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Saturday June 22nd, 2002 |
From the Departments of Anesthesia, Dentistry and Physiology, McGill University, Montreal, Quebec, Canada.
Address correspondence to: Dr. M. Catherine Bushnell, Anesthesia Research Unit, 3655 Promenade Sir William Osler, Room 1220, Montreal, Quebec H3G 1Y6, Canada. Phone: 514-398-3493; Fax: 514-398-8241; E-mail: catherine.bushnell{at}mcgill.ca
THE use of quantitative sensory testing and non-invasive functional brain imaging in humans has allowed pain researchers to study the neural basis of the complex sensory and emotional experience of pain. Pain is normally related to potential or real tissue damage, but it is highly influenced by our experiences, memories, and expectations. As characterized by Melzack,1 pain can be described in terms of sensations (burning, stinging, aching, cutting) or in terms of the emotions it evokes (agonizing, fearful, depressing). Much has been learned from animal research about how the nervous system processes nociceptive information. However, only by examining perception in conjunction with neural activity in awake humans can we begin to truly understand how the brain processes the complex pain experience.
Quantitative sensory testing and brain imaging to identify a common neural substrate of pain
Neuronal activity in the human brain can be imaged using a number of techniques, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI), electroencephalographic (EEG) dipole source analysis, magnetoencephalographic analysis (MEG), and single photon emission computed tomography (SPECT). Although each of these techniques has advantages and disadvantages in terms of spatial and temporal resolution, sensitivity, and cost, all provide measures that we can use as indirect indices of neuronal activity. Despite the technical differences among these methods, results derived from each are generally congruous, thus helping to validate each individual method.
The first imaging studies of pain were conducted in the 1970's by Lassen and colleagues2 using the radioisotope Xenon133. This technique provided little spatial resolution, but the results suggested that there was an increased blood flow to the frontal lobes during pain. The first articles on modern human pain imaging were published in the early 1990's,3,4 and they showed that multiple cortical and subcortical regions are activated during the presentation of simple noxious cutaneous heat stimuli to normal subjects. Since these first studies, a number of other studies confirm that multiple brain regions are activated by painful stimuli. The cortical regions most commonly activated by painful heat include primary somatosensory cortex (S1) and secondary somatosensory cortex (S2), both probably related to pain sensations, and anterior cingulate (ACC) and insular (IC) cortices, both components of the limbic system, thus implicating them in the affective component of pain.3–9 Subcortical activations are also observed, most notably in thalamus, basal ganglia, and cerebellum.3–6
An examination of the literature quickly reveals many differences, as well as similarities, in brain regions reported to be activated by pain. Some of these differences could be attributable to variations in technical procedures and statistical analyses, as well as sample size differences. An important point to remember is that, as with any statistical test, a negative result does not strictly imply the absence of neuronal activity in the specific region; it only means that no activation was detected using a stringent statistical requirement that biases results towards many more false negative than false positive findings.
Although technical factors may account for some differences among studies, often the differences could reflect true variations in underlying perceptual processes. Not all pain is the same; the experimental context and psychological state of the subjects may have an important influence on both the perception and the underlying neural activity. The pain experience will vary in different experiments, depending upon the environment, experimenter, instructions, stimulus and procedural design. A simple experiment conducted in our laboratory shows that when a subject must pay attention to a painful thermal stimulus, in order to perform a discrimination task, the cortical activity evoked by the pain is significantly higher than when the subject must pay attention to an auditory stimulus during the presentation of the pain.10 This type of evidence shows the importance of acquiring detailed perceptual data during human brain imaging studies. Although the physical parameters of the noxious stimulus may be the same in two conditions, the perception may greatly vary.
