Until recently our understanding of pain generation, mechanisms, and transmission from the spinal cord to the brain has been based primarily on animal studies, which have yielded a wealth of knowledge about nociceptive processing, analgesia, and plasticity. Animal models often permit rapid advances in understanding many underlying disease mechanisms — understanding that can be translated to human models. However, with neuropathic pain (NP) translating what has been learned in animals to humans can require invasive procedures.
5.1 Brain network for pain in humans
With recently introduced noninvasive
neuroimaging technologies we can directly examine and compare the human central nervous system (CNS) in both healthy subjects and chronic pain patients and translate knowledge gleaned from animal research more confidently to humans. Many human neuroimaging studies have focused on defining brain regions that respond to various experimental noxious stimuli and on conceptualizing a “pain matrix” — a matrix of brain regions mapped to components of pain perception (sensory-discriminative, affective, reward, motivational, attentional and evaluative) (Melzack, 1999; Price, 2000
). Some brain regions and their surmised pain components include anterior cingulate cortex (affective, attentional), insula (affective, attentional), amygdala (affect, reward), nucleus accumbens and striatum (reward), prefrontal cortex (motivational-affective, cognitive), and primary and secondary somatosensory cortices (S1, S2; sensory-discriminative, cognitive) (Melzack, 1999; Price, 2000
; Mackey and Maeda, 2004
; Apkarian et al., 2005
). Additional regions include periaqueductal gray, premotor cortex, parietal cortex, and hypothalamus.
Recent research suggests that the “pain matrix” concept may be outdated. Newer studies reveal subtleties in the pain experience and its associated brain-activation patterns, suggesting that assigning specific pain components to specific brain regions is overly simplistic. For instance, the insular cortex (IC) is now thought to play a variety of roles. For example, the posterior IC is somatotopically organized (Brooks et al., 2005); stimulating it in awake humans causes well-localized pain (Ostrowsky et al., 2002). Additionally, activation of the posterior IC has been reported in numerous acute and chronic pain studies (see Apkarian et al., 2005
), using graded noxious heat or cold stimuli (Brooks et al., 2002) and allodynic stimulation in neuropathic pain patients (Schweinhardt et al., 2006). Homeostatic afferent input is thought to project to the mid-posterior insula, where it is re-represented in the ipsilateral anterior insula, a region that may mediate interoception (the subjective evaluation of the internal physiological state of the body) (Craig et al., 2002). These more recent data suggest that the IC and other brain structures participate in the multidimensional experience of pain. As investigators refine their neuroimaging tools and methods, it is expected that we will learn that brain structures formerly thought to have simple roles in pain, will turn out to be quite complex.
Neuroimaging has also helped elucidate many neural correlates of factors well-known to modulate the experience of pain — attention (Petrovic et al., 2000), anticipation (Koyama et al., 2005), placebo (Wager et al., 2004), empathy (Singer et al., 2004; Zaki et al., 2007), fear/anxiety (Ochsner et al., 2006
) and direct control (deCharms et al., 2005
) — as well as the neural correlates of individual differences in the experience of pain (Coghill et al., 2003; Ochsner et al., 2006
; Henderson et al., 2008). Based on these results we hypothesize that there is not simply a direct link between the degree of nociception and the overall experience of pain and furthermore, voluntary brain mechanisms can modulate that pain experience.
5.2 Functional changes in chronic pain
Changes in brain activity associated with neuropathic pain (NP) conditions are less thoroughly investigated than the brain's response to acutely evoked noxious stimuli (see Apkarian et al., 2005
). NP is caused by lesion or dysfunction of the peripheral or central nervous systems (see 4.1). NP is challenging to treat, often responding poorly to traditional analgesic medications (Dworkin et al., 2007), but it affects well over three million individuals in the US and can become continuous, lifelong, and disabling. Recent research in animal and human subjects has yielded several possible mechanisms of NP, although there is still a considerable amount to be learned. One critical challenge to understanding NP is determining to what degree the CNS, particularly the brain, contributes to NP's generation and maintenance. Neuroimaging has recently provided important clues to these challenges.
Earlier positron emission tomography (PET) neuroimaging work demonstrated that the “pain matrix” (see section 5.1) is involved in chronic NP (Hsieh et al., 1995; Willoch et al., 2000). PET and other functional magnetic resonance imaging (fMRI) studies show that NP leads to activity changes in the normal pain-processing network. The brain regions of NP patients react differently depending on whether the stimulation is evoked on the affected or unaffected side (Becerra et al., 2006). Stimulation to unaffected regions in NP patients seems to evoke a normal brain response (Peyron et al., 2004). The various NP conditions are associated with abnormal central processing of pain and the chronicity of these conditions may be related to central plasticity and changes over time (Iadarola et al., 1995; Ducreux et al., 2006). For example, investigators using neuroimaging tools to investigate spontaneous pain in NP patients have consistently found evidence of reduced thalamic activity on the side contralateral to the affected limb (Hsieh et al., 1995). Brain sites of abnormal activity may vary depending on the specific NP syndrome and the type of stimulus applied (e.g., heat, cold, and mechanical) (Becerra et al., 2006). In summary, NP may result in plasticity within structures associated with acute evoked pain, leading to abnormalities in the processing and perception of pain.
