects of the μ-opioid agonist fentanyl on regional cerebral blood flow (rCBF) after pain-related activation in the brain have also been explored. Using painful cold with or without fentanyl, Casey and colleagues (2000) showed that the increases in rCBF elicited by the stimulus were prominently reduced by the μ-opioid agonist in most regions, thus confirming an inhibitory effect of fentanyl on measures of pain-induced neuronal activity. Other studies have confirmed the effects of the μ-opioid agonist remifentanil on pain-evoked cortical activity in the ACC and IC (Petrovic et al 2002, Wise et al 2002, 2004).

Dynamic changes in the activity of the endogenous opioid system and μ-opioid receptors have also been examined by using a combination of a selective μ-opioid radiotracer, [¹¹C]carfentanil, and models of sustained muscular or cutaneous pain in healthy subjects (Zubieta et al 2001, Bencherif et al 2002, Zubieta et al 2003, Wager et al 2007). Reductions in the in vivo availability of μ-opioid receptors, reflecting activation of this neurotransmitter system, were observed in the ACC, PFC, IC, thalamus, ventral basal ganglia (nucleus accumbens and ventral pallidum), amygdala, and PAG. Activation of certain elements of this neurotransmitter system was also linearly correlated with suppression of the sensory and affective qualities of the pain, as rated by the volunteers (Zubieta et al 2001). An area within the dorsal ACC was uniquely associated with suppression of the affective quality of pain, and this same region has been implicated in the representation of pain affect (Rainville et al 1997). These findings confirm the widespread involvement of μ-opioid receptors in regulation of the experience of pain, including not only areas involved in descending inhibition (PAG, thalamus, and amygdala) but also areas probably involved in more complex functions such as assessment of stimulus salience, as well as affective and integrative aspects of the pain experience (e.g., ventral basal ganglia, IC, ACC, and PFC). Furthermore, substantial interindividual differences have been observed in both receptor-binding levels and the magnitude of activation of this neurotransmitter system, and recent evidence suggests that the brain opiate system may be altered in some chronic pain patients (see later).

An additional contribution to variability in μ-opioid receptor binding and the capacity to activate this neurotransmitter system in response to sustained pain has been described as a function of a common polymorphism of the catechol O-methyltransferase (COMT) enzyme. Substitution of valine (Val) by methionine (Met) at codon 158 of the COMT gene is associated with a three-fold to four-fold reduction in the capacity to metabolize catecholamines (e.g., noradrenaline and dopamine). The alleles are co-dominant, which results in the lowest COMT function in Met homozygous individuals, highest in Val homozygotes, and intermediate in heterozygotes. These alterations in catecholaminergic neurotransmission result in downstream changes in the capacity to activate responses of the μ-opioid system to sustained pain, with the lowest function in Met/Met, intermediate in Met/Val, and highest in Val/Val subjects. Furthermore, there appear to be compensatory changes in μ-opioid receptor binding in opposite directions (Zubieta et al 2003). Aside from the importance of this work in understanding interindividual variations in the regulation of pain, it also describes a point of interaction between neurotransmitter systems, such as the catecholaminergic and opioidergic systems, involved in responses to stress, salient stimuli, and reward with pain regulatory mechanisms. These interactions are observed at the level of dopaminergic pathways, such as the ventral basal ganglia and anterior cortical regions, but also in areas with prominent noradrenergic innervation, such as the thalamus.

