the National Academy of Sciences colloquium ‘ ‘ The Neurobiology of Pain , ’ ’ held

Anatomical, physiological, and lesion data implicate multiple cortical regions in the complex experience of pain. These regions include primary and secondary somatosensory cortices, anterior cingulate cortex, insular cortex, and regions of the frontal cortex. Nevertheless, the role of different cortical areas in pain processing is controversial, particularly that of primary somatosensory cortex (S1). Human brain-imaging studies do not consistently reveal painrelated activation of S1, and older studies of cortical lesions and cortical stimulation in humans did not uncover a clear role of S1 in the pain experience. Whereas studies from a number of laboratories show that S1 is activated during the presentation of noxious stimuli as well as in association with some pathological pain states, others do not report such activation. Several factors may contribute to the different results among studies. First, we have evidence demonstrating that S1 activation is highly modulated by cognitive factors that alter pain perception, including attention and previous experience. Second, the precise somatotopic organization of S1 may lead to small focal activations, which are degraded by sulcal anatomical variability when averaging data across subjects. Third, the probable mixed excitatory and inhibitory effects of nociceptive input to S1 could be disparately represented in different experimental paradigms. Finally, statistical considerations are important in interpreting negative findings in S1. We conclude that, when these factors are taken into account, the bulk of the evidence now strongly supports a prominent and highly modulated role for S1 cortex in the sensory aspects of pain, including localization and discrimination of pain intensity. The role of primary somatosensory cortex (S1) in pain perception has long been in dispute. In the early 20th century, Head and Holmes (1) observed that patients with longstanding cortical lesions did not show deficits in pain perception. Similarly, Penfield and Boldrey (2), based on studies of electrical stimulation of patients’ exposed cerebral cortices during epilepsy surgery, concluded that pain probably has little or no cortical representation. In more recent studies of S1 cortex in monkeys, single-cell recordings in both anesthetized (3) and awake (4) monkeys revealed so few nociceptive neurons that their functional significance was uncertain. Other evidence suggests that S1 cortex may indeed play an important role in pain perception. Despite the lack of profound deficits in pain perception after widespread cortical lesions, patients do show at least transient deficits following cortical lesions (1, 5). Furthermore, Young and Blume (6) have reported that some patients with epileptic foci involving S1 cortex experience painful seizures. Anatomical evidence from primates demonstrates that regions of thalamus containing nociceptive neurons project to S1 cortex (7–9), thus providing the possible framework necessary to support the processing of nociceptive information within S1. Additionally, despite the small numbers of nociceptive neurons observed in monkey S1 cortex, their responses parallel pain perception in humans (10, 11). For example, by using optical imaging and neuronal recording techniques, Tommerdahl et al. (11) showed that nociceptive activity in area 3a of S1 cortex exhibited slow temporal summation and poststimulus response persistence after repeated cutaneous heat stimulation, which parallel perceptual consequences of the stimulation in humans. Finally, bilateral ablation of S1 cortex in monkeys disrupts their ability to discriminate intensities of noxious heat (D. R. Kenshalo, Jr., D. A. Thomas, and R. Dubner, unpublished observations). Findings from human brain imaging studies have produced inconsistent results pertaining to the role of S1 cortex in pain perception. The first three modern brain imaging studies of pain, published in the early 1990s, produced vastly different results in terms of S1 cortex. By using positron emission tomography (PET) and repeated 5-sec heat stimuli presented to six spots on the arm, Talbot et al. (12) found a significant activation focus in S1 cortex contralateral to the stimulated arm. By using similar heat stimuli, but repetitively presented to a single spot on the dorsal hand, Jones et al. (13) failed to observe significant activation in S1 cortex. Finally, by using single photon-emission computed tomography, Apkarian et al. (14) found that submerging the fingers in hot water for 3 minutes led to a decrease in S1 activity. Jones and colleagues (15, 16) postulated that the experimental procedures used by Talbot et al., particularly moving the stimulus among six spots during the scans, differentially direct more attention to the pain stimulus than to the control stimulus, and thus produce an attention-related modulation of S1 cortical activity. They further postulated that the presence or absence of pain, itself, is probably not a main determinant of S1 activation. More recent studies support the idea that attention can significantly modulate pain-evoked S1 activity, but little evidence supports the premise that pain is not a major determinant of S1 activity during painful stimulation. Table 1 shows the methods and results of a number of human brain imaging studies of pain, by using PET, single photonemission computed tomography, functional MRI, and magnetoencephalographic imaging. In the various studies, pain stimuli include phasic and tonic heat, cold, chemical irritants, electric shock, ischemia, visceral distension, headache, and neuropathic pain. As can be seen in Table 1, there is little consistency among the studies as to whether S1 is activated by pain. Some studies involving thermal, chemical, or electrical stimulation reveal S1 activation, whereas others using similar stimuli do not. Several factors that may contribute to these PNAS is available online at www.pnas.org. Abbreviations: S1, primary somatosensory cortex; PET, positron emission tomography; rCBF, regional cerebral blood flow. *To whom reprint requests should be addressed. e-mail: bushnell@ med.mcgill.ca.