fMRI of Physiological Pain – a new understanding of brain regionsinvolved in pain processing in humans
Much of the work in fMRI of pain has utilized thermal stimuli (contact peltier thermodes or laser) to activate pain circuits. Other types of stimuli, including electrical and mechanical (pressure) have not been as extensively used either in the intact system or where sensitization has been experimentally induced (see Table 3). The accumulation of data has begun to identify brain regions involved in pain processing – from peripheral ganglia to central limbic and brainstem structures previously only implicated in animal studies in the preclinical literature (see Table 1).
Some of these regions are part of well-defined pain circuits (e.g., PAG, parabrachial nuclei) while for others such as the nucleus accumbens, their specific role in pain processing is not well understood [17,18]. Studies have reported specificity of somatotopic organization of structures outside of the primary somatosensory cortex involved in pain processing in humans; these such as the insula [19] and the trigeminal system [14,20]. Indeed, the results of human imaging help focus attention on specific regions, including the nucleus accumbens (involved in emotional salience), the insula (involved in specific interpretation of noxious stimuli) or the amygdala (involved in fear), opening new vistas for understanding how the human brain evaluates pain. The ability to evaluate activity and organize active regions into neural circuits that subserve specific pain/analgesia functions (i.e., sensory, emotional, autonomic, endogenous analgesic circuits) is a step forward. A number of studies have already begun this task including segregation of function within a structure (e.g., PAG [17] and NAc [18]), defining analgesia as a rewarding process [21], and functional differentiation of activation sites within a particular brain region (e.g., cognitive and affective regions within the anterior cingulate [17]).
What is needed now is to further evaluate these brain areas, some of whose role is newly defined in pain processing in humans, at a functional level. Several new fMRI approaches will aid this effort including techniques that allow definition of large scale systems organization [22]; techniques that define circuits/functional connectivity [23]; and automated parcellation of brain structures [24,25] including the thalamus [26]. Imaging studies have not only unveiled new regions involved in pain processing, but have also contributed new insights into the functioning of these regions in experimental pain. For example, the hippocampus, classically associated with memory, has been shown to be involved in pain-induced anxiety [27-29].
fMRI of Chronic Pain
Imaging clinical conditions is fraught with issues that make it more challenging, including the fact that it is difficult to assemble a cohort with similar symptoms, duration of disease, medication history, age distribution, etc. Among clinical conditions, chronic pain has a particularly wide spectrum of patient presentations and medical histories. However, studies have begun to evaluate CNS changes that occur in patients with chronic pain (see review by Apkarian and colleagues [30]), including those with neuropathic pain, fibromyalgia, complex regional pain syndrome and visceral pain (Table 2).
A number of important issues are emerging in the evaluation of chronic pain conditions as fMRI and associated imaging technologies become more sophisticated. Chronic pain produces changes that become manifest as alterations in the central nervous system. One may term this "centralization of hyperalgesia" or "centralization of pain". This has been evaluated across diseases including fibromyalgia [6], chronic back pain [31], and irritable bowel syndrome [32]. During functional imaging of fibromyalgia and chronic back pain, enhanced responses to thermal or mechanical stimuli that are applied heterotopically (i.e., away from the actual location of the pain) are present in a number of CNS regions, including non-sensory regions. Differences in specific responses to brush, heat and cold in affected vs. intact regions in patients with neuropathic pain have also been reported [33]. One feature that seems to be of in common with chronic pain patients is significantly greater frontal lobe activation in chronic pain sufferers [30]. This feature, suggests that in chronic pain CNS activity in regions involved in cognitive processing differs between acute and chronic pain. These insights are further complicated by the new and revolutionary recognition that, in chronic pain, neuronal loss occurs in significant pain pathways including the thalamus and the lateral prefrontal cortex [34]. The role of this neurodegeneration in producing either the altered CNS responses or the pain state is not understood.
Maladaptative changes in non-sensory circuits may contribute to the psychological states, including depression, anxiety and amotivation that are often seen in these patients. Thus the study of specific brain regions such as the nucleus accumbens (involved in probability assessments and reward evaluation), the amygdala (involved in orientating to and the memory of motivationally salient stimuli), the hippocampus (involved in evaluating the expectancy of an unknown condition), the prefrontal cortex (involved in cognitive and planning functions around emotional stimuli or regarding rewarding or aversive outcomes) and the anterior cingulated cortex (involved in the rank ordering of the value or salience of the stimulus) may provide new insights into brain functioning in these co-morbid conditions. Such insights should provide immediate benefits to the understanding of the calcitrant nature of chronic pain to therapeutic interventions.
Our increased recognition that multiple neural systems are involved in pain processing and affect pain perception (reward/aversion circuitry, the role of anticipation, neural systems interpreting different pain types albeit at the same intensity, opponent systems and drug effects) suggests that multiple neural circuitries are likely affected in chronic pain. Results published thus far indicate that: (1) Pain intensity is probably not a good marker for changes in chronic pain state. Neural imaging may be able to define a correlation between CNS activation and patient answers to a simple subjective questionnaire that assesses emotional and other components of pain and suffering; (2) Neural systems interpreting components of the pain response (e.g., emotional, empathy, anticipation etc.) are clearly complex, and we still have no understanding of how these may change in the chronic pain condition; and (3) Standards will need to be applied across imaging facilities in order to interpret and compare data across studies.
fMRI of Human Surrogate Pain Models
Defining valid surrogate models has been a problem in both animal and human models of pain [35-37]. In human studies, mechanical (heat) or chemical (capsaicin) sensitization of skin and testing in primary and secondary regions affected has been used as a surrogate for neuropathic pain (hyperalgesia/allodynia to thermal and mechanical stimuli) [38]. Recently fMRI has been used to evaluate the capsaicin – induced hyperalgesia model (see Table 3). While many of these studies report increased activation in a number of brain regions, some of the more recent studies begin to define the utility of fMRI in dissecting mechanistic changes or insights using this model [39-41]. These studies demonstrate differences in brain activation in response to stimuli of equivalent pain intensity delivered in sensitized vs. non-sensitized state, providing further evidence that pain intensity by itself is probably not a useful measure of the status of the underlying pain processing circuitry [41]. An alternate explanation may be that there are mechanistic differences between these two states. Changes in perceived pain intensity may reflect acute changes in CNS sensory pathways but may not correlate with changes in CNS emotional pathways which may be relevant to an individuals' overall response to pain and may predict future pain conditions. Eventually, fMRI should allow the direct comparison of activation in specific CNS regions in experimental models with the activation seen in patients with neuropathic pain. Comparing such objective measures should allow us to determine where the model differs from the disease and to assess the validity of such models for evaluating potential therapies.
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