Combining the measurement of multiple perceptual features with human brain imaging allows researchers to examine the neural underpinnings of different aspects of the pain experience. Using correlation analyses, we have compared the neural substrate of the sensory and affective dimensions of the pain experience. The affective component of pain, i.e., how unpleasant is the pain experience, is highly influenced by the intensity of the pain sensation. However, since other factors, such as the meaning of the pain and the context in which the pain is experienced, also contribute to the unpleasantness of the pain, the two dimensions can be dissociated. In the clinical situation, this often occurs, for example, abdominal pain after eating at an outstanding French restaurant is usually attributed to indigestion and thus does not produce strong negative feelings. On the other hand, if the individual has intestinal cancer, a similar pain sensation might be perceived as extremely unpleasant. Nevertheless, in the experimental situation, unless the meaning or context is specifically manipulated, there is a strong correlation between pain intensity and pain unpleasantness.11 In an effort to dissociate the sensory and affective dimensions of pain, we have used hypnotic suggestions in experimental subjects to selectively alter the perceived intensity or unpleasantness of a heat pain stimulus presented to the subject's hand. Using an analysis of correlations between the subject's perceptions and changes in cerebral blood flow evoked by the pain, we found that pain-evoked activation in S1 was most highly related to the sensory dimension of pain, whereas that in ACC was best related to the affective dimension.7,12
Researchers have now examined cortical activation patterns related to many types of painful stimuli, including cutaneous noxious cold,6,13,14 electrical muscle stimulation,15 capsaicin-evoked pain and allodynia,16 colonic distension,17 esophageal distension,18 and ethanol cutaneous injection.19 As with studies of heat-evoked neural activation, there are substantial commonalities in regions activated by these different stimuli, with the most frequently activated areas including S1, S2, ACC and IC. These similarities suggest that when an individual recognizes something as "pain", there is a common cortical network that is activated. It could be the activation of this network that produces the cognition of pain.
Despite the activation of a common cortical network, there are substantial differences in cortical and subcortical sites showing significant activation in response to the various types of painful stimulation. Such differences could be attributed to the same technical and statistical differences discussed above, or to varying pain intensities, different cognitive states or variations specifically related to the modality of pain. A direct comparison of different modalities in the same subjects and the acquisition of detailed psychophysical evaluations of independent aspects of the individuals' cognitive state are necessary to identify the source of variability in results.
Among the cortical sites commonly activated by pain, S1 cortex perhaps shows the least reliable pain-related activation, even though electrophysiological data show that nociceptive neurons are present in this region.20 Only about half of studies imaging pain in humans show a significant activation in S1.10 This variation may be due to the factors described above, and may be enhanced by the topographic organization of S1, in which only a small amount of tissue is dedicated to a given body region.
Examination of central nervous system (CNS) abnormalities contributing to altered pain processing in humans.
Chronic intractable pain is commonly associated with a variety of injuries to the peripheral and/or CNS. Neuropathic pain of peripheral origin includes such syndromes as diabetic neuropathy, post-herpetic neuropathy, trigeminal neuralgia, phantom limb pain, and complex regional pain. Neuropathic pain of predominantly central origin is associated with a variety of pathological conditions, including multiple sclerosis, spinal cord injury, hemispherectomy, and stroke. Despite the wide variety of peripheral and CNS tissue damage that can lead to neuropathic pain, there are surprising similarities in symptoms across syndromes. Virtually all neuropathic pain syndromes are characterized by spontaneous ongoing pain, hyperalgesia (increased sensitivity to normally painful stimuli), and tactile and thermal allodynia (pain evoked by normally nonpainful stimuli, such as lightly brushing or cooling the skin).