Dopamine and Pain

Although brain dopamine is best known for its role in pleasure, motivation, and motor control, there is now substantial evidence that it also plays a role in pain modulation. Animal studies involving either electrical stimulation of dopaminergic structures, such as the striatum, nucleus accumbens, or ventral tegmental area, or administration of compounds that increase synaptic levels of dopamine, such as dopamine reuptake inhibitors, show that increased dopaminergic activity attenuates nocifensive behavior in animals (Chudler and Dong 1995, Altier and Stewart 1999, Magnusson and Fisher 2000). On the other hand, deactivation of dopaminergic structures leads to hyperalgesia in animals (Saade et al 1997, Magnusson and Martin 2002, Chudler and Lu 2008). Using competitive binding PET methods and the dopamine D₂/D₃ radiotracer [¹¹C]raclopride with sustained muscular pain, studies have shown that healthy individuals release dopamine in the striatum in response to pain (Scott et al 2006, Wood et al 2007b). These and other human PET studies indicate that the binding potential of [¹¹C]raclopride in healthy subjects is related to their pain sensitivity (Hagelberg et al 2002, 2004, Pertovaara et al 2004, Martikainen et al 2005, Scott et al 2006, Wood et al 2007b). Together, this evidence suggests that one role of striatal dopamine is pain regulation. Recent evidence suggests that some chronic pain states may be associated with altered dopaminergic neurotransmission, as detailed later in this chapter.

Mechanisms Underlying Psychological Modulation of Pain

Attentional and emotional factors are known to modulate pain perception in the clinic and in the laboratory (Beydoun et al 1993, Villemure and Bushnell 2002, Roy et al 2008). Nevertheless, the mechanisms underlying such modulation have been difficult to explore in animal studies. The advent of human brain imaging provided an important new avenue for deciphering the neural basis of psychological modulation of pain. In recent years, brain imaging experiments have explored the mechanisms underlying attentional and emotional modulation of pain, as well as activity related to the expectation of pain and placebo analgesia.

Cerebral Processing of Clinical Pain

Several methods have been used to examine the processing of clinical pain. Brain activation associated with ongoing pain without experimental provocation has been investigated with CBF PET studies (Di Piero et al 1991, Hsieh et al 1995). Spontaneous fluctuations in ongoing pain have been exploited with fMRI (Apkarian et al 2001, Baliki et al 2006), and other studies have provoked pain typical for certain clinical conditions, such as dynamic mechanical allodynia and static mechanical hyperalgesia in the case of neuropathic pain (Petrovic et al 1999, Peyron et al 2004, Maihofner et al 2005, Schweinhardt et al 2006), to examine processing of clinical pain. All these different approaches have shown that brain activation associated with clinical pain states overlaps with areas that process acute pain stimuli. Nevertheless, differences are observed for clinical pain and can be grouped broadly into three categories. (1) S1 and S2 are less consistently activated (Apkarian et al 2005), perhaps particularly in the case of ongoing pain (Hsieh et al 1995), which might imply that sensory discrimination is less pronounced for ongoing pain than for brief stimuli. (2) Some brain areas exhibit increased activation (Apkarian et al 2005, Tillisch et al 2010). Baliki and colleagues (2006) used an interesting approach in analyzing patients with chronic low back pain that helped in understanding the engagement of additional forebrain areas in clinical pain: when activations present during periods of rapidly increasing pain were statistically separated from periods of sustained high-level pain, activations associated with the rapid increases in pain were similar to those observed in healthy people during acute pain. Conversely, a different brain circuit was engaged that involved the PFC and amygdala during periods of high sustained pain. The finding of more frequent PFC activation with clinical pain than with experimental pain had been shown previously in a meta-analysis (Apkarian et al 2005), and increased amygdala activation was recently corroborated in a meta-analysis of rectal distention in patients with irritable bowel syndrome (IBS) (Tillisch et al 2010) (Fig. 7-8). The same meta-analysis also found brain stem structures to more frequently be activated in IBS patients than in controls (Tillisch et al 2010) (see Fig. 7-8). In view of the importance of the PFC for higher-order processing, increased prefrontal activation is likely to reflect the more elaborated emotional and cognitive states associated with clinical pain than with experimental pain (Apkarian et al 2005). Moreover, as outlined earlier, the PFC plays an important role in pain modulation, in particular, in mediating the pain modulatory effects of psychological states. Therefore, increased prefrontal activation could also reflect increased engagement of pain facilitatory or inhibitory circuits, depending on the exact area. In the case of IBS and potentially other functional pain syndromes, increased amygdala activation might reflect a contribution of arousal and emotion circuitry to pain amplification, which could be manifested by more prominent brain stem activation (Tillisch et al 2010). (3) Thalamic activation is decreased. Chronic pain conditions are often accompanied by reduced spontaneous activity in the thalamus and an associated abnormal burst discharge (Gucer et al 1978, Hirayama et al 1989, Lenz et al 1989). PET studies show areas of reduced thalamic perfusion that spatially correspond to the electrophysiological changes (Di Piero et al 1991, Hsieh et al 1995, Iadarola et al 1995, Peyron et al 1995, Duncan et al 1998). Reversal of thalamic hypoperfusion with successful pain relief has been described in patients with cancer pain (Di Piero et al 1991) and various neuropathic pain conditions (Hsieh et al 1995, Iadarola et al 1995, Peyron et al 1995, Duncan et al 1998). In the case of neuropathic pain, decreased spontaneous activity in the thalamus is consistent with deafferentation of the somatosensory system, and it is therefore not straightforward to establish any pain-relevant pathophysiology of decreased thalamic activity. However, a clever study of a patient with Wallenberg’s syndrome allowed differentiation of deafferentation and pain (Garcia-Larrea et al 2006) and showed that thalamic hypoactivity contralateral to the pain did not merely reflect deafferentation but appeared to be related to pain pathophysiology. In addition, it is intriguing to note that thalamic hypoperfusion has been observed in patients with fibromyalgia (reviewed by Williams and Gracely 2006), which is not linked to deafferentation.

Cerebral Processing of Experimental Pain in Chronic Pain States

Instead of imaging brain activation associated with clinical pain, it would be more practical in many instances to use acute experimental stimuli to probe the pain-processing circuitry in patients with chronic pain. Such studies have been performed predominantly in patients with so-called functional pain syndromes, including fibromyalgia, IBS, and vulvovestibulitis. In line with the generalized hyperalgesia that is observed in many of these patients, activation of pain-processing regions is typically increased when stimuli are used that are of the same intensity as in the healthy control group (e.g., Verne et al 2003, Cook et al 2004, Giesecke et al 2004, Pukall et al 2005). Increased brain activation indicates that the nociceptive signal is amplified somewhere along the pain transmission pathways, although it does not pinpoint the mechanism of amplification. In an interesting study, Lawal and colleagues (2006) found enhanced activation even in response to subliminal esophageal stimulation in IBS patients, perhaps suggesting that at least part of the amplification is related to non-psychological factors. When the perceived intensity is equated between patients and controls rather than stimulus intensity, brain activation is not generally different in patients (Giesecke et al 2004). In conclusion, the enhanced brain activation in response to experimental pain stimuli confirms patients’ reports of increased pain sensitivity. In the next section, studies are presented that provide more specific information on how altered cerebral pain modulation might amplify the processing and experience of pain.

