This paper was presented at the National Academy of Sciences colloquium “The Neurology of Pain,” held December 11–13, 1998, at the Arnold and Mabel Beckman Center in Irvine, CA.

K ENNETH L. C ASEY

Neurology Service, Veterans Affairs Medical Center, University of Michigan, 2215 Fuller Road, Ann Arbor, MI 48105

ABSTRACT Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Forebrain Mediation of Pain. Pain is a conscious experience that includes discriminative, affective-motivational, and cognitive components that produce the unified sensation of pain. These components are each mediated through separate, interactive forebrain mechanisms ( 1 ). For example, the ability to localize somatic stimuli in time, space, and along a continuum of intensities is greatly impaired following lesions limited to the primary somatosensory (S1) cortex or the ventral posterolateral thalamus. These lesions do not produce analgesia, however, because the aversive nature of noxious stimuli, although poorly localized, is still evident in the behavior of animals and the verbal reports of humans ( 2 ). Neurons in the S1 cortex and ventral posterolateral thalamus, including those responding primarily to noxious stimuli, have small, contralateral receptive fields consistent with the mediation of spatial stimulus localization ( 3 ). In contrast, lesions within the anterior cingulate cortex have no effect on innocuous or nociceptive somesthetic discriminative functions, but impair the recognition of the noxious or aversive quality of the stimulus in animals and the perceived affective quality of pain in humans ( 4 , 5 ). Anterior cingulate neurons that respond to noxious stimuli have large, often bilateral receptive fields, consistent with a limited role in spatial discriminative capacity ( 6 ). There is no comparable information about the neuronal substrate for the cognitive dimension of pain, but there are numerous studies and observations showing the profound influences of attention, suggestion, and emotional state on the perception of pain ( 7 ). The broad range of environmental influences, such as attention, fear, and the placebo effect on the perception of pain suggests that cortical association areas and their subcortical connections are critical participants in mediating the cognitive aspects of pain.

The Forebrain Modulation of Pain. The processing of nociceptive stimuli is modulated by the forebrain at spinal, brainstem, and diencephalic levels. Stimulation of the cerebral cortex or thalamus can facilitate or suppress the responses of spinothalamic or trigeminothalamic tract neurons ( 8 , 9 ). In the awake monkey, the response of trigeminothalamic cells to noxious heat depends on behavioral state ( 10 , 11 ). Corticobulbar and corticothalamic neurons have marked effects on the excitability of brainstem and thalamic cells that receive nociceptive input ( 12 – 16 ).

Because of the large volume of the human forebrain in relation to that of the spinal cord (77% vs. 2% of central nervous system volume), these descending modulatory influences may assume greater importance in humans than in other species, such as the laboratory rat, where the forebrain is less anatomically dominant (31% vs. 35% of central nervous system volume) ( 17 ). The human spinothalamic tract, for example, contains an estimated 2,000 to 5,000 fibers whereas the corticospinal tract, which includes fibers terminating in the superficial layers of the dorsal horn ( 18 , 19 ), is estimated to contain from 5 × 10⁵ to 1 × 10⁶ fibers ( 20 , 21 ). Corticothalamic influences are also likely to be dominant in the human; in the cat, approximately 50% of the estimated 5,000 to 9,000 synapses on thalamocortical projection neurons are presumed to be of cortical origin, whereas only 15% are formed by ascending afferent fibers ( 22 ).

The Physiological Rationale of Positron Emission Tomography (PET). Synaptic activity generates increases in cerebral blood flow (CBF). This physiological fact is the basis for both PET and functional magnetic resonance imaging (fMRI). The most commonly used fMRI method relies on local shifts in the magnetic field that accompany the shift from deoxyhemoglobin to oxyhemoglobin within activated perfused tissue ( 23 ). PET and fMRI are complementary methods of assessing brain activity. This article will be limited to a discussion of PET.