The specific causes of these various types of neuropathic pain are not well understood, but accumulating evidence suggests multiple and varied underlying mechanisms. For peripheral neuropathies, there is evidence suggesting that some symptoms can be accounted for either by the sensitization of primary afferent fibres normally responsive to noxious stimuli (A
or C-fibres) or by the formation of neuromas, which could also cause activation of primary afferent nociceptive fibres.21 In neuropathic pain of peripheral origin, such as diabetic neuropathy, some patients have minimal sensory loss in the painful area but have severe allodynia, whereas others show the opposite: greater sensory loss but a variable degree of allodynia. Fields et al.21 propose that the main source of pain observed in neuropathic pain patients with preserved sensation comes from aberrant primary afferent nociceptor activity ("irritable nociceptor"), whereas the pain seen in patients with impaired thermosensory and nociceptor function comes from an alteration of CNS activity ("deafferentation type pain"). Changes in the CNS could involve structural reorganization, whereby previously nonexistent connections form between Aß fibres and nociceptive neurons in the spinal cord22 or could result from an interruption of thermal and/or tactile pathways that normally inhibit pain transmission.23
Central neuropathic pain is defined as pain due to CNS damage along the spino-thalamo-cortical pathway. Investigators have proposed varied explanations for the pathophysiology underlying this syndrome, including: 1) aberrant bursting of nociceptive neurons in the thalamus or elsewhere;24 2) up regulation or down regulation of receptors for neurotransmitters;25 and 3) disinhibition of pain by damage to endogenous pain modulatory pathways.23 Although clinical features of central pain are similar to those of peripheral neuropathic pain, there are a number of differences. First, emotional or physical stress exacerbates central pain in up to half of cases;26 this phenomenon is seldom reported for peripheral neuropathic pain. Similarly, cold-evoked allodynia and exacerbation of ongoing pain in a cool environment is a much more common feature of central than of peripheral neuropathic pain.26 The most common description of the spontaneous pain of central origin is burning or scalding, with the second most common description being aching or throbbing.26 Although both of these symptoms are sometimes seen in neuropathic pain of peripheral origin, they are more prevalent for central pain. Almost all patients with central pain have a deficit of pinprick and/or thermal sensation (both subserved primarily by A primary afferent fibres), whereas only some peripheral neuropathic pain patients have such a deficit.26 Since in central pain patients there is no peripheral nerve damage, the sensory deficit most likely arises from a disturbance of central processing of information arising from these inputs.
Human brain imaging can serve to examine changes in functions of neural regions associated with pathological pain states. One example of this in terms of pain processing is the observation that there is a reorganization of S1 cortex associated with phantom-limb pain. Studies using MEG and fMRI show that following an upper limb amputation, there is a reorganization of the face representation in S1 cortex, with the focus of activation evoked by facial stimulation shifted toward the cortex normally dedicated to the representation of the upper extremity.27,28 This reorganization is absent in amputees who do not experience phantom-limb pain. Further, in cases where the phantom-limb pain can be temporarily blocked by local or regional anesthesia, there is a rapid change in the cortical representation of the face area, reestablishing its expected location.28
Another pain-associated change in neural functioning that has been observed using human brain imaging is a thalamic hypo-perfusion in neuropathic pain patients.29 This is demonstrated by a mismatch of thalamic activity between the left and right thalami during a condition of rest in certain patients experiencing neuropathic pain of peripheral or central origin, with the thalamus contralateral to the painful area showing less activity than the thalamus ipsilateral to the pain. This observation is consistent with a disinhibition mechanism, in which the interruption of normal thalamic input leads to a reduction in endogenous nociceptive inhibition. A regulation of thalamic activity provides a theoretical explanation for the therapeutic effect of thalamic stimulation for the control of neuropathic pain.30 In our laboratory, we have used functional brain imaging to examine possible mechanisms subserving the therapeutic effects of thalamic stimulation.31 To examine possible neural pathways evoked by thalamic stimulation that could underlie the relief some patients experience, we measured regional changes in cerebral blood flow in five patients who had received successful long-term pain relief with thalamic stimulation. We found that, consistent with a disinhibition hypothesis, thalamic stimulation produces activation in regions of the cerebral cortex that receive tactile information (S1) and innocuous thermal information (IC). Since both touch and temperature are known to reduce pain transmission,32,33 these activations suggest that the reactivation of thalamo-cortical sensory pathways leads to pain relief in at least some neuropathic pain patients.
Conclusions
Results of quantitative sensory testing and functional brain imaging studies in humans experiencing pain indicate that there is a network of cortical and subcortical structures that subserve this experience, whether the pain originates from peripheral tissue damage or from CNS abnormalities. The sensory and emotional experience associated with pain varies widely among individuals, as well as within the same individual at different times and in different contexts, thus highlighting the importance of combining rigorous sensory testing and brain imaging. The experiential dissimilarities are reflected in varying patterns of neural activation observed in different experimental studies. However, despite the dissimilarities among studies, many commonalities emerge, including the activation of sensory regions such as S1 and S2 and limbic areas such as ACC and IC. The degree of activation of these regions is dependent on cognitive factors, such as attentional state, that alter our perception of pain. Thus, when a patient experiences pain, independent of its origin, at least some components of this cortical network are likely to be activated.
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