Evidence for Altered Supraspinal Pain Modulation in Clinical Pain

The idea that faulty supraspinal pain modulatory circuitry contributes to clinical pain has become increasingly popular in recent years, perhaps also because in many instances a mismatch between perceived pain intensity and objectifiable (peripheral) disease cannot be resolved with current diagnostic tools. Although animal data provide strong evidence for an altered balance between endogenous pain inhibition and facilitation, data in humans are still relatively scarce. As discussed in detail in Chapter 8, the central nervous system (CNS) can augment pain processing through increased facilitation or decreased inhibition. It is well known from the animal literature that pathways that modulate ascending nociceptive signals descend from the brain stem to the spinal cord (Fields and Heinricher 1985, Porreca et al 2002). Consequently, the brain stem has received much attention in human pain imaging studies in recent years. A study in healthy volunteers in whom sensitization to punctuate stimuli was achieved by capsaicin injection provided evidence that the brain stem is also involved in pain facilitation in humans (Lee et al 2008). Evidence in patients comes from a study of individuals with painful hip osteoarthritis (Gwilym et al 2009). Patients rated punctuate stimuli as “sharper” when applied to the lateral aspect of the thigh (i.e., in an area of spinal convergence with sensory innervation of the hip joint). Increased activation in response to the punctuate stimuli was observed in the ACC, dorsolateral PFC, and PAG. The magnitude of PAG activation correlated with the degree of patients’ neuropathic pain symptoms (Fig. 7-9), as measured by the PainDETECT questionnaire. Thus, this study provides evidence that brain stem mechanisms might play a role in neuropathic symptoms in a disorder that has traditionally been considered a nociceptive condition.

Animal studies have largely concentrated on the brain stem as the site of endogenous pain modulation, but many studies in healthy volunteers have shown that the higher brain centers are important pain modulators, at least in humans, that mediate the effects of cognition, emotion, and other high-order processes on pain processing. The medial PFC appears to be an important site of supraspinal pain facilitation. Patients with rheumatoid arthritis were shown to activate the medial PFC exclusively in response to clinically relevant pain and not with disease-irrelevant pain (Schweinhardt et al 2008). The degree of activation in this region correlated with the severity of depressive symptoms in this largely not clinically depressed sample. Importantly, medial PFC hyperactivity was related to a measure of the patients’ clinical pain that partly accounted for systemic inflammation, thus indicating that the medial PFC was indeed involved in enhancing clinical pain. In keeping with a pain facilitatory role, activity in the medial PFC in patients with IBS has been shown to disrupt a functional connection between the lateral PFC and PAG (Mayer et al 2005), two areas that have been implicated in endogenous pain inhibition. (At this point, it has to be emphasized that current human brain imaging methods cannot differentiate between activation in brain stem facilitatory or inhibitory circuitries because of their close proximity. Therefore, the PAG is considered in some studies to be part of a facilitatory circuit and in others to contribute to pain inhibition, in line with the dual role that the PAG (and other brain stem structures) is known to have in pain modulation. Inferences regarding the nature of the signal can currently be based only on other variables, such as patients’ symptoms.)

A study in healthy volunteers provides another compelling demonstration of the antagonistic actions of different areas of the PFC: activation of the (dorso-) lateral PFC suppressed activity in an orbital frontal–rostral cingulate–medial thalamus network associated with the unpleasantness of capsaicin-related pain in healthy volunteers (Lorenz et al 2002, 2003).

Functional Reorganization of the Somatosensory Cortex

EEG and MEG studies in humans have advanced our understanding of cortical reorganization in phantom limb pain. Animal experiments had demonstrated that the receptive fields of neurons in S1 that respond to innocuous stimuli move to adjacent skin areas when nerve lesions or amputations interrupt their original input. This reorganization of receptive fields of deafferentiated neurons was initially thought to be a protective mechanism against the development of phantom sensations. When this prediction was tested in human amputees, however, the opposite relationship was observed: the amount of phantom limb pain was positively correlated with the amount of cortical reorganization, as determined by using innocuous somatosensory stimuli (Flor et al 1995, Montoya et al 1998, Grusser et al 2001, Karl et al 2001). This observation parallels findings that greater damage to the somatosensory pathways is associated with greater pain, such as with syringomyelia and post-herpetic neuralgia (Fields et al 1998, Hatem et al 2010, Petersen and Rowbotham 2010). Interestingly, however, the positive correlation between S1 reorganization and pain in amputees is maintained during pharmacological pain relief (Birbaumer et al 1997, Huse et al 2001), thus indicating that the extent of damage to the somatosensory afferents is not the only factor driving this relationship. Correspondingly, similar maladaptive plasticity in S1 and reversal with successful treatment have been described for non-specific chronic low back pain (Flor et al 1997) and complex regional pain syndrome (CRPS) type 1 (Maihofner et al 2003, 2004, Pleger et al 2006), conditions without detectable nerve lesions. Primate data support an effect of nociceptive afferent input on S1 processing of innocuous stimuli in the context of an intact somatosensory system and suggest modulation of the response of rapidly adapting neurons in area 3b/1 by γ-aminobutyric acid (GABA) released on activation of nociceptive neurons in area 3a as a potential mechanism (Whitsel et al 2010). In contrast, the opposite relationship—the pathophysiological contribution of S1 reorganization to pain—is still not well understood. Nevertheless, treatment approaches aimed at enhancing and correcting sensorimotor input have been shown to result in relief of pain in patients with CRPS (Pleger et al 2005, Moseley et al 2008) and amputees, in whom concomitant normalization of S1 maps relating to non-noxious input was observed (Lotze et al 1999, MacIver et al 2008).

Structural Brain Alterations in Patients with Chronic Pain

In recent years it has become clear that individuals who suffer from long-term pain have structural brain changes, first demonstrated by Apkarian and colleagues (2004) (Fig. 7-10). Most studies thus far have investigated gray matter, but more recently, alterations in white matter have also been demonstrated. Gray matter is typically observed to be decreased in important pain-processing or pain-modulating regions such as the ACC, IC, thalamus, and frontal cortex (Apkarian et al 2004, Schmidt-Wilcke et al 2005, Rocca et al 2006, Schmidt-Wilcke et al 2006, Kuchinad et al 2007, Schmidt-Wilcke et al 2008, Davis et al 2008, Geha et al 2008, Kim et al 2008, Schmitz et al 2008, Valfre et al 2008, Burgmer et al 2009, Obermann et al 2009, Rodriguez-Raecke et al 2009, Valet et al 2009, Vartiainen et al 2009, Seminowicz et al 2010), as well as in the (para-) hippocampus (Schmidt-Wilcke et al 2005, Kuchinad et al 2007, Lutz et al 2008, Valet et al 2009). Greater decreases in gray matter are observed in patients with longer pain duration (Apkarian et al 2004, Schmidt-Wilcke et al 2005, Rocca et al 2006, Kuchinad et al 2007, Geha et al 2008, Kim et al 2008, Schmitz et al 2008, Valfre et al 2008, Valet et al 2009) (see Fig. 7-10), thus suggesting that alterations in gray matter are a consequence of pain or (prolonged) nociceptive input. This concept is further supported by two additional lines of evidence. First, a longitudinal study in a rat model of neuropathic pain demonstrated prefrontal changes that occurred several months after nerve injury (Seminowicz et al 2009). Second, DaSilva and colleagues (2008) observed that the reduced thickness of the sensorimotor cortex in patients with trigeminal neuralgia was co-localized with activation related to provocation of the patients’ dynamic mechanical allodynia, thus indicating that excessive nociceptive input might lead to reductions in gray matter.

Several studies have now demonstrated that gray matter concentrations return to baseline levels when the pain resolves (Gwilym et al 2010, Obermann et al 2009, Rodriguez-Raecke et al 2009), a finding indicating that neuronal death is almost certainly not responsible for the observed reductions in gray matter. There is, however, evidence that changes in neuronal tissue, such as perhaps reduced dendritic or synaptic density, might contribute to the observed reductions in gray matter: several studies in patients with chronic pain have shown decreased levels of the neuronal marker N-acetylaspartate (NAA) with proton magnetic resonance spectroscopy (¹H-MRS). Grachev and colleagues (2000) were the first to report decreased NAA levels in patients with chronic pain and, in fact, related this finding to potential morphometric alterations. Unfortunately, studies combining measurements of NAA and gray matter in the same patients are still largely missing. A preliminary study of 20 healthy elderly individuals with varying levels of chronic pain found pain severity to be related to lower NAA levels in the hippocampus, as well as to reduced hippocampal volumes (Zimmerman et al 2009), thus suggesting that smaller hippocampi might be partly explained by a decrease in neuronal tissue. Several additional studies have reported decreased NAA levels in various brain regions without providing information on gray matter concentrations. Two studies of fibromyalgia observed decreased hippocampal NAA levels (Emad et al 2008, Wood et al 2009), and one of them reported an inverse relationship between NAA and the severity of fibromyalgia (as measured by the fibromyalgia impact questionnaire [FIQ]) (Wood et al 2009). Decreased NAA levels have also been observed in the thalamus (Fukui et al 2006, Sorensen et al 2008) and PFC (Grachev et al 2000, 2002a, 2002b), regions that are frequently affected by decreased gray matter, as predicted by Grachev and colleagues (Grachev et al 2000) and in which altered pain processing has been demonstrated in chronic pain patients.

The functional significance of changes in gray matter is largely unknown. A few animal studies indicate that alterations in cerebral gray matter might contribute to pain itself, as well as to the sequelae of living with pain. Rapid morphological and functional changes occurred in the medial PFC after spared-nerve injury, and interestingly, an index of sensitization (N-methyl-D-aspartate [NMDA]/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] ratio of the synaptic current elicited by afferent fiber stimulation) correlated with the tactile thresholds in the injured paw (Metz et al 2009). In the longitudinal rat study described earlier, the occurrence of prefrontal gray matter alterations coincided with the development of anxiety-like behavior several months after induction of the pain (Seminowicz et al 2009).

Relatively recently, researchers have begun to study white matter alterations in the brains of patients with chronic pain. Geha and colleagues (2008) found decreased diffusion directionality (fractional anisotropy [FA]) in the cingulum of patients with CRPS, which could possibly indicate decreased tract myelination or reduced parallel fiber organization. Fewer white matter connections were found to originate in patients from this spot of altered diffusion than in control subjects. Furthermore, the ventral medial PFC, an area of decreased gray matter, showed an altered anatomical connectivity pattern, thus adding further evidence to impaired white matter connectivity in the patients in this study (Geha et al 2008). Some clinical significance of decreased diffusion directionality is provided by a study of patients with fibromyalgia in which a relationship was demonstrated between decreased FA in the thalamocortical tract and the degree of stiffness experienced by patients (Lutz et al 2008). Schmitz and colleagues assessed the concentration of white matter in migraine patients rather than investigating the diffusion properties of white matter. They found that patients with a high attack frequency had decreased white matter concentrations in the frontal and parietal areas (Schmitz et al 2008), thus suggesting that migraine attacks lead to white matter damage.

Neurochemical Alterations in Patients with Chronic Pain

¹H-MRS can provide information on brain chemicals other than NAA, including choline-containing compounds, which indicate membrane turnover and cellular density, and glutamate/glutamine. Elevated glutamate levels, which relate to intracellular and extracellular neurotransmitter levels, have been observed in the IC during the interictal phase in migraine patients (Prescot et al 2009), as well as in patients with fibromyalgia (Harris et al 2008, 2009). Glutamate levels in the insula decreased after treatment of fibromyalgia patients, and a striking relationship was observed between decreased glutamate and improvement in clinical pain, as well as increased pressure pain thresholds (Harris et al 2008). Although more studies of this kind are needed and should preferably examine levels of GABA simultaneously, these observations provide compelling evidence that the presence of chronic pain has an underlying chemical basis in the brain.

Another methodology that can be used to study neurochemistry and, in particular, neurotransmitters, is PET. With the respective tracers, alterations in opioidergic and dopaminergic neurotransmitter systems have been observed in patients with chronic pain. Several studies have reported decreased binding of exogenously administered opioidergic tracers in key pain-processing areas in a variety of different pain conditions, including rheumatoid arthritis (Jones et al 1994), peripheral neuropathic pain (Jones et al 1999, Maarrawi et al 2007), and fibromyalgia (Harris et al 2007). Following pain reduction, normalization of binding levels was observed (Jones et al 1994). Decreased binding of the tracer can be due to either decreased receptor availability/affinity or increased endogenous opioid release. The latter explanation is supported by increased cerebrospinal fluid met-enkephalin immunoreactivity in chronic pain patients (Langemark et al 1995, Baraniuk et al 2004). Although increased release of endogenous opioids is likely to reflect engagement of endogenous antinociceptive systems, the situation is different for central neuropathic pain, in which a lateralized decrease of binding extending the anatomical damage has been observed (Maarrawi et al 2007). This finding suggests opioid receptor loss or inactivation, perhaps caused by metabolic depression and/or degeneration of opioid receptor–bearing neurons secondary to central lesions. Differences in central opioidergic systems in patients with central and peripheral neuropathic pain could explain their different sensitivities to opiate medications.

Several investigations of the dopaminergic system point to an attenuation of dopaminergic activity in some chronic pain states. This is interesting because the dopaminergic pathways seem to be important for endogenous pain modulation (see earlier in this chapter and reviews in animals [Altier and Stewart 1999] and humans [Hagelberg et al 2004]). Reductions in presynaptic dopaminergic function, as measured by the dopamine precursor [¹⁸F]fluorodopa, have been reported in idiopathic burning mouth syndrome (Jaaskelainen et al 2001), as well as in fibromyalgia (Wood et al 2007a). These data are consistent with findings of increases in D₂ (but not D₁) receptor binding in the basal ganglia in patients with burning mouth syndrome and atypical facial pain (Hagelberg et al 2003a, 2003b) because increased receptor availability could signify lower endogenous dopamine levels. One study in patients thus far has investigated release of dopamine in response to a pain challenge. Although healthy controls release dopamine in the striatum during tonic noxious muscle stimulation (Scott et al 2006, Wood et al 2007b), the dopamine response of fibromyalgia patients was not found to differ between painful and non-painful muscle stimulation (Wood et al 2007b).

Migraine

Functional and structural imaging studies have provided evidence that migraine headaches are related to episodic dysfunction of the brain stem nuclei involved in the trigeminovascular nociceptive system. Increases in rCBF occur in the dorsal midbrain and the dorsolateral pons during migraine attacks (Weiller et al 1995, Bahra et al 2001, Afridi et al 2005a, 2005b). The persistence of increased brain stem rCBF despite relief of symptoms with sumatriptan (Weiller et al 1995) has been interpreted as brain stem dysfunction being inherent to migraine rather than being caused by the attacks. The pathophysiological relevance of these observations is emphasized by reports that electrical stimulation of the dorsal midbrain can provoke migraine-like headache when stimulated in patients implanted with electrodes for pain control (Raskin et al 1987, Veloso et al 1998). Furthermore, lesions in the dorsal midbrain have been reported to produce migraine (Haas et al 1993, Goadsby 2002a). Finally, structural abnormalities in the brain stem have been reported in migraine, such as increased PAG density (Rocca et al 2006) and perturbation of iron homeostasis (Welch et al 2001).

Migraine with Aura

In at least 20% of patients, migraine attacks are preceded by transient neurological symptoms, the most prevalent one being visual auras. Similarities between migraine visual aura and cortical spreading depression (CSD) have led to the hypothesis that CSD is responsible for the aura symptoms (Olesen et al 1981, Lauritzen 1994). This view has been greatly advanced and substantiated by brain imaging studies. CSD is characterized by a slowly propagating wave (2–6 mm/min) of sustained strong neuronal depolarization that generates transient (on the order of seconds), intense spike activity as it progresses into the tissue, followed by neural suppression that can last for minutes. The depolarization phase is associated with an increase in rCBF, whereas the phase of reduced neural activity is associated with a reduction in rCBF (Lauritzen 1994). fMRI studies show cerebrovascular changes at a rate typical for CSD in the cortex of migraineurs while experiencing a visual aura (Welch et al 1998, Hadjikhani et al 2001). These changes in fMRI signal develop first in the extrastriate cortex, contralateral to the visual changes, and then slowly migrate toward more anterior regions of the visual cortex, in agreement with retinotopic progression of the visual percept from the center of vision toward the periphery. As would be predicted if the aura symptoms were caused by CSD, Hadjikhani and colleagues (2001) showed that scintillations, which correspond to increased visual activity, were paralleled by increases in fMRI signal and that subsequent decreases in fMRI signal corresponded perceptually to scotomas. Similar results have also been obtained with MEG (Bowyer et al 2001).

Although more work needs to be done, animal studies do provide a link between brain stem dysfunction and vascular changes, which predominantly affect the occipital cortex (Lance et al 1983, Goadsby and Duckworth 1989). These results support the conceptualization of migraine as a neurovascular disorder with primary brain stem dysfunction leading to secondary changes in blood flow in the posterior circulation, which could lead to CSD in susceptible patients (Denuelle et al 2008).

Cluster Headache

Traditionally, cluster headache was thought to be a vascular condition. However, its strong circadian and seasonal rhythmicity (Goadsby 2002b) cannot be readily explained by a vascular hypothesis and led to the concept of a CNS origin for cluster headache (Strittmatter et al 1996). More specifically, dysfunction of the hypothalamic area is postulated as the primary cause of acute cluster attacks given the role that this area plays in circadian rhythm and sleep–wake cycling. Brain imaging studies lend much support to this hypothesis. PET studies have shown significant activation during nitroglycerin-induced acute cluster headache in the ipsilateral posterior hypothalamus as compared with the headache-free state (May et al 1998, 2000). Such hypothalamic activation was not observed in patients outside the bout in whom nitroglycerin did not provoke an attack. In contrast to migraine, no brain stem activation was found during the acute attack. This is remarkable because migraine and cluster headache have often been discussed as related disorders. The importance of hypothalamic activation in cluster headache is further emphasized by a study in healthy volunteers in whom experimental pain was induced by injection of capsaicin into the forehead (May et al 1998). Sensory innervation of the forehead is provided by the ophthalmic division of the trigeminal nerve (i.e., the division in which pain in cluster headache predominantly occurs). In fact, the acute attack of pain and some of the autonomic symptoms characteristic of cluster headache (conjunctival injection, lacrimation) may be regarded as manifestations of the trigeminal autonomic reflex (Goadsby and Edvinsson 1994). No hypothalamic activation was observed following injection of capsaicin into the forehead, thus highlighting the idea that the hypothalamus is primarily affected in cluster headache. The notion of hypothalamic abnormalities is further corroborated by increased gray matter volume in this region (May et al 1999), as well as by decreased levels of the neuronal marker NAA and choline, a marker of membrane turnover and cellular density (Lodi et al 2006, Wang et al 2006).

Based on evidence of the pathophysiological relevance of the posterior hypothalamus, deep brain stimulation of the border zone between the posterior hypothalamus and the ventral tegmental area has been introduced for intractable cluster headaches and yields promising results (Leone et al 2008). In light of the involvement of the trigeminal system, it is interesting that a PET study of hypothalamic electrical stimulation in patients with cluster headaches found increased rCBF in an area compatible with the trigeminal ganglion/nucleus, in addition to activation of the stimulation site (May et al 2006). Animal studies have described anatomical connections between hypothalamic nuclei and the trigeminal nucleus (Malick and Burstein 1998, Malick et al 2000).

In summary, current data suggest that migraine and cluster headache, far from being primarily vascular disorders, are conditions whose genesis is to be found in the CNS. These are excellent examples of how brain imaging has advanced our understanding of chronic pain conditions.

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