Neuroimaging studies of phantom-limb pain have helped us understand the mechanisms of NP. Such pain often follows traumatic injury to a limb; the pain has a clear, dramatic peripheral origin. Animal research showed that after limb amputation, central plasticity changes occur despite the fact that the original peripheral etiology has healed. Microelectrode recordings in the somatosensory cortex after an animal's appendage had been amputated revealed a rapid reorganization of somatosensory cortical maps (Merzenich et al., 1984; see also Zhuo, 2007). Subsequent studies using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) techniques showed that a similar reorganization occurred in humans (Ramachandran, 1993; Lotze et al., 2001). These cortical plastic changes differed in phantom-limb patients who experienced pain from those who did not (Lotze et al., 2001). Similar patterns of cortical reorganization were observed in patients with complex regional pain syndrome (CRPS) (Maihöfner et al., 2003). A recent neuroimaging study suggests that cortical reorganization (in S1 and S2) and pain perception in CRPS can be reversed with behavioral treatment consisting of graded sensorimotor retuning therapy (Pleger et al., 2005). Functional neuroimaging has helped translate the knowledge gained from basic science work into the better understanding of clinical NP conditions.
5.3 Biochemical and structural changes in chronic pain
Functional imaging has been the primary tool to investigate brain activity in NP patients and healthy volunteers. Recently, a number of novel brain imaging techniques have been developed and applied to pain research, including magnetic resonance spectroscopy (MRS) and voxel based morphometry (VBM).
Imaging of the human CNS's biochemical environment has helped reveal abnormalities in chronic pain (see also section 4.3). Investigators used MRS to characterize the biochemical differences in brain regions of healthy individuals and those with chronic pain. Specifically, investigators observed decreased N-acetylaspartate (NAA) in the dorsolateral prefrontal cortex of patients with chronic low back pain (Grachev et al., 2000) and CRPS type I (Grachev et al., 2002) as well as decreases in NAA in the thalami of NP patients (Fukui et al., 2006). Investigators have proposed NAA, a marker of neuronal activity found only in mature neurons (Miller, 1991), as a possible biomarker of neuronal health and function that can be assessed non-invasively using MRS (Grachev et al., 2000, 2002; Fukui et al., 2006). Investigators are using this information to generate and confirm hypotheses about the mechanisms of clinical NP. This field is expected to advance rapidly with the introduction of methods to imaging a variety of neurotransmitters such as glutamate, glycine and GABA (Ross and Bluml, 2001).
VBM is a structural imaging
technique that measures differences in local concentrations of brain tissue through a voxel-wise comparison of multiple brain images (Ashburner and Friston, 2000). It has been applied sparsely to pain research. One of the earliest studies found a 5-11% reduction of global cortical gray matter density in patients with low back pain compared with aged and gender matched controls (Apkarian et al., 2004b
). This gray matter reduction correlated with the duration of pain. A more recent study compared phantom limb patients to matched controls and noted a reduction in gray matter in the posterolateral thalamus contralateral to the side of the amputation (Draganski et al., 2006). This gray matter reduction was positively correlated with the duration of time since the amputation, but not the severity or frequency of pain. These VBM studies need to be expanded and replicated. Additionally, the question regarding the cellular basis for the morphometric variations remains unanswered and may require the direct comparison to histological data. Combining these methods may ultimately yield useful information about the mechanisms of the maladaptive plasticity underlying NP.
5.4 Cortical plasticity – cause or consequence of chronic pain?
Many questions remain regarding the role of brain dysregulation in chronic pain such as NP. The causal relationship of changes noted in NP patient studies has yet to be determined. Does the abnormal brain activity contribute to the NP or does the abnormal brain cause the NP? How can we characterize individual differences in NP patients? Do these differences correlate with specific brain changes? For example, recent studies have identified considerable individual variability in pain sensitivity, even within subclasses of neuropathic disorders such as postherpetic neuralgia (Pappagallo et al., 2000). Chronic NP may therefore reflect varying degrees of central dysregulation, ranging from purely abnormal peripheral nociceptive input to pain that is mediated solely through dysregulated central mechanisms. Central sensitization is likely to depend on a combination of the specific neuropathic condition and individual trait factors.
Although we do not yet know the central cause-effect relationships underlying NP, neuroimaging can help advance our understanding of both pharmacologic and non-pharmacologic treatments. Despite the variety of available analgesics, many chronic NP patients receive inadequate relief, and physicians treating them face daunting obstacles. To optimize compliance, minimize side-effects, and maximize analgesia, each anti-neuropathic medication needs to be started at a low dose and titrated to effect over many weeks, a “labor-intensive” process (Collins et al., 2000). Unfortunately, each anti-neuropathic medication produces pain relief for only a minority of NP patients (Katz et al., 2008). Not surprisingly, few physicians have the patience to persist in a strategy involving months of frustrating, side-effect-laden medication trials. Pharmacologic neuroimaging may be a novel method to optimize the matching of a particular drug to a particular NP patient. It may also provide important information related to both the drug's activity and the underlying mechanism of NP. For example, recently investigators studied the effect of topical lidocaine patch therapy (Lidoderm) in postherpetic neuralgia patients and noted reward-related brain regions (amygdala and ventral striatum) that changed only after long-term treatment. These brain regions also best reflected changes in pain with treatment (Geha et al., 2007).
Neuroimaging will play an important role in characterizing the central correlates of different types of neuropathic pain, helping to separate aberrant nociceptive processing in the periphery and spine from the influences of central amplification of pain. This discrimination will help clinicians rapidly diagnose individual cases of NP and more effectively treat the peripheral and central dysregulation elements